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Monday, April 30, 2018
This Months Highlights
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JASN this Month: Something Old, Something New
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Repairing the GBM Step by Step
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WNKs on the Fly
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Insights into CKD from Metabolite GWAS
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Using Large Datasets to Understand CKD
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The Quest for Better Biomarkers of Bone Turnover in CKD
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HDL in CKD--The Devil Is in the Detail
The picture of HDL cholesterol (HDL-C) as the "good" cholesterol has eroded. This is even more surprising because there exists strong evidence that HDL-C is associated with cardiovascular disease (CVD) in the general population as well as in patients with impairment of kidney function and/or progression of CKD. However, drugs that dramatically increase HDL-C have mostly failed to decrease CVD events. Furthermore, genetic studies took the same line, as genetic variants that have a pronounced influence on HDL-C concentrations did not show an association with cardiovascular risk. For many, this was not surprising, given that an HDL particle is highly complex and carries >80 proteins and several hundred lipid species. Simply measuring cholesterol might not reflect the variety of biologic effects of heterogeneous HDL particles. Therefore, functional studies and the involvement of HDL components in the reverse cholesterol transport, including the cholesterol efflux capacity, have become a further focus of study during recent years. As also observed for other aspects, CKD populations behave differently compared with non-CKD populations. Although clear disturbances have been observed for the "functionality" of HDL particles in patients with CKD, this did not necessarily translate into clear-cut associations with outcomes.
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The Ebb and Flow of Echocardiographic Cardiac Function Parameters in Relationship to Hemodialysis Treatment in Patients with ESRD
Cardiovascular disease is the leading cause of mortality in patients receiving hemodialysis. Cardiovascular events in these patients demonstrate a day-of-week pattern; i.e., they occur more commonly during the last day of the long interdialytic interval and the first session of the week. The hemodialysis process causes acute decreases in cardiac chamber size and pulmonary circulation loading and acute diastolic dysfunction, possibly through myocardial stunning and other non–myocardial-related mechanisms; systolic function, in contrast, is largely unchanged. During interdialytic intervals volume overload, acid-base, and electrolyte shifts, as well as arterial and myocardial wall changes, result in dilatation of right cardiac chambers and pulmonary circulation overload. Recent studies suggest that these alterations are more extended during the long interdialytic interval or the first dialysis session of the week and are associated with excess volume overload or removal, respectively, thus adding a mechanism for the day-of-week pattern of mortality in patients receiving hemodialysis. This review summarizes the existing data from echocardiographic studies of cardiac morphology and function during the hemodialysis session, as well as during the interdialytic intervals.
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Protein S Protects against Podocyte Injury in Diabetic Nephropathy
Background Diabetic nephropathy (DN) is a leading cause of ESRD in the United States, but the molecular mechanisms mediating the early stages of DN are unclear.
Methods To assess global changes that occur in early diabetic kidneys and to identify proteins potentially involved in pathogenic pathways in DN progression, we performed proteomic analysis of diabetic and nondiabetic rat glomeruli. Protein S (PS) among the highly upregulated proteins in the diabetic glomeruli. PS exerts multiple biologic effects through the Tyro3, Axl, and Mer (TAM) receptors. Because increased activation of Axl by the PS homolog Gas6 has been implicated in DN progression, we further examined the role of PS in DN.
Results In human kidneys, glomerular PS expression was elevated in early DN but suppressed in advanced DN. However, plasma PS concentrations did not differ between patients with DN and healthy controls. A prominent increase of PS expression also colocalized with the expression of podocyte markers in early diabetic kidneys. In cultured podocytes, high-glucose treatment elevated PS expression, and PS knockdown further enhanced the high-glucose–induced apoptosis. Conversely, PS overexpression in cultured podocytes dampened the high-glucose– and TNF-α–induced expression of proinflammatory mediators. Tyro3 receptor was upregulated in response to high glucose and mediated the anti-inflammatory response of PS. Podocyte-specific PS loss resulted in accelerated DN in streptozotocin-induced diabetic mice, whereas the transient induction of PS expression in glomerular cells in vivo attenuated albuminuria and podocyte loss in diabetic OVE26 mice.
Conclusions Our results support a protective role of PS against glomerular injury in DN progression.
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Mechanism of Hyperkalemia-Induced Metabolic Acidosis
Background Hyperkalemia in association with metabolic acidosis that are out of proportion to changes in glomerular filtration rate defines type 4 renal tubular acidosis (RTA), the most common RTA observed, but the molecular mechanisms underlying the associated metabolic acidosis are incompletely understood. We sought to determine whether hyperkalemia directly causes metabolic acidosis and, if so, the mechanisms through which this occurs.
