Deletion of protein tyrosine phosphatase SHP-1 restores SUMOylation of podocin and reverses the progression of diabetic kidney disease.

Both clinical and experimental data suggest that podocyte injury is involved in the onset and progression of diabetic kidney disease (DKD). Although the mechanisms underlying the development of podocyte loss are not completely understood, critical structural proteins such as podocin play a major role in podocyte survival and function. We have reported that the protein tyrosine phosphatase SHP-1 expression increased in podocytes of diabetic mice and glomeruli of patients with diabetes. However, the in vivo contribution of SHP-1 in podocytes is unknown. Conditional podocyte-specific SHP-1-deficient mice (Podo-SHP-1-/-) were generated to evaluate the impact of SHP-1 deletion at four weeks of age (early) prior to the onset of diabetes and after 20 weeks (late) of diabetes (DM; Ins2+/C96Y) on kidney function (albuminuria and glomerular filtration rate) and kidney pathology. Ablation of the SHP-1 gene specifically in podocytes prevented and even reversed the elevated albumin/creatinine ratio, glomerular filtration rate progression, mesangial cell expansion, glomerular hypertrophy, glomerular basement membrane thickening and podocyte foot process effacement induced by diabetes. Moreover, podocyte-specific deletion of SHP-1 at an early and late stage prevented diabetes-induced expression of collagen IV, fibronectin, transforming growth factor-ß, transforming protein RhoA, and serine/threonine kinase ROCK1, whereas it restored nephrin, podocin and cation channel TRPC6 expression. Mass spectrometry analysis revealed that SHP-1 reduced SUMO2 post-translational modification of podocin while podocyte-specific deletion of SHP-1 preserved slit diaphragm protein complexes in the diabetic context. Thus, our data uncovered a new role of SHP-1 in the regulation of cytoskeleton dynamics and slit diaphragm protein expression/stability, and its inhibition preserved podocyte function preventing DKD progression.

Enhanced SHP-1 Expression in Podocyturia Is Associated with Kidney Dysfunction in Patients with Diabetes.

Background: Diabetic kidney disease (DKD) remains the leading cause of end stage kidney disease worldwide. Despite significant advances in kidney care, there is a need to improve noninvasive techniques to predict the progression of kidney disease better for patients with diabetes. After injury, podocytes are shed in urine and may be used as a biologic tool. We previously reported that SHP-1 is upregulated in the kidney of diabetic mice, leading to podocyte dysfunction and loss. Our objective was to evaluate the expression levels of SHP-1 in urinary podocytes and kidney tissues of patients with diabetes. Methods: In this prospective study, patients with and without diabetes were recruited for the quantification of SHP-1 in kidney tissues, urinary podocytes, and peripheral blood monocytes. Immunochemistry and mass spectrometry techniques were applied for kidney tissues. Urinary podocytes were counted, and expression of SHP-1 and podocyte markers were measured by quantitative PCR. Results: A total of 66 participants (diabetic n=48, nondiabetic n=18) were included in the analyses. Diabetes was associated with increased SHP-1 expression in kidney tissues (P=0.03). Nephrin and podocin mRNA was not significantly increased in urinary podocytes from patients with diabetes compared with those without diabetes, whereas levels of SHP-1 mRNA expression significantly correlated with HbA1c and estimated glomerular filtration rate (eGFR). Additionally, follow-up (up to 2 years post recruitment) evaluation indicated that SHP-1 mRNA expression continued to increase with eGFR decline. Conclusions: Levels of SHP-1 in urinary podocytes may serve as an additional marker of glomerular disease progression in this population.

Task demands moderate the effect of emotion on attentional capture.

The current experiment examined the effect of task demands on attention to emotional images. Eighty participants viewed pairs of images, with each pair consisting of an emotional (negative or positive) and a neutral image, or two neutral images. Participants' eye movements were recorded during picture viewing, and participants were either asked (1) which picture contains more colour? (colour task), (2) are the images equally pleasant? (pleasantness task), (3) which picture do you prefer? (preference task), or (4) were given no task instructions (control task). Although the results did not suggest that emotional images strongly captured attention, emotional images were looked at earlier than neutral images. Importantly, the pattern of results was dependent on the task instructions; while the preference and colour task conditions showed early attentional biases to emotional images, only positive images were looked at earlier in the pleasantness task condition, and no early attentional biases were observed in the control task. Moreover, total fixation duration was increased for positive images in the preference task condition, but not in the other task conditions. It was concluded that attention to emotional stimuli can be modified by the demands of the task during viewing. However, further research should consider additional factors, such as the cognitive load of the viewing tasks and the content of the images used.

