Tragic faces of the deadly US flu outbreak
As the nation continues to fight the flu, some families are sharing their stories in hopes of preventing others from facing similar tragedies.
Wednesday, January 31, 2018
FOX NEWS: Tragic faces of the deadly US flu outbreak
Tragic faces of the deadly US flu outbreak
As the nation continues to fight the flu, some families are sharing their stories in hopes of preventing others from facing similar tragedies.
This Months Highlights
from Journal of the American Society of Nephrology current issue http://ift.tt/2DQOCze
Insights into the Regulation of Collecting Duct Homeostasis by Small Noncoding RNAs
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Any Progress in the Treatment of Antibody-Mediated Rejection?
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Making the Right Decision: Do Clinical Decision Support Systems for AKI Improve Patient Outcomes?
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Banff Classification of Polyomavirus Nephropathy: A New Tool for Research and Clinical Practice
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Editorial Note: From Both Sides Now
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Should We Increase GFR with Bardoxolone in Alport Syndrome?
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Bardoxolone--the Phoenix?
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Clinical Translation of Mesenchymal Stromal Cell Therapies in Nephrology
Mesenchymal stromal cells have emerged as potential candidates for cell-based therapies to modulate the immune response in organ transplantation and repair tissues after acute or chronic injury. Preclinical studies have shown convincingly in rodent models that mesenchymal stromal cells can prolong solid organ graft survival and that they can induce immune tolerance, accelerate recovery from AKI, and promote functional improvement in chronic nephropathies. Multiple complex properties of the cells, including immunomodulatory, anti-inflammatory, and proregenerative effects, seem to contribute. The promising preclinical studies have encouraged investigators to explore the safety, tolerability, and efficacy of mesenchymal stromal cell–based therapy in pilot clinical trials, including those for bone marrow and solid organ transplantation, autoimmune diseases, and tissue and organ repair. Here, we review the available data on culture-expanded mesenchymal stromal cells tested in renal transplantation, AKI, and CKD. We also briefly discuss the relevant issues that must be addressed to ensure rigorous assessment of the safety and efficacy of mesenchymal stromal cell therapies to allow the translation of this research into the practice of clinical nephrology.
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Metabolic Acidosis and Subclinical Metabolic Acidosis in CKD
Metabolic acidosis is not uncommon in CKD and is linked with bone demineralization, muscle catabolism, and higher risks of CKD progression and mortality. Clinical practice guidelines recommend maintaining serum total CO2 at ≥22 mEq/L to help prevent these complications. Although a definitive trial testing whether correcting metabolic acidosis improves clinical outcomes has not been conducted, results from small, single-center studies support this notion. Furthermore, biologic plausibility supports the notion that a subset of patients with CKD have acid-mediated organ injury despite having a normal serum total CO2 and might benefit from oral alkali before overt acidosis develops. Identifying these individuals with subclinical metabolic acidosis is challenging, but recent results suggest that urinary acid excretion measurements may be helpful. The dose of alkali to provide in this setting is unknown as well. The review discusses these topics and the prevalence and risk factors of metabolic acidosis, mechanisms of acid-mediated organ injury, results from interventional studies, and potential harms of alkali therapy in CKD.
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BP Measurement in Clinical Practice: Time to SPRINT to Guideline-Recommended Protocols
Hypertension is the leading chronic disease risk factor in the world and is especially important in patients with CKD, nearly 90% of whom have hypertension. Recently, in the Systolic BP Intervention Trial (SPRINT), intensive lowering of clinic systolic BP to a target <120 mm Hg, compared with a standard BP target of <140 mm Hg, reduced risk for cardiovascular disease and all-cause mortality. However, because BP was measured unobserved using an automated device, some investigators have questioned the ability to translate SPRINT results into routine clinical practice, in which measurement of BP is typically less standardized. In this review, we discuss the BP measurement techniques used in major observational studies and clinical trials that form the evidence base for our current approach to treating hypertension, evaluate the effect of measurement technique on BP readings, and explore how ambulatory BP data from the SPRINT trial may inform this discussion. We conclude by arguing for implementation of guideline-recommended BP measurement techniques in routine clinical practice.
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Tissue-Resident Lymphocytes in the Kidney
It has become evident that nonlymphoid tissues are populated by distinct subsets of innate and adaptive lymphocytes that are characterized by minimal exchange with recirculating counterparts. Especially at barrier sites, such as the skin, gut, and lung, these tissue-resident lymphocyte populations are ideally positioned to quickly respond to pathogens and other environmental stimuli. The kidney harbors several classes of innate and innate-like lymphocytes that have been described to contribute to this tissue-resident population in other organs, including innate lymphoid cells, natural killer cells, natural killer T cells, mucosal-associated invariant T cells, and T cells. Additionally, a substantial proportion of the adaptive lymphocytes that are found in the kidney displays a surface phenotype suggestive of tissue residency, such as CD69+CD4+ T cells. In this review, we summarize recent advances in the understanding of tissue-resident lymphocyte populations, review the available evidence for the existence of these populations in the kidney, and discuss the potential physiologic and pathophysiologic roles thereof in kidney.