Methods We studied a genetic model of hyperkalemia that results from early distal convoluted tubule (DCT)–specific overexpression of constitutively active Ste20/SPS1-related proline-alanine–rich kinase (DCT-CA-SPAK).
Results DCT-CA-SPAK mice developed hyperkalemia in association with metabolic acidosis and suppressed ammonia excretion; however, titratable acid excretion and urine pH were unchanged compared with those in wild-type mice. Abnormal ammonia excretion in DCT-CA-SPAK mice associated with decreased proximal tubule expression of the ammonia-generating enzymes phosphate-dependent glutaminase and phosphoenolpyruvate carboxykinase and overexpression of the ammonia-recycling enzyme glutamine synthetase. These mice also had decreased expression of the ammonia transporter family member Rhcg and decreased apical polarization of H+-ATPase in the inner stripe of the outer medullary collecting duct. Correcting the hyperkalemia by treatment with hydrochlorothiazide corrected the metabolic acidosis, increased ammonia excretion, and normalized ammoniagenic enzyme and Rhcg expression in DCT-CA-SPAK mice. In wild-type mice, induction of hyperkalemia by administration of the epithelial sodium channel blocker benzamil caused hyperkalemia and suppressed ammonia excretion.
Conclusions Hyperkalemia decreases proximal tubule ammonia generation and collecting duct ammonia transport, leading to impaired ammonia excretion that causes metabolic acidosis.
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Laminin-521 Protein Therapy for Glomerular Basement Membrane and Podocyte Abnormalities in a Model of Pierson Syndrome
Background Laminin α5β21 (LM-521) is a major component of the GBM. Mutations in LAMB2 that prevent LM-521 synthesis and/or secretion cause Pierson syndrome, a rare congenital nephrotic syndrome with diffuse mesangial sclerosis and ocular and neurologic defects. Because the GBM is uniquely accessible to plasma, which permeates endothelial cell fenestrae, we hypothesized that intravenous delivery of LM-521 could replace the missing LM-521 in the GBM of Lamb2 mutant mice and restore glomerular permselectivity.
Methods We injected human LM-521 (hLM-521), a macromolecule of approximately 800 kD, into the retro-orbital sinus of Lamb2–/– pups daily. Deposition of hLM-521 into the GBM was investigated by fluorescence microscopy. We assayed the effects of hLM-521 on glomerular permselectivity by urinalysis and the effects on podocytes by desmin immunostaining and ultrastructural analysis of podocyte architecture.
Results Injected hLM-521 rapidly and stably accumulated in the GBM of all glomeruli. Super-resolution imaging showed that hLM-521 accumulated in the correct orientation in the GBM, primarily on the endothelial aspect. Treatment with hLM-521 greatly reduced the expression of the podocyte injury marker desmin and attenuated the foot process effacement observed in untreated pups. Moreover, treatment with hLM-521 delayed the onset of proteinuria but did not prevent nephrotic syndrome, perhaps due to its absence from the podocyte aspect of the GBM.
Conclusions These studies show that GBM composition and function can be altered in vivo via vascular delivery of even very large proteins, which may advance therapeutic options for patients with abnormal GBM composition, whether genetic or acquired.
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Lipoxins Regulate the Early Growth Response-1 Network and Reverse Diabetic Kidney Disease
Background The failure of spontaneous resolution underlies chronic inflammatory conditions, including microvascular complications of diabetes such as diabetic kidney disease. The identification of endogenously generated molecules that promote the physiologic resolution of inflammation suggests that these bioactions may have therapeutic potential in the context of chronic inflammation. Lipoxins (LXs) are lipid mediators that promote the resolution of inflammation.
Methods We investigated the potential of LXA4 and a synthetic LX analog (Benzo-LXA4) as therapeutics in a murine model of diabetic kidney disease, ApoE–/– mice treated with streptozotocin.