Immunoglobulin A nephropathy in association with inflammatory bowel diseases: results from a national study and systematic literature review.

BACKGROUND: Little is known about clinical characteristics and kidney outcomes in patients with biopsy-proven immunoglobulin A nephropathy (IgAN) in a context of inflammatory bowel disease (IBD). METHODS: We conducted a retrospective multicentre study with a centralized histological review to analyse the presentation, therapeutic management and outcome of 24 patients suffering from IBD-associated IgAN relative to a cohort of 134 patients with primary IgAN without IBD. RESULTS: Crohn's disease and ulcerative colitis accounted for 75 and 25% of IBD-associated IgAN cases, respectively. IBD was diagnosed before IgAN in 23 cases (a mean of 9 years previously) and was considered active at IgAN onset in 23.6% of patients. Hypertension was present in 41.7% of patients. The urinary protein:creatinine ratio exceeded 100 mg/mmol in 70.8% of patients (mean 254 mg/mmol). Estimated glomerular filtration rate (eGFR) was >60 mL/min/1.73 m2 in 13/24 patients and only 1 patient required dialysis. In the Oxford mesangial hypercellularity, endocapillary cellularity, segmental sclerosis and interstitial fibrosis/tubular atrophy with crescents classification of renal biopsies, 57% were M1, 48% E1, 76% S1, 57% T1-2 and 38% C1-2. Steroids were administered in 50% of cases. After a mean follow-up of 7.2 years, 4 patients (16.7%) had a poor kidney outcome: end-stage renal disease (n = 3) or a >50% decrease in eGFR from initial values (n = 1). A similar evolution was observed in patients with primitive IgAN. CONCLUSIONS: This first case series suggests that IBD-associated IgAN has frequent inflammatory lesions at onset and variable long-term outcomes.

One-stop shop for variceal surveillance: integration of unsedated ultrathin endoscopy into the routine clinic visit.

BACKGROUND: The endoscopic appearance of oesophageal varices determines the need for prophylaxis. However, as the point prevalence of varices is low (25%), the majority of surveillance endoscopies are unnecessary and costly. Narrow diameter, ultrathin (UT) endoscopes are more tolerable than conventional upper gastrointestinal (UGI) endoscopes and can be used without sedation. We hypothesised that unsedated UT endoscopy for variceal surveillance could be implemented during the routine outpatient clinic visit allowing accurate diagnosis of varices and the timely provision of prophylaxis. METHODS: Patients with cirrhosis awaiting surveillance endoscopy were identified. UT endoscopy was scheduled during routine clinic review at the same time as ultrasound surveillance for hepatocellular carcinoma. UGI endoscopy was performed unsedated using the E.G Scan II disposable endoscope. Varices were graded using the modified Paquet classification. Video recordings of procedures were reviewed by blinded assessors and agreement was assessed using the kappa statistic. RESULTS: 40 patients (80% male) underwent unsedated UT endoscopy. All procedures were successful and tolerated well in 98% of cases. Median procedure time was 2 min (IQR 1-3). Varices were found in 37.5% (17.5% grade 1 and 20% grade 2). Patients with grade 2 varices were prescribed non-selective beta blockers at the clinic appointment. Kappa statistic for the finding of any varices was 0.636 (p=0.001) and 0.8-1.0 for diagnosis of grade 2 varices (p<0.0001). CONCLUSIONS: Outpatient unsedated ultrathin endoscopy in patients with cirrhosis is accurate, safe and feasible. This integrative care model is convenient, particularly for regional communities, and is likely to result in significant cost savings associated with variceal surveillance.

Housing, opportunities, motivation and engagement (HOME) for homeless youth at-risk for opioid use disorder: study protocol for a randomized controlled trial.