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Phospholipase A2 Receptor 1 Epitope Spreading at Baseline Predicts Reduced Likelihood of Remission of Membranous Nephropathy
The phospholipase A2 receptor (PLA2R1) is the major autoantigen in primary membranous nephropathy. Several PLA2R1 epitopes have been characterized, and a retrospective study identified PLA2R1 epitope spreading as a potential indicator of poor prognosis. Here, we analyzed the predictive value of anti-PLA2R1 antibody (PLA2R1-Ab) titers and epitope spreading in a prospective cohort of 58 patients positive for PLA2R1-Ab randomly allocated to rituximab (n=29) or antiproteinuric therapy alone (n=29). At baseline, the epitope profile (CysR, CysRC1, CysRC7, or CysRC1C7) did not correlate with age, sex, time from diagnosis, proteinuria, or serum albumin, but epitope spreading strongly correlated with PLA2R1-Ab titer (P<0.001). Ten (58.8%) of the 17 patients who had epitope spreading at baseline and were treated with rituximab showed reversal of epitope spreading at month 6. In adjusted analysis, epitope spreading at baseline was associated with a decreased remission rate at month 6 (odds ratio, 0.16; 95% confidence interval, 0.04 to 0.72; P=0.02) and last follow-up (median, 23 months; odds ratio, 0.14; 95% confidence interval, 0.03 to 0.64; P=0.01), independently from age, sex, baseline PLA2R1-Ab level, and treatment group. We propose that epitope spreading at baseline be considered in the decision for early therapeutic intervention in patients with primary membranous nephropathy.
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TRPC5 Does Not Cause or Aggravate Glomerular Disease
Transient receptor potential channel 5 (TRPC5) is highly expressed in brain and kidney and mediates calcium influx and promotes cell migration. In the kidney, loss of TRPC5 function has been reported to benefit kidney filter dynamics by balancing podocyte cytoskeletal remodeling. However, in vivo gain-in-function studies of TRPC5 with respect to kidney function have not been reported. To address this gap, we developed two transgenic mouse models on the C57BL/6 background by overexpressing either wild-type TRPC5 or a TRPC5 ion-pore mutant. Compared with nontransgenic controls, neither transgenic model exhibited an increase in proteinuria at 8 months of age or a difference in LPS-induced albuminuria. Moreover, activation of TRPC5 by Englerin A did not stimulate proteinuria, and inhibition of TRPC5 by ML204 did not significantly lower the level of LPS-induced proteinuria in any group. Collectively, these data suggest that the overexpression or activation of the TRPC5 ion channel does not cause kidney barrier injury or aggravate such injury under pathologic conditions.
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Serum Response Factor Is Essential for Maintenance of Podocyte Structure and Function
Podocytes contain an intricate actin cytoskeleton that is essential for the specialized function of this cell type in renal filtration. Serum response factor (SRF) is a master transcription factor for the actin cytoskeleton, but the in vivo expression and function of SRF in podocytes are unknown. We found that SRF protein colocalizes with podocyte markers in human and mouse kidneys. Compared with littermate controls, mice in which the Srf gene was conditionally inactivated with NPHS2-Cre exhibited early postnatal proteinuria, hypoalbuminemia, and azotemia. Histologic changes in the mutant mice included glomerular capillary dilation and mild glomerulosclerosis, with reduced expression of multiple canonical podocyte markers. We also noted tubular dilation, cell proliferation, and protein casts as well as reactive changes in mesangial cells and interstitial inflammation. Ultrastructure analysis disclosed foot process effacement with loss of slit diaphragms. To ascertain the importance of SRF cofactors in podocyte function, we disabled the myocardin-related transcription factor A and B genes. Although loss of either SRF cofactor alone had no observable effect in the kidney, deficiency of both recapitulated the Srf-null phenotype. These results establish a vital role for SRF and two SRF cofactors in the maintenance of podocyte structure and function.
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Intragraft Molecular Pathways Associated with Tolerance Induction in Renal Transplantation
The modern immunosuppression regimen has greatly improved short-term allograft outcomes but not long-term allograft survival. Complications associated with immunosuppression, specifically nephrotoxicity and infection risk, significantly affect graft and patient survival. Inducing and understanding pathways underlying clinical tolerance after transplantation are, therefore, necessary. We previously showed full donor chimerism and immunosuppression withdrawal in highly mismatched allograft recipients using a bioengineered stem cell product (FCRx). Here, we evaluated the gene expression and microRNA expression profiles in renal biopsy samples from tolerance-induced FCRx recipients, paired donor organs before implant, and subjects under standard immunosuppression (SIS) without rejection and with acute rejection. Unlike allograft samples showing acute rejection, samples from FCRx recipients did not show upregulation of T cell– and B cell–mediated rejection pathways. Gene expression pathways differed slightly between FCRx samples and the paired preimplantation donor organ samples, but most of the functional gene networks overlapped. Notably, compared with SIS samples, FCRx samples showed upregulation of genes involved in pathways, like B cell receptor signaling. Additionally, prediction analysis showed inhibition of proinflammatory regulators and activation of anti-inflammatory pathways in FCRx samples. Furthermore, integrative analyses (microRNA and gene expression profiling from the same biopsy sample) identified the induction of regulators with demonstrated roles in the downregulation of inflammatory pathways and maintenance of tissue homeostasis in tolerance-induced FCRx samples compared with SIS samples. This pilot study highlights the utility of molecular intragraft evaluation of pathways related to FCRx-induced tolerance and the use of integrative analyses for identifying upstream regulators of the affected downstream molecular pathways.
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Modulation of Renal GLUT2 by the Cannabinoid-1 Receptor: Implications for the Treatment of Diabetic Nephropathy
Altered glucose reabsorption via the facilitative glucose transporter 2 (GLUT2) during diabetes may lead to renal proximal tubule cell (RPTC) injury, inflammation, and interstitial fibrosis. These pathologies are also triggered by activating the cannabinoid-1 receptor (CB1R), which contributes to the development of diabetic nephropathy (DN). However, the link between CB1R and GLUT2 remains to be determined. Here, we show that chronic peripheral CB1R blockade or genetically inactivating CB1Rs in the RPTCs ameliorated diabetes-induced renal structural and functional changes, kidney inflammation, and tubulointerstitial fibrosis in mice. Inhibition of CB1R also downregulated GLUT2 expression, affected the dynamic translocation of GLUT2 to the brush border membrane of RPTCs, and reduced glucose reabsorption. Thus, targeting peripheral CB1R or inhibiting GLUT2 dynamics in RPTCs has the potential to treat and ameliorate DN. These findings may support the rationale for the clinical testing of peripherally restricted CB1R antagonists or the development of novel renal-specific GLUT2 inhibitors against DN.