Results Intraperitoneal injection of LXs attenuated the development of diabetes-induced albuminuria, mesangial expansion, and collagen deposition. Notably, LXs administered 10 weeks after disease onset also attenuated established kidney disease, with evidence of preserved kidney function. Kidney transcriptome profiling defined a diabetic signature (725 genes; false discovery rate P≤0.05). Comparison of this murine gene signature with that of human diabetic kidney disease identified shared renal proinflammatory/profibrotic signals (TNF-α, IL-1β, NF-B). In diabetic mice, we identified 20 and 51 transcripts regulated by LXA4 and Benzo-LXA4, respectively, and pathway analysis identified established (TGF-β1, PDGF, TNF-α, NF-B) and novel (early growth response–1 [EGR-1]) networks activated in diabetes and regulated by LXs. In cultured human renal epithelial cells, treatment with LXs attenuated TNF-α–driven Egr-1 activation, and Egr-1 depletion prevented cellular responses to TGF-β1 and TNF-α.
Conclusions These data demonstrate that LXs can reverse established diabetic complications and support a therapeutic paradigm to promote the resolution of inflammation.
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Intracellular Chloride and Scaffold Protein Mo25 Cooperatively Regulate Transepithelial Ion Transport through WNK Signaling in the Malpighian Tubule
Background With No Lysine kinase (WNK) signaling regulates mammalian renal epithelial ion transport to maintain electrolyte and BP homeostasis. Our previous studies showed a conserved role for WNK in the regulation of transepithelial ion transport in the Drosophila Malpighian tubule.
Methods Using in vitro assays and transgenic Drosophila lines, we examined two potential WNK regulators, chloride ion and the scaffold protein mouse protein 25 (Mo25), in the stimulation of transepithelial ion flux.
Results In vitro, autophosphorylation of purified Drosophila WNK decreased as chloride concentration increased. In conditions in which tubule intracellular chloride concentration decreased from 30 to 15 mM as measured using a transgenic sensor, Drosophila WNK activity acutely increased. Drosophila WNK activity in tubules also increased or decreased when bath potassium concentration decreased or increased, respectively. However, a mutation that reduces chloride sensitivity of Drosophila WNK failed to alter transepithelial ion transport in 30 mM chloride. We, therefore, examined a role for Mo25. In in vitro kinase assays, Drosophila Mo25 enhanced the activity of the Drosophila WNK downstream kinase Fray, the fly homolog of mammalian Ste20-related proline/alanine-rich kinase (SPAK), and oxidative stress-responsive 1 protein (OSR1). Knockdown of Drosophila Mo25 in the Malpighian tubule decreased transepithelial ion flux under stimulated but not basal conditions. Finally, whereas overexpression of wild-type Drosophila WNK, with or without Drosophila Mo25, did not affect transepithelial ion transport, Drosophila Mo25 overexpressed with chloride-insensitive Drosophila WNK increased ion flux.
Conclusions Cooperative interactions between chloride and Mo25 regulate WNK signaling in a transporting renal epithelium.
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Nephrin-Binding Ephrin-B1 at the Slit Diaphragm Controls Podocyte Function through the JNK Pathway
Background B-type ephrins are membrane-bound proteins that maintain tissue function in several organs. We previously reported that ephrin-B1 is localized at the slit diaphragm of glomerular podocytes. However, the function of ephrin-B1 at this location is unclear.
Methods We analyzed the phenotype of podocyte-specific ephrin-B1 knockout mice and assessed the molecular association of ephrin-B1 and nephrin, a key molecule of the slit diaphragm, in HEK293 cells and rats with anti-nephrin antibody-induced nephropathy.
Results Compared with controls, ephrin-B1 conditional knockout mice displayed altered podocyte morphology, disarrangement of the slit diaphragm molecules, and proteinuria. Ephrin-B1 expressed in HEK293 cells immunoprecipitated with nephrin, which required the basal regions of the extracellular domains of both proteins. Treatment of cells with an anti-nephrin antibody promoted the phosphorylation of nephrin and ephrin-B1. However, phosphorylation of ephrin-B1 did not occur in cells expressing a mutant nephrin lacking the ephrin-B1 binding site or in cells treated with an Src kinase inhibitor. The phosphorylation of ephrin-B1 enhanced the phosphorylation of nephrin and promoted the phosphorylation of c-Jun N-terminal kinase (JNK), which was required for ephrin-B1–promoted cell motility in wound-healing assays. Notably, phosphorylated JNK was detected in the glomeruli of control mice but not ephrin-B1 conditional knockout mice. In rats, the phosphorylation of ephrin-B1, JNK, and nephrin occurred in the early phase (24 hours) of anti-nephrin antibody-induced nephropathy.
Conclusions Through interactions with nephrin, ephrin-B1 maintains the structure and barrier function of the slit diaphragm. Moreover, phosphorylation of ephrin-B1 and, consequently, JNK are involved in the development of podocyte injury.