BACKGROUND: Homeless youth experience high rates of substance use disorders, exposures to violence, mental and physical health conditions, and mortality. They have been particularly affected by the opioid crisis. However, no study to date has used a randomized controlled design to test preventive interventions of opioid and other drug use among this vulnerable population. Resolution of youth homelessness through housing and supportive services including prevention services, often referred to as "Housing First," has great potential to reduce the likelihood for the development of an opioid use disorder as well as other problem behaviors associated with living on the streets. Housing First has been tested through randomized trials among homeless adults with mental health and substance use disorders, but has not been empirically tested for opioid prevention among homeless youth. METHODS: Homeless youth will be recruited from a drop-in shelter site frequented by disconnected youth; they will be screened for eligibility, including current homelessness, age 18-24 years, and not currently meeting criteria for opioid use disorder (OUD). In a controlled trial, 240 youth will then be randomized to one of two conditions, (1) housing + opioid and related risk prevention services, or (2) opioid and related risk prevention services alone. This project utilizes existing efficacious models of prevention to address opioid-related risks, including motivational interviewing, strengths-based outreach and advocacy, and an HIV risk preventive intervention. Follow-up will be conducted at 3, 6, 9 and 12-months post-baseline. The economic cost of each intervention will be determined to support implementation decisions with other providers and their funders. DISCUSSION: This study will provide essential information for researchers and providers on the efficacy of housing + opioid and related risk prevention services in an RCT for effects on opioid use and mechanisms underlying change. Because youth experiencing homelessness are at increased risk for a variety of adverse outcomes, the proposed intervention may produce substantial health care benefits to the youths and society at large. Trial registration ClinicalTrials.gov, NCT04135703, Registered October 13, 2019, https://clinicaltrials.gov/ct2/show/NCT04135703?term=NCT04135703&draw=2&rank=1#contacts.

Performance of simple serum-based tests to exclude cirrhosis prior to hepatitis C treatment in non-hospital settings in Australia.

BACKGROUND: Current guidelines suggest using transient elastography (TE) or aspartate aminotransferase to platelet ratio index (APRI) score <1 to exclude cirrhosis prior to commencing treatment for hepatitis C virus (HCV). Recently, fibrosis-4 (FIB-4) <0.93 has been shown to have a high negative predictive value (NPV) for the presence of cirrhosis. AIMS: To assess FIB-4 and APRI in a cohort of HCV patients and to validate FIB-4 <0.93 in populations of HCV-infected individuals with differing cirrhosis prevalence, including secondary care, primary care and prisons. METHODS: From our treatment database, we identified patients with complete data (n = 793). We calculated FIB-4 and APRI and correlated this with the presence of cirrhosis, determined by TE. We analysed the performance of FIB-4 and APRI using area under the receiver operating curve analysis. We calculated sensitivity, specificity, positive predictive value, NPV and number of patients misclassified using published cut-offs in populations with varying cirrhosis prevalence. RESULTS: FIB-4 was superior to APRI for the diagnosis of cirrhosis (area under the receiver operating curve 0.868 vs 0.802). In secondary care (cirrhosis prevalence 32%), APRI <1 had a NPV of 80% and misclassified 14% of patients. FIB-4 <0.93 had a NPV of 97% and misclassified 1%. In primary care and prison (cirrhosis prevalence 13% and 8%), the NPV for APRI <1 was 93% and 96%, respectively, but 5% of patients with cirrhosis were misclassified. FIB-4 <0.93 had excellent NPV in both primary care (97%) and prisoners (100%). CONCLUSIONS: FIB-4 <0.93 is highly efficient at ruling out cirrhosis in HCV patients and allows TE to be appropriately avoided, thereby streamlining treatment algorithms.

Cationic zinc is required for factor XII recruitment and activation by stimulated platelets and for thrombus formation in vivo.

BACKGROUND: Although divalent zinc (Zn2+ ) is known to bind factor (F)XII and affect its sensitivity to autoactivation, little is known about the role of Zn2+ in the binding of FXII to platelets, where FXII activation is thought to occur in vivo, and the function of Zn2+ during thrombus formation following vascular injury remains poorly understood. OBJECTIVES: To evaluate the role of Zn2+ in platelet-dependent FXIIa generation. METHODS: FXII binding to platelets and FXII activation by stimulated platelets were assessed using flow cytometry and a platelet-dependent thrombin generation assay. The mouse cremaster laser injury model was used to evaluate the impact of Zn2+ chelation on thrombus formation in vivo. RESULTS: Our data demonstrate that stimulated platelets support FXII-dependent thrombin generation and that FXII activation by platelets requires the presence of Zn2+ . By contrast, thrombin generation by stimulated endothelial cells occurred independently of FXII and Zn2+ . Using flow cytometry, we found that FXII-fluorescein-5-isothiocyanate binds to the surfaces of stimulated platelets in a specific and Zn2+ -dependent manner, whereas resting platelets demonstrated minimal binding. Other physiologically-relevant divalent cations are unable to support this interaction. Consistent with these findings, the Zn2+ -specific chelator ethylenediaminetetraacetic acid calcium disodium salt confers thromboprotection in the mouse cremaster laser injury model without causing increased bleeding. We observed an identical phenotype in FXII null mice tested in the same system. CONCLUSIONS: Our results suggest a novel role for Zn2+ in the binding and activation of FXII at the platelet surface, an interaction that appears crucial to FXII-dependent thrombin generation but dispensable for hemostasis.