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MicroRNA-709 Mediates Acute Tubular Injury through Effects on Mitochondrial Function
Mitochondrial dysfunction has important roles in the pathogenesis of AKI, yet therapeutic approaches to improve mitochondrial function remain limited. In this study, we investigated the pathogenic role of microRNA-709 (miR-709) in mediating mitochondrial impairment and tubular cell death in AKI. In a cisplatin-induced AKI mouse model and in biopsy samples of human AKI kidney tissue, miR-709 was significantly upregulated in the proximal tubular cells (PTCs). The expression of miR-709 in the renal PTCs of patients with AKI correlated with the severity of kidney injury. In cultured mouse PTCs, overexpression of miR-709 markedly induced mitochondrial dysfunction and cell apoptosis, and inhibition of miR-709 ameliorated cisplatin-induced mitochondrial dysfunction and cell injury. Further analyses showed that mitochondrial transcriptional factor A (TFAM) is a target gene of miR-709, and genetic restoration of TFAM attenuated mitochondrial dysfunction and cell injury induced by cisplatin or miR-709 overexpression in vitro. Moreover, antagonizing miR-709 with an miR-709 antagomir dramatically attenuated cisplatin-induced kidney injury and mitochondrial dysfunction in mice. Collectively, our results suggest that miR-709 has an important role in mediating cisplatin-induced AKI via negative regulation of TFAM and subsequent mitochondrial dysfunction. These findings reveal a pathogenic role of miR-709 in acute tubular injury and suggest a novel target for the treatment of AKI.
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Chromatin Conformation Links Distal Target Genes to CKD Loci
Genome-wide association studies (GWASs) have identified many genetic risk factors for CKD. However, linking common variants to genes that are causal for CKD etiology remains challenging. By adapting self-transcribing active regulatory region sequencing, we evaluated the effect of genetic variation on DNA regulatory elements (DREs). Variants in linkage with the CKD-associated single-nucleotide polymorphism rs11959928 were shown to affect DRE function, illustrating that genes regulated by DREs colocalizing with CKD-associated variation can be dysregulated and therefore, considered as CKD candidate genes. To identify target genes of these DREs, we used circular chromosome conformation capture (4C) sequencing on glomerular endothelial cells and renal tubular epithelial cells. Our 4C analyses revealed interactions of CKD-associated susceptibility regions with the transcriptional start sites of 304 target genes. Overlap with multiple databases confirmed that many of these target genes are involved in kidney homeostasis. Expression quantitative trait loci analysis revealed that mRNA levels of many target genes are genotype dependent. Pathway analyses showed that target genes were enriched in processes crucial for renal function, identifying dysregulated geranylgeranyl diphosphate biosynthesis as a potential disease mechanism. Overall, our data annotated multiple genes to previously reported CKD-associated single-nucleotide polymorphisms and provided evidence for interaction between these loci and target genes. This pipeline provides a novel technique for hypothesis generation and complements classic GWAS interpretation. Future studies are required to specify the implications of our dataset and further reveal the complex roles that common variants have in complex diseases, such as CKD.
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Progressive Renal Disease Established by Renin-Coding Adeno-Associated Virus-Driven Hypertension in Diverse Diabetic Models
Progress in research and developing therapeutics to prevent diabetic kidney disease (DKD) is limited by a lack of animal models exhibiting progressive kidney disease. Chronic hypertension, a driving factor of disease progression in human patients, is lacking in most available models of diabetes. We hypothesized that superimposition of hypertension on diabetic mouse models would accelerate DKD. To test this possibility, we induced persistent hypertension in three mouse models of type 1 diabetes and two models of type 2 diabetes by adeno-associated virus delivery of renin (ReninAAV). Compared with LacZAAV-treated counterparts, ReninAAV-treated type 1 diabetic Akita/129 mice exhibited a substantial increase in albumin-to-creatinine ratio (ACR) and serum creatinine level and more severe renal lesions. In type 2 models of diabetes (C57BKLS db/db and BTBR ob/ob mice), compared with LacZAAV, ReninAAV induced significant elevations in ACR and increased the incidence and severity of histopathologic findings, with increased serum creatinine detected only in the ReninAAV-treated db/db mice. The uninephrectomized ReninAAV db/db model was the most progressive model examined and further characterized. In this model, separate treatment of hyperglycemia with rosiglitazone or hypertension with lisinopril partially reduced ACR, consistent with independent contributions of these disorders to renal disease. Microarray analysis and comparison with human DKD showed common pathways affected in human disease and this model. These results identify novel models of progressive DKD that provide researchers with a facile and reliable method to study disease pathogenesis and support the development of therapeutics.
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Tonicity-Responsive Enhancer-Binding Protein Mediates Hyperglycemia-Induced Inflammation and Vascular and Renal Injury
Diabetic nephropathy (DN) has become the single leading cause of ESRD in developed nations. Bearing in mind the paucity of effective treatment for DN and progressive CKD, novel targets for treatment are sorely needed. We previously reported that increased activity of tonicity-responsive enhancer-binding protein (TonEBP) in monocytes was associated with early DN in humans. We now extend these findings by testing the hypotheses that TonEBP in macrophages promotes hyperglycemia-mediated proinflammatory activation and chronic renal inflammation leading to DN and CKD, and TonEBP genetic variability in humans is associated with inflammatory, renal, and vascular function–related phenotypes. In a mouse model of DN, compared with the wild-type phenotype, TonEBP haplodeficiency associated with reduced activation of macrophages by hyperglycemia, fewer macrophages in the kidney, lower renal expression of proinflammatory genes, and attenuated DN. Furthermore, in a cohort of healthy humans, genetic variants within TonEBP associated with renal function, BP, and systemic inflammation. One of the genetic variants associated with renal function was replicated in a large population-based cohort. These findings suggest that TonEBP is a promising target for minimizing diabetes- and stress-induced inflammation and renovascular injury.