Facilitating treatment of HCV in primary care in regional Australia: closing the access gap.

BACKGROUND: Australia has unrestricted access to direct-acting antivirals (DAA) for hepatitis C virus (HCV) treatment. In order to increase access to treatment, primary care providers are able to prescribe DAA after fibrosis assessment and specialist consultation. Transient elastography (TE) is recommended prior to commencement of HCV treatment; however, TE is rarely available outside secondary care centres in Australia and therefore a requirement for TE could represent a barrier to access to HCV treatment in primary care. OBJECTIVES: In order to bridge this access gap, we developed a community-based TE service across the Sunshine Coast and Wide Bay areas of Queensland. DESIGN: Retrospective analysis of a prospectively recorded HCV treatment database. INTERVENTIONS: A nurse-led service equipped with two mobile Fibroscan units assesses patients in eight locations across regional Queensland. Patients are referred into the service via primary care and undergo nurse-led TE at a location convenient to the patient. Patients are discussed at a weekly multidisciplinary team meeting and a treatment recommendation made to the referring GP. Treatment is initiated and monitored in primary care. Patients with cirrhosis are offered follow-up in secondary care. RESULTS: 327 patients have undergone assessment and commenced treatment in primary care. Median age 48 years (IQR 38-56), 66% male. 57% genotype 1, 40% genotype 3; 82% treatment naïve; 10% had cirrhosis (liver stiffness >12.5 kPa). The majority were treated with sofosbuvir-based regimens. 26% treated with 8-week regimens. All patients had treatment prescribed and monitored in primary care. Telephone follow-up to confirm sustained virological response (SVR) was performed by clinic nurses. 147 patients remain on treatment. 180 patients have completed treatment. SVR data were not available for 19 patients (lost to follow-up). Intention-to-treat SVR rate was 85.5%. In patients with complete data SVR rate was 95.6%. CONCLUSION: Community-based TE assessment facilitates access to HCV treatment in primary care with excellent SVR rates.

Archetype Analysis Identifies Distinct Profiles in Renal Transplant Recipients with Transplant Glomerulopathy Associated with Allograft Survival.

BACKGROUND: Transplant glomerulopathy, a common glomerular lesion observed after kidney transplant that is associated with poor prognosis, is not a specific entity but rather the end stage of overlapping disease pathways. Its heterogeneity has not been precisely characterized to date. METHODS: Our study included consecutive kidney transplant recipients from three centers in France and one in Canada who presented with a diagnosis of transplant glomerulopathy (Banff cg score ≥1 by light microscopy), on the basis of biopsies performed from January of 2004 through December of 2014. We used an unsupervised archetype analysis of comprehensive pathology findings and clinical, immunologic, and outcome data to identify distinct groups of patients. RESULTS: Among the 8207 post-transplant allograft biopsies performed during the inclusion period, we identified 552 biopsy samples (from 385 patients) with transplant glomerulopathy (incidence of 6.7%). The median time from transplant to transplant glomerulopathy diagnosis was 33.18 months. Kidney allograft survival rates at 3, 5, 7, and 10 years after diagnosis were 69.4%, 57.1%, 43.3%, and 25.5%, respectively. An unsupervised learning method integrating clinical, functional, immunologic, and histologic parameters revealed five transplant glomerulopathy archetypes characterized by distinct functional, immunologic, and histologic features and associated causes and distinct allograft survival profiles. These archetypes showed significant differences in allograft outcomes, with allograft survival rates 5 years after diagnosis ranging from 88% to 22%. Based on those results, we built an online application, which can be used in clinical practice on the basis of real patients. CONCLUSIONS: A probabilistic data-driven archetype analysis approach applied in a large, well defined multicenter cohort refines the diagnostic and prognostic features associated with cases of transplant glomerulopathy. Reducing heterogeneity among such cases can improve disease characterization, enable patient-specific risk stratification, and open new avenues for archetype-based treatment strategies and clinical trials optimization.

Multiplexed, high-throughput measurements of cell contraction and endothelial barrier function.

Vascular leakage, protein exudation, and edema formation are events commonly triggered by inflammation and facilitated by gaps that form between adjacent endothelial cells (ECs) of the vasculature. In such paracellular gap formation, the role of EC contraction is widely implicated, and even therapeutically targeted. However, related measurement approaches remain slow, tedious, and complex to perform. Here, we have developed a multiplexed, high-throughput screen to simultaneously quantify paracellular gaps, EC contractile forces, and to visualize F-actin stress fibers, and VE-cadherin. As proof-of-principle, we examined barrier-protective mechanisms of the Rho-associated kinase inhibitor, Y-27632, and the canonical agonist of the Tie2 receptor, Angiopoietin-1 (Angpt-1). Y-27632 reduced EC contraction and actin stress fiber formation, whereas Angpt-1 did not. Yet both agents reduced thrombin-, LPS-, and TNFα-induced paracellular gap formation. This unexpected result suggests that Angpt-1 can achieve barrier defense without reducing EC contraction, a mechanism that has not been previously described. This insight was enabled by the multiplex nature of the force-based platform. The high-throughput format we describe should accelerate both mechanistic studies and the screening of pharmacological modulators of endothelial barrier function.

PAR1 agonists stimulate APC-like endothelial cytoprotection and confer resistance to thromboinflammatory injury.

Stimulation of protease-activated receptor 1 (PAR1) on endothelium by activated protein C (APC) is protective in several animal models of disease, and APC has been used clinically in severe sepsis and wound healing. Clinical use of APC, however, is limited by its immunogenicity and its anticoagulant activity. We show that a class of small molecules termed "parmodulins" that act at the cytosolic face of PAR1 stimulates APC-like cytoprotective signaling in endothelium. Parmodulins block thrombin generation in response to inflammatory mediators and inhibit platelet accumulation on endothelium cultured under flow. Evaluation of the antithrombotic mechanism showed that parmodulins induce cytoprotective signaling through Gßγ, activating a PI3K/Akt pathway and eliciting a genetic program that includes suppression of NF-κB-mediated transcriptional activation and up-regulation of select cytoprotective transcripts. STC1 is among the up-regulated transcripts, and knockdown of stanniocalin-1 blocks the protective effects of both parmodulins and APC. Induction of this signaling pathway in vivo protects against thromboinflammatory injury in blood vessels. Small-molecule activation of endothelial cytoprotection through PAR1 represents an approach for treatment of thromboinflammatory disease and provides proof-of-principle for the strategy of targeting the cytoplasmic surface of GPCRs to achieve pathway selective signaling.

Tie2 protects the vasculature against thrombus formation in systemic inflammation.

Disordered coagulation contributes to death in sepsis and lacks effective treatments. Existing markers of disseminated intravascular coagulation (DIC) reflect its sequelae rather than its causes, delaying diagnosis and treatment. Here we show that disruption of the endothelial Tie2 axis is a sentinel event in septic DIC. Proteomics in septic DIC patients revealed a network involving inflammation and coagulation with the Tie2 antagonist, angiopoietin-2 (Angpt-2), occupying a central node. Angpt-2 was strongly associated with traditional DIC markers including platelet counts, yet more accurately predicted mortality in 2 large independent cohorts (combined N = 1,077). In endotoxemic mice, reduced Tie2 signaling preceded signs of overt DIC. During this early phase, intravital imaging of microvascular injury revealed excessive fibrin accumulation, a pattern remarkably mimicked by Tie2 deficiency even without inflammation. Conversely, Tie2 activation normalized prothrombotic responses by inhibiting endothelial tissue factor and phosphatidylserine exposure. Critically, Tie2 activation had no adverse effects on bleeding. These results mechanistically implicate Tie2 signaling as a central regulator of microvascular thrombus formation in septic DIC and indicate that circulating markers of the Tie2 axis could facilitate earlier diagnosis. Finally, interventions targeting Tie2 may normalize coagulation in inflammatory states while averting the bleeding risks of current DIC therapies.

Antibody-Mediated Rejection Due to Preexisting versus De Novo Donor-Specific Antibodies in Kidney Allograft Recipients.