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Reduced Expression of Glutathione S-Transferase {alpha}4 Promotes Vascular Neointimal Hyperplasia in CKD
Neointima formation is the leading cause of arteriovenous fistula (AVF) failure. We have shown that CKD accelerates this process by transforming the vascular smooth muscle cells (SMCs) lining the AVF from a contractile to the synthetic phenotype. However, the underlying mechanisms affecting this transformation are not clear. Previous studies have shown that the α-class glutathione transferase isozymes have an important role in regulating 4-hydroxynonenal (4-HNE)–mediated proliferative signaling of cells. Here, using both the loss- and gain-of-function approaches, we investigated the role of glutathione S-transferase α4 (GSTA4) in modulating cellular 4-HNE levels for the transformation and proliferation of SMCs. Compared with non-CKD controls, mice with CKD had downregulated expression of GSTA4 at the mRNA and protein levels, with concomitant increase in 4-HNE in arteries and veins. This effect was associated with upregulated phosphorylation of MAPK signaling pathway proteins in proliferating SMCs. Overexpressing GSTA4 blocked 4-HNE–induced SMC proliferation. Additionally, inhibitors of MAPK signaling inhibited the 4-HNE–induced responses. Compared with wild-type mice, mice lacking GSTA4 exhibited increased CKD-induced neointima formation in AVF. Transient expression of an activated form of GSTA4, achieved using a combined Tet-On/Cre induction system in mice, lowered levels of 4-HNE and reduced the proliferation of SMCs. Together, these results demonstrate the critical role of GSTA4 in blocking CKD-induced neointima formation and AVF failure.
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Suppression of microRNA Activity in Kidney Collecting Ducts Induces Partial Loss of Epithelial Phenotype and Renal Fibrosis
microRNAs (miRNAs) are sequence-specific inhibitors of post-transcriptional gene expression. The physiologic function of these noncoding RNAs in postnatal renal tubules still remains unclear. Surprisingly, they appear to be dispensable for mammalian proximal tubule (PT) function. Here, we examined the effects of miRNA suppression in collecting ducts (CDs). To conclusively evaluate the role of miRNAs, we generated three mouse models with CD-specific inactivation of key miRNA pathway genes Dicer, Dgcr8, and the entire Argonaute gene family (Ago1, 2, 3, and 4). Characterization of these three mouse models revealed that inhibition of miRNAs in CDs spontaneously evokes a renal tubule injury–like response, which culminates in progressive tubulointerstitial fibrosis (TIF) and renal failure. Global miRNA profiling of microdissected renal tubules showed that miRNAs exhibit segmental distribution along the nephron and CDs. In particular, the expression of miR-200c is nearly 70-fold higher in CDs compared with PTs. Accordingly, miR-200s are downregulated in Dicer-KO CDs, its direct target genes Zeb1, Zeb2, and Snail2 are upregulated, and miRNA-depleted CDs undergo partial epithelial-to-mesenchymal transition (EMT). Thus, miRNAs are essential for CD homeostasis. Downregulation of CD-enriched miRNAs and the subsequent induction of partial EMT may be a new mechanism for TIF progression.
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Activated Hedgehog-GLI Signaling Causes Congenital Ureteropelvic Junction Obstruction
Intrinsic ureteropelvic junction obstruction is the most common cause of congenital hydronephrosis, yet the underlying pathogenesis is undefined. Hedgehog proteins control morphogenesis by promoting GLI-dependent transcriptional activation and inhibiting the formation of the GLI3 transcriptional repressor. Hedgehog regulates differentiation and proliferation of ureteric smooth muscle progenitor cells during murine kidney-ureter development. Histopathologic findings of smooth muscle cell hypertrophy and stroma-like cells, consistently observed in obstructing tissue at the time of surgical correction, suggest that Hedgehog signaling is abnormally regulated during the genesis of congenital intrinsic ureteropelvic junction obstruction. Here, we demonstrate that constitutively active Hedgehog signaling in murine intermediate mesoderm–derived renal progenitors results in hydronephrosis and failure to develop a patent pelvic-ureteric junction. Tissue obstructing the ureteropelvic junction was marked as early as E13.5 by an ectopic population of cells expressing Ptch2, a Hedgehog signaling target. Constitutive expression of GLI3 repressor in Ptch1-deficient mice rescued ectopic Ptch2 expression and obstructive hydronephrosis. Whole transcriptome analysis of isolated Ptch2+ cells revealed coexpression of genes characteristic of stromal progenitor cells. Genetic lineage tracing indicated that stromal cells blocking the ureteropelvic junction were derived from intermediate mesoderm–derived renal progenitors and were distinct from the smooth muscle or epithelial lineages. Analysis of obstructive ureteric tissue resected from children with congenital intrinsic ureteropelvic junction obstruction revealed a molecular signature similar to that observed in Ptch1-deficient mice. Together, these results demonstrate a Hedgehog-dependent mechanism underlying mammalian intrinsic ureteropelvic junction obstruction.
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Extracellular Adenosine Stimulates Vacuolar ATPase-Dependent Proton Secretion in Medullary Intercalated Cells
Acidosis is an important complication of AKI and CKD. Renal intercalated cells (ICs) express the proton pumping vacuolar H+-ATPase (V-ATPase) and are extensively involved in acid-base homeostasis. H+ secretion in type A intercalated cells (A-ICs) is regulated by apical vesicle recycling and stimulated by cAMP. In other cell types, cAMP is increased by extracellular agonists, including adenosine, through purinergic receptors. Adenosine is a Food and Drug Administration–approved drug, but very little is known about the effect of adenosine on IC function. Therefore, we investigated the role of adenosine in the regulation of V-ATPase in ICs. Intravenous treatment of mice with adenosine or agonists of ADORA2A and ADORA2B purinergic P1 receptors induced V-ATPase apical membrane accumulation in medullary A-ICs but not in cortical A-ICs or other IC subtypes. Both receptors are located in A-IC apical membranes, and adenosine injection increased urine adenosine concentration and decreased urine pH. Cell fractionation showed that adenosine or an ADORA2A or ADORA2B agonist induced V-ATPase translocation from vesicles to the plasma membrane and increased protein kinase A (PKA)–dependent protein phosphorylation in purified medullary ICs that were isolated from mice. Either ADORA2A or ADORA2B antagonists or the PKA inhibitor mPKI blocked these effects. Finally, a fluorescence pH assay showed that adenosine activates V-ATPase in isolated medullary ICs. Our study shows that medullary A-ICs respond to luminal adenosine through ADORA2A and ADORA2B receptors in a cAMP/PKA pathway–dependent mechanism to induce V-ATPase–dependent H+ secretion.
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Redirecting TGF-{beta} Signaling through the {beta}-Catenin/Foxo Complex Prevents Kidney Fibrosis
TGF-β is a key profibrotic factor, but targeting TGF-β to prevent fibrosis also abolishes its protective anti-inflammatory effects. Here, we investigated the hypothesis that we can redirect TGF-β signaling by preventing downstream profibrotic interaction of β-catenin with T cell factor (TCF), thereby enhancing the interaction of β-catenin with Foxo, a transcription factor that controls differentiation of TGF-β induced regulatory T cells (iTregs), and thus, enhance anti-inflammatory effects of TGF-β. In iTregs derived from EL4 T cells treated with recombinant human TGF-β1 (rhTGF-β1) in vitro, inhibition of β-catenin/TCF transcription with ICG-001 increased Foxp3 expression, interaction of β-catenin and Foxo1, binding of Foxo1 to the Foxp3 promoter, and Foxo transcriptional activity. Moreover, the level of β-catenin expression positively correlated with the level of Foxo1 binding to the Foxp3 promoter and Foxo transcriptional activity. T cell fate mapping in Foxp3gfp Ly5.1/5.2 mice revealed that coadministration of rhTGF-β1 and ICG-001 further enhanced the expansion of iTregs and natural Tregs observed with rhTGF-β1 treatment alone. Coadministration of rhTGF-β1 with ICG-001 also increased the number of Tregs and reduced inflammation and fibrosis in the kidney fibrosis models of unilateral ureteric obstruction and ischemia-reperfusion injury. Notably, ICG-001 prevented the fibrosis in distant organs (lung and liver) caused by rhTGF-β1. Together, our results show that diversion of β-catenin from TCF- to Foxo-mediated transcription inhibits the β-catenin/TCF–mediated profibrotic effects of TGF-β while enhancing the β-catenin/Foxo–mediated anti-inflammatory effects. Targeting β-catenin/Foxo may be a novel therapeutic strategy in the treatment of fibrotic diseases that lead to organ failure.
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Overweight and Obesity Are Predictors of Progression in Early Autosomal Dominant Polycystic Kidney Disease
The association of overweight/obesity with disease progression in patients with autosomal dominant polycystic kidney disease (ADPKD) remains untested. We hypothesized that overweight/obesity associates with faster progression in early-stage ADPKD. Overall, 441 nondiabetic participants with ADPKD and an eGFR>60 ml/min per 1.73 m2 who participated in the Halt Progression of Polycystic Kidney Disease Study A were categorized on the basis of body mass index (BMI; calculated using nonkidney and nonliver weight) as normal weight (18.5–24.9 kg/m2; reference; n=192), overweight (25.0–29.9 kg/m2; n=168), or obese (≥30 kg/m2; n=81). We evaluated the longitudinal (5-year) association of overweight/obesity with change in total kidney volume (TKV) by magnetic resonance imaging using linear regression and multinomial logistic regression models. Among participants, mean±SD age was 37±8 years, annual percent change in TKV was 7.4%±5.1%, and BMI was 26.3±4.9 kg/m2. The annual percent change in TKV increased with increasing BMI category (normal weight: 6.1%±4.7%, overweight: 7.9%±4.8%, obese: 9.4%±6.2%; P<0.001). In the fully adjusted model, higher BMI associated with greater annual percent change in TKV (β=0.79; 95% confidence interval [95% CI], 0.18 to 1.39, per 5-unit increase in BMI). Overweight and obesity associated with increased odds of annual percent change in TKV ≥7% compared with <5% (overweight: odds ratio, 2.02; 95% CI, 1.15 to 3.56; obese: odds ratio, 3.76; 95% CI, 1.81 to 7.80). Obesity also independently associated with greater eGFR decline (slope) versus normal weight (fully adjusted β =–0.08; 95% CI, –0.15 to –0.02). In conclusion, overweight and, particularly, obesity are strongly and independently associated with rate of progression in early-stage ADPKD.