Antibody-mediated rejection (ABMR) can occur in patients with preexisting anti-HLA donor-specific antibodies (DSA) or in patients who develop de novo DSA. However, how these processes compare in terms of allograft injury and outcome has not been addressed. From a cohort of 771 kidney biopsy specimens from two North American and five European centers, we performed a systematic assessment of clinical and biologic parameters, histopathology, circulating DSA, and allograft gene expression for all patients with ABMR (n=205). Overall, 103 (50%) patients had preexisting DSA and 102 (50%) had de novo DSA. Compared with patients with preexisting DSA ABMR, patients with de novo DSA ABMR displayed increased proteinuria, more transplant glomerulopathy lesions, and lower glomerulitis, but similar levels of peritubular capillaritis and C4d deposition. De novo DSA ABMR was characterized by increased expression of IFNγ-inducible, natural killer cell, and T cell transcripts, but less expression of AKI transcripts compared with preexisting DSA ABMR. The preexisting DSA ABMR had superior graft survival compared with the de novo DSA ABMR (63% versus 34% at 8 years after rejection, respectively; P<0.001). After adjusting for clinical, histologic, and immunologic characteristics and treatment, we identified de novo DSA ABMR (hazard ratio [HR], 1.82 compared with preexisting DSA ABMR; 95% confidence interval [95% CI], 1.07 to 3.08; P=0.03); low eGFR (<30 ml/min per 1.73 m2) at diagnosis (HR, 3.27; 95% CI, 1.48 to 7.23; P<0.001); ≥0.30 g/g urine protein-to-creatinine ratio (HR, 2.44; 95% CI, 1.47 to 4.09; P<0.001); and presence of cg lesions (HR, 2.25; 95% CI, 1.34 to 3.79; P=0.002) as the main independent determinants of allograft loss. Our findings support the transplant of kidneys into highly sensitized patients and should encourage efforts to monitor patients for de novo DSA.

KLF2 and KLF4 control endothelial identity and vascular integrity.

Maintenance of vascular integrity in the adult animal is needed for survival, and it is critically dependent on the endothelial lining, which controls barrier function, blood fluidity, and flow dynamics. However, nodal regulators that coordinate endothelial identity and function in the adult animal remain poorly characterized. Here, we show that endothelial KLF2 and KLF4 control a large segment of the endothelial transcriptome, thereby affecting virtually all key endothelial functions. Inducible endothelial-specific deletion of Klf2 and/or Klf4 reveals that a single allele of either gene is sufficient for survival, but absence of both (EC-DKO) results in acute death from myocardial infarction, heart failure, and stroke. EC-DKO animals exhibit profound compromise in vascular integrity and profound dysregulation of the coagulation system. Collectively, these studies establish an absolute requirement for KLF2/4 for maintenance of endothelial and vascular integrity in the adult animal.

The clinicopathologic characteristics of kidney diseases related to monotypic IgA deposits.

Monoclonal gammopathy of renal significance (MGRS) regroups renal disorders caused by a monoclonal immunoglobulin without overt hematological malignancy. MGRS includes tubular disorders, glomerular disorders with organized deposits, and glomerular disorders with non-organized deposits, such as proliferative glomerulonephritis with monoclonal IgG deposits. Since glomerular involvement related to monotypic IgA deposits is poorly described we performed retrospective analysis and defined clinico-biological characteristics, renal pathology, and outcome in 19 referred patients. This analysis allowed distinction between 2 types of glomerulopathies, α-heavy chain deposition disease (5 patients) and glomerulonephritis with monotypic IgA deposits (14 patients) suggestive of IgA-proliferative glomerulonephritis with monoclonal immunoglobulin deposits in 12 cases. Clinicopathologic characteristics of α-heavy chain deposition disease resemble those of the γ-heavy chain disease, except for a higher frequency of extra-capillary proliferation and extra-renal involvement. IgA-proliferative glomerulonephritis with monoclonal immunoglobulin deposits should be differentiated from diseases with polytypic IgA deposits, given distinct clinical, histological, and pathophysiological features. Similarly to IgG-proliferative glomerulonephritis with monoclonal immunoglobulin deposits, overt hematological malignancy was infrequent, but sensitive serum and bone marrow studies revealed a subtle plasma cell proliferation in most patients with IgA-proliferative glomerulonephritis with monoclonal immunoglobulin deposits. Anti-myeloma agents appeared to favorably influence renal prognosis. Thus, potential progression towards symptomatic IgA multiple myeloma suggests that careful hematological follow-up is mandatory. This series expands the spectrum of renal disease in MGRS.