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Longitudinal FGF23 Trajectories and Mortality in Patients with CKD
Elevated fibroblast growth factor 23 (FGF23) levels, measured at a single time, are strongly associated with increased risk of mortality in patients with CKD. There are minimal data on serial FGF23 measurements in CKD. In a prospective case-cohort study of the Chronic Renal Insufficiency Cohort, we measured FGF23 at two to five annual time points (mean 4.0±1.2) in a randomly selected subcohort of 1135 participants, of whom 203 died, and all remaining 390 participants who died through mid-2013. Higher FGF23 was independently associated with increased risk of death in multivariable-adjusted analyses of time-varying FGF23 (hazard ratio per 1-SD increase in ln-transformed FGF23, 1.84; 95% CI, 1.67 to 2.03). Median FGF23 was stable over 5 years of follow-up, but its gradually right-skewed distribution suggested a subpopulation with markedly elevated FGF23. Trajectory analysis revealed three distinct trajectories: stable FGF23 in the majority of participants (slope of lnFGF23 per year =0.03, 95% CI, 0.02 to 0.04, n=724) and smaller subpopulations with slowly (slope=0.14, 95% CI, 0.12 to 0.16, n=486) or rapidly (slope=0.46, 95% CI, 0.38 to 0.54, n=99) rising levels. Compared with stable FGF23, participants with slowly rising FGF23 trajectories were at 4.49-fold higher risk of death (95% CI, 3.17 to 6.35) and individuals with rapidly rising FGF23 trajectories were at 15.23-fold higher risk of death (95% CI, 8.24 to 28.14) in fully adjusted analyses. Trajectory analyses that used four or three annual FGF23 measurements yielded qualitatively similar results. In conclusion, FGF23 levels are stable over time in the majority of patients with CKD, but serial measurements identify subpopulations with rising levels and exceptionally high risk of death.
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A Randomized Trial of Bortezomib in Late Antibody-Mediated Kidney Transplant Rejection
Late antibody-mediated rejection (ABMR) is a leading cause of kidney allograft failure. Uncontrolled studies have suggested efficacy of the proteasome inhibitor bortezomib, but no systematic trial has been undertaken to support its use in ABMR. In this randomized, placebo-controlled trial (the Bortezomib in Late Antibody-Mediated Kidney Transplant Rejection [BORTEJECT] Trial), we investigated whether two cycles of bortezomib (each cycle: 1.3 mg/m2 intravenously on days 1, 4, 8, and 11) prevent GFR decline by halting the progression of late donor-specific antibody (DSA)–positive ABMR. Forty-four DSA-positive kidney transplant recipients with characteristic ABMR morphology (median time after transplant, 5.0 years; pretransplant DSA documented in 19 recipients), who were identified on cross-sectional screening of 741 patients, were randomly assigned to receive bortezomib (n=21) or placebo (n=23). The 0.5-ml/min per 1.73 m2 per year (95% confidence interval, –4.8 to 5.8) difference detected between bortezomib and placebo in eGFR slope (primary end point) was not significant (P=0.86). We detected no significant differences between bortezomib- and placebo-treated groups in median measured GFR at 24 months (33 versus 42 ml/min per 1.73 m2; P=0.31), 2-year graft survival (81% versus 96%; P=0.12), urinary protein concentration, DSA levels, or morphologic or molecular rejection phenotypes in 24-month follow-up biopsy specimens. Bortezomib, however, associated with gastrointestinal and hematologic toxicity. In conclusion, our trial failed to show that bortezomib prevents GFR loss, improves histologic or molecular disease features, or reduces DSA, despite significant toxicity. Our results reinforce the need for systematic trials to dissect the efficiency and safety of new treatments for late ABMR.
from Journal of the American Society of Nephrology current issue http://ift.tt/2DToEex
Dynamic Prognostic Score to Predict Kidney Allograft Survival in Patients with Antibody-Mediated Rejection
No tool is available for the early assessment of response to antibody-mediated rejection (ABMR) therapies in kidney allograft recipients. This study was designed to define a dynamic composite prognostic ABMR score to predict kidney allograft survival, integrating the disease characteristics at diagnosis and the response to treatment. Among 1978 kidney recipients who underwent transplant between 2008 and 2014, we included 278 patients diagnosed with active ABMR and receiving standard treatment, including plasma exchange, intravenous Ig, and rituximab. Patients were prospectively assessed at diagnosis and after treatment for clinical data, histologic characteristics (allograft biopsy specimen), and donor-specific anti-HLA antibodies (DSA). The dynamic ABMR prediction model included GFR (P<0.001) and presence of interstitial fibrosis/tubular atrophy (P=0.003) at diagnosis and changes in GFR (P<0.001), peritubular capillaritis Banff score (P=0.002), and DSA mean fluorescence intensity (P<0.001) after treatment. Overall, this model showed good calibration and discrimination (C-statistic=0.84). The ABMR prognostic score derived from the prediction model identified three risk strata with 6-year kidney allograft survival rates of 6.0% (high-risk group, n=40), 44.9% (intermediate-risk group, n=36), and 84.4% (low-risk group, n=202), and it provided greater net clinical benefit to patients than did considering them all to have the same level of risk of allograft loss. The performance of the ABMR prognostic score was validated in an independent cohort of 202 kidney recipients with ABMR (C-statistic=0.79). The ABMR prognostic score could be used to inform therapeutic decisions in clinical practice and for the design of clinical trials.
from Journal of the American Society of Nephrology current issue http://ift.tt/2ErCXrI
FOX NEWS: Family blames Tamiflu for their teenage son's suicide
Family blames Tamiflu for their teenage son's suicide
An Indiana family tells Fox 59 News they believe their son committed suicide less than 24-hours after he took Tamiflu following a flu diagnoses.
FOX NEWS: New photos show mother right after giving birth in car, says it was 'perfect'
New photos show mother right after giving birth in car, says it was 'perfect'
New photographs captured the moment an Australian mother gave birth in the back seat of her car.
FOX NEWS: Go figure! Woman stops gorging on raw bacon, loses 150 pounds, clears up skin condition
Go figure! Woman stops gorging on raw bacon, loses 150 pounds, clears up skin condition
An obese woman from Melbourne, Florida who struggled with out-of-control eating ends up clearing up a skin problem after losing 150 pounds.
FOX NEWS: New photos show mother right after giving drug-free birth in car, says it was 'perfect'
New photos show mother right after giving drug-free birth in car, says it was 'perfect'
New photographs captured the moment an Australian mother gave birth in the back seat of her car.
Dr. Brenda Fitzgerald, C.D.C. Director, Resigns Over Tobacco and Other Investments
By SHEILA KAPLAN from NYT Health http://ift.tt/2rY8gba
FOX NEWS: Cancer survival rates improve in some parts of the world, but wide gaps remain
Cancer survival rates improve in some parts of the world, but wide gaps remain
Cancer patients' survival rates are improving, even for some of the deadliest types such as lung cancer, but there are huge disparities between countries, particularly for children, according to a study published in The Lancet.
Tuesday, January 30, 2018
FOX NEWS: Atlanta hospital opens mobile ER to handle flu cases
Atlanta hospital opens mobile ER to handle flu cases
As the flu epidemic overwhelms Georgia, one Atlanta hospital has set up a mobile unit to handle flu patients.
FOX NEWS: Early pregnancy weight gain linked to baby's size at birth
Early pregnancy weight gain linked to baby's size at birth
Women who gain more weight in early pregnancy are more likely to deliver unusually large babies, who may be prone to a host of health problems later in life, new research shows.
FOX NEWS: Woman claiming to have stage 4 breast cancer lied, raised over $30G fraudulently, police say
Woman claiming to have stage 4 breast cancer lied, raised over $30G fraudulently, police say
A Michigan woman claimed she was battling stage four breast cancer and got all her friends together to help raise money for treatments.
FOX NEWS: Tragic faces of the deadly US flu outbreak
Tragic faces of the deadly US flu outbreak
As the nation continues to fight the flu, some families are sharing their stories in hopes of preventing others from facing similar tragedies.
FOX NEWS: Flu kills 7-year-old boy one day after diagnosis
Flu kills 7-year-old boy one day after diagnosis
A 7-year old Virginia boy has died from the flu just one day after being diagnosed.
Monday, January 29, 2018
FOX NEWS: Tragic faces of the deadly US flu outbreak
Tragic faces of the deadly US flu outbreak
As the nation continues to fight the flu, some families are sharing their stories in hopes of preventing others from facing similar tragedies.
FOX NEWS: Junk-food addict lost 162 pounds to grant late mother's deathbed wish
Junk-food addict lost 162 pounds to grant late mother's deathbed wish
A British woman is celebrating her amazing weight loss after keeping her promise to her dying mother.
FOX NEWS: Tragic faces of the deadly U.S. flu outbreak
Tragic faces of the deadly U.S. flu outbreak
As the nation continues to fight the flu, some families are sharing their stories in hopes of preventing others from facing similar tragedies.
FOX NEWS: Florida teen fulfills dying wish, marries high school sweetheart
Florida teen fulfills dying wish, marries high school sweetheart
A Florida teenager with terminal cancer fulfilled his dying wish on Sunday and married his high school sweetheart after the local community rallied together to put together the special day.
FOX NEWS: Flu deaths prompt warnings from victims' families as outbreak continues
Flu deaths prompt warnings from victims' families as outbreak continues
As the nation continues to fight the flu, some families are sharing their stories in hopes of preventing others from facing similar tragedies.
FOX NEWS: Super Bowl events take steps to fight flu as estimated 1 million to attend
Super Bowl events take steps to fight flu as estimated 1 million to attend
Super Bowl visitors could face more exposure to the flu at Super Bowl-related events, and organizers are taking precautions.
Scientists Discover a Bone-Deep Risk for Heart Disease
By GINA KOLATA from NYT Health http://ift.tt/2EkPHQJ
Saturday, January 27, 2018
FOX NEWS: Flu deaths prompt warnings from victims' families as outbreak continues
Flu deaths prompt warnings from victims' families as outbreak continues
As the nation continues to fight the flu, some families are sharing their stories in hopes of preventing others from facing similar tragedies.
FOX NEWS: Florida teen's dying wish to marry high school sweetheart to come true
Florida teen's dying wish to marry high school sweetheart to come true
Dustin Snyder, 19, is set to marry his high school sweetheart Sierra Siverio in Plant City, Fla. on Sunday.
Friday, January 26, 2018
FOX NEWS: Breast implants tied to increased risk of rare blood cancer
Breast implants tied to increased risk of rare blood cancer
Women who get breast implants may be more likely to develop a rare type of cancer known as anaplastic large cell lymphoma, a small Dutch study suggests.
Citing Deaths of Lab Monkeys, F.D.A. Ends an Addiction Study
By SHEILA KAPLAN from NYT Health http://ift.tt/2rI8IKu
FOX NEWS: Mobile stroke unit brings hospital to patients – and could save lives
Mobile stroke unit brings hospital to patients – and could save lives
UCLA and the Los Angeles County Fire Department are using a Mobile Stroke Unit to treat stroke victims in the field, saving them brain cells and possibly their life
More Than 150 Women Described Sexual Abuse By Lawrence Nassar. Will Their Testimony Help Them Heal?
By BENEDICT CAREY from NYT Health http://ift.tt/2FkVMvY
FOX NEWS: 'Tough flu season' hitting baby boomers hard, CDC says
'Tough flu season' hitting baby boomers hard, CDC says
The flu season is still ravaging the country according to health officials at the Centers for Disease Control and Prevention.