Host Biomarkers Are Associated With Response to Therapy and Long-Term Mortality in Pediatric Severe Malaria.

Background. Host responses to infection are critical determinants of disease severity and clinical outcome. The development of tools to risk stratify children with malaria is needed to identify children most likely to benefit from targeted interventions. Methods. This study investigated the kinetics of candidate biomarkers of mortality associated with endothelial activation and dysfunction (angiopoietin-2 [Ang-2], soluble FMS-like tyrosine kinase-1 [sFlt-1], and soluble intercellular adhesion molecule-1 [sICAM-1]) and inflammation (10 kDa interferon γ-induced protein [CXCL10/IP-10] and soluble triggering receptor expressed on myeloid cells-1 [sTREM-1]) in the context of a randomized, double-blind, placebo-controlled, parallel-arm trial evaluating inhaled nitric oxide versus placebo as adjunctive therapy to parenteral artesunate for severe malaria. One hundred eighty children aged 1-10 years were enrolled at Jinja Regional Referral Hospital in Uganda and followed for up to 6 months. Results. There were no differences between the 2 study arms in the rate of biomarker recovery. Median levels of Ang-2, CXCL10, and sFlt-1 were higher at admission in children who died in-hospital (n = 15 of 180; P < .001, P = .027, and P = .004, respectively). Elevated levels of Ang-2, sTREM-1, CXCL10, and sICAM-1 were associated with prolonged clinical recovery times in survivors. The Ang-2 levels were also associated with postdischarge mortality (P < .0001). No biomarkers were associated with neurodisability. Conclusions. Persistent endothelial activation and dysfunction predict survival in children admitted with severe malaria.

Dysregulation of angiopoietin-1 plays a mechanistic role in the pathogenesis of cerebral malaria.

Cerebral malaria is a leading cause of global morbidity and mortality. Interventions targeting the underlying pathophysiology of cerebral malaria may improve outcomes compared to treatment with antimalarials alone. Microvascular leak plays an important role in the pathogenesis of cerebral malaria. The angiopoietin (Ang)-Tie-2 system is a critical regulator of vascular function. We show that Ang-1 expression and soluble Tie-2 expression were associated with disease severity and outcome in a prospective study of Ugandan children with severe malaria and in a preclinical murine model of experimental cerebral malaria. Ang-1 was necessary for maintenance of vascular integrity and survival in a mouse model of cerebral malaria. Therapeutic administration of Ang-1 preserved blood-brain barrier integrity and, in combination with artesunate treatment, improved survival beyond that with artesunate alone. These data define a role for dysregulation of the Ang-Tie-2 axis in the pathogenesis of cerebral malaria and support the evaluation of Ang-Tie-2-based interventions as potential adjunctive therapies for treating severe malaria.

Gene control of tyrosine kinase TIE2 and vascular manifestations of infections.

Ligands of the endothelial-enriched tunica interna endothelial cell kinase 2 (Tie2) are markedly imbalanced in severe infections associated with vascular leakage, yet regulation of the receptor itself has been understudied in this context. Here, we show that TIE2 gene expression may constitute a novel vascular barrier control mechanism in diverse infections. Tie2 expression declined rapidly in wide-ranging models of leak-associated infections, including anthrax, influenza, malaria, and sepsis. Forced Tie2 suppression sufficed to attenuate barrier function and sensitize endothelium to permeability mediators. Rapid reduction of pulmonary Tie2 in otherwise healthy animals attenuated downstream kinase signaling to the barrier effector vascular endothelial (VE)-cadherin and induced vascular leakage. Compared with wild-type littermates, mice possessing one allele of Tie2 suffered more severe vascular leakage and higher mortality in two different sepsis models. Common genetic variants that influence TIE2 expression were then sought in the HapMap3 cohort. Remarkably, each of the three strongest predicted cis-acting SNPs in HapMap3 was also associated with the risk of acute respiratory distress syndrome (ARDS) in an intensive care unit cohort of 1,614 subjects. The haplotype associated with the highest TIE2 expression conferred a 28% reduction in the risk of ARDS independent of other major clinical variables, including disease severity. In contrast, the most common haplotype was associated with both the lowest TIE2 expression and 31% higher ARDS risk. Together, the results implicate common genetic variation at the TIE2 locus as a determinant of vascular leak-related clinical outcomes from common infections, suggesting new tools to identify individuals at unusual risk for deleterious complications of infection.