This Flu Season Is the Worst in Nearly a Decade
By DONALD G. McNEIL Jr. from NYT Health http://ift.tt/2DBU60I
FOX NEWS: Teens eating more Tide Pods than ever, despite efforts to stop trend
Teens eating more Tide Pods than ever, despite efforts to stop trend
The American Association of Poison Control Centers released a report that the number of teenagers eating Tide Pods has skyrocketed.
FOX NEWS: Flu deaths prompt warnings from victims' families as outbreak continues
Flu deaths prompt warnings from victims' families as outbreak continues
As the nation continues to fight the flu, some families are sharing their stories in hopes of preventing others from facing similar tragedies.
Thursday, January 25, 2018
FOX NEWS: Flu outbreak prompts Florida district to close schools Friday
Flu outbreak prompts Florida district to close schools Friday
A Florida school district said Thursday that it plans to cancel classes Friday in an effort to contain the spread of flu in the area.
FOX NEWS: New Jersey man receives kidney transplant after viral t-shirt plea
New Jersey man receives kidney transplant after viral t-shirt plea
A New Jersey man with a creative approach to finding a kidney donor unexpectedly got the help he needed from a stranger across the country, Pix 11 reported.
FOX NEWS: Oregon boy, 8, dies from flesh-eating bacteria days after falling off bike
Oregon boy, 8, dies from flesh-eating bacteria days after falling off bike
Like most 8-year-old boys, Liam Flanagan has had his fair share of tumbles while playing outside.
FOX NEWS: Doctors discover small light bulb inside a child after coughing fit
Doctors discover small light bulb inside a child after coughing fit
Doctors in India investigating a baby's cough were shocked to find a tiny LED light bulb in her right lung.
F.D.A. Panel Rejects Philip Morris’ Claim That Tobacco Stick Is Safer Than Cigarettes
By SHEILA KAPLAN from NYT Health http://ift.tt/2ndTuY1
FOX NEWS: Symptoms of deadly flu strain spreading across US tend to 'escalate rapidly,' doctor says
Symptoms of deadly flu strain spreading across US tend to 'escalate rapidly,' doctor says
Last Friday, the CDC reported that 30 children have died so far this season from flu-related illness compared to eight at this time last year.
FOX NEWS: Symptoms of deadly flu strain spreading across U.S. tend to 'escalate rapidly,' doctor says
Symptoms of deadly flu strain spreading across U.S. tend to 'escalate rapidly,' doctor says
Last Friday, the CDC reported that 30 children have died so far this season from flu-related illness compared to eight at this time last year.
FOX NEWS: Florida family says 12-year-old son has died from flu
Florida family says 12-year-old son has died from flu
Dr. Marc Siegel reacts to the rise in deaths across the U.S.
FOX NEWS: Flu deaths prompt warnings from victims' families as outbreak continues
Flu deaths prompt warnings from victims' families as outbreak continues
It doesn't matter if you run marathons or play sports, when it comes to the flu, no one is completely immune.
Wednesday, January 24, 2018
FOX NEWS: Dog suffers burns, swollen eye after being dyed purple, animal services says
Dog suffers burns, swollen eye after being dyed purple, animal services says
An animal services team in Florida is pleading with pet owners after a dog suffered burns, eye swelling and nearly died after being colored purple with human hair dye.
New Findings Could Save Lives of More Stroke Patients
By DENISE GRADY from NYT Health http://ift.tt/2n9lyMX
FOX NEWS: Smart contact lens helps diabetics monitor blood sugar levels
Smart contact lens helps diabetics monitor blood sugar levels
New technology has been developed in South Korea that will measure diabetes patients' glucose levels with a smart contact lens.
FOX NEWS: How are the cold and flu different?
How are the cold and flu different?
Knowing the difference between the common cold and the flu can be crucial to your well-being -- and that of your loved ones -- this winter.
FOX NEWS: Model shares bloated IBS photos and harrowing syndrome story
Model shares bloated IBS photos and harrowing syndrome story
Beautiful Australian model chronicles her struggle with irritable bowel syndrome (IBS) by revealing her new bikini body on Instagram.
FOX NEWS: Flu deaths prompt warnings from victims' families as outbreak continues
Flu deaths prompt warnings from victims' families as outbreak continues
It doesn't matter if you run marathons or play sports, when it comes to the flu, no one is completely immune.
FOX NEWS: Single mother dies from flu-related cause two days after docs tell her to go home and rest
Single mother dies from flu-related cause two days after docs tell her to go home and rest
Family and friends are devastated after 36-year old Tandy Harmon died of the flu.
FOX NEWS: Do e-cigarettes help or harm? Report says not clear yet
Do e-cigarettes help or harm? Report says not clear yet
Vaping with e-cigarettes that contains nicotine can be addictive and teenagers may be more likely to get hooked on nicotine according to a new report from the National Academy of Sciences, Engineering and Medicine.
Tuesday, January 23, 2018
FOX NEWS: How are the cold and flu different?
How are the cold and flu different?
Knowing the difference between the cold and the flu can be crucial to your well-being -- and that of your loved ones -- this winter.
New Index Rates Drug Companies in Fight Against ‘Superbugs’
By DONALD G. McNEIL Jr. from NYT Health http://ift.tt/2Dxuy4Y
Science Group Ranks Evidence on E-Cigarette Safety
By SHEILA KAPLAN from NYT Health http://ift.tt/2G8WwWa
FOX NEWS: 5-year-old girl survives rattlesnake bite
5-year-old girl survives rattlesnake bite
A 5-year-old girl Texas girl is recovering in the hospital after surviving a venomous rattlesnake bite.