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Gpr97 Exacerbates AKI by Mediating Sema3A Signaling
Background G protein-coupled receptors (GPCRs) participate in a variety of physiologic functions, and several GPCRs have critical physiologic and pathophysiologic roles in the regulation of renal function. We investigated the role of Gpr97, a newly identified member of the adhesion GPCR family, in AKI.
Methods AKI was induced by ischemia–reperfusion or cisplatin treatment in Gpr97-deficient mice. We assessed renal injury in these models and in patients with acute tubular necrosis by histologic examination, and we conducted microarray analysis and in vitro assays to determine the molecular mechanisms of Gpr97 function.
Results Gpr97 was upregulated in the kidneys from mice with AKI and patients with biopsy-proven acute tubular necrosis compared with healthy controls. In AKI models, Gpr97-deficient mice had significantly less renal injury and inflammation than wild-type mice. Gpr97 deficiency also attenuated the AKI-induced expression of semaphorin 3A (Sema3A), a potential early diagnostic biomarker of renal injury. In NRK-52E cells subjected to oxygen–glucose deprivation, siRNA-mediated knockdown of Gpr97 further increased the expression of survivin and phosphorylated STAT3 and reduced toll-like receptor 4 expression. Cotreatment with recombinant murine Sema3A protein counteracted these effects. Finally, additional in vivo and in vitro studies, including electrophoretic mobility shift assays and luciferase reporter assays, showed that Gpr97 deficiency attenuates ischemia–reperfusion-induced expression of the RNA-binding protein human antigen R, which post-transcriptionally regulates Sema3A expression.
Conclusions Gpr97 is an important mediator of AKI, and pharmacologic targeting of Gpr97-mediated Sema3A signaling at multiple levels may provide a novel approach for the treatment of AKI.
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Genome-Wide Mapping of DNA Accessibility and Binding Sites for CREB and C/EBP{beta} in Vasopressin-Sensitive Collecting Duct Cells
Background Renal water excretion is controlled by vasopressin, in part through regulation of the transcription of the aquaporin-2 gene (Aqp2).
Methods To identify enhancer regions likely to be involved in the regulation of Aqp2 and other principal cell–specific genes, we used several next generation DNA-sequencing techniques in a well characterized cultured cell model of collecting duct principal cells (mpkCCD). To locate enhancers, we performed the assay for transposase-accessible chromatin using sequencing (ATAC-Seq) to identify accessible regions of DNA and integrated the data with data generated by chromatin immunoprecipitation followed by next generation DNA-sequencing (ChIP-Seq) for CCCTC binding factor (CTCF) binding, histone H3 lysine-27 acetylation, and RNA polymerase II.
Results We identified two high-probability enhancers centered 81 kb upstream and 5.8 kb downstream from the Aqp2 transcriptional start site. Motif analysis of these regions and the Aqp2 promoter identified several potential transcription factor binding sites, including sites for two b-ZIP transcription factors: CCAAT/enhancer binding protein-β (C/EBPβ) and cAMP-responsive element binding protein (CREB). To identify genomic binding sites for both, we conducted ChIP-Seq using well characterized antibodies. In the presence of vasopressin, C/EBPβ, a pioneer transcription factor critical to cell-specific gene expression, bound strongly at the identified enhancer downstream from Aqp2. However, over multiple replicates, we found no detectable CREB binding sites within 390 kb of Aqp2. Thus, any role for CREB in the regulation of Aqp2 gene transcription is likely to be indirect.
Conclusions The analysis identified two enhancer regions pertinent to transcriptional regulation of the Aqp2 gene and showed C/EBPβ (but not CREB) binding.
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Similar Biophysical Abnormalities in Glomeruli and Podocytes from Two Distinct Models
Background FSGS is a pattern of podocyte injury that leads to loss of glomerular function. Podocytes support other podocytes and glomerular capillary structure, oppose hemodynamic forces, form the slit diaphragm, and have mechanical properties that permit these functions. However, the biophysical characteristics of glomeruli and podocytes in disease remain unclear.
Methods Using microindentation, atomic force microscopy, immunofluorescence microscopy, quantitative RT-PCR, and a three-dimensional collagen gel contraction assay, we studied the biophysical and structural properties of glomeruli and podocytes in chronic (Tg26 mice [HIV protein expression]) and acute (protamine administration [cytoskeletal rearrangement]) models of podocyte injury.
Results Compared with wild-type glomeruli, Tg26 glomeruli became progressively more deformable with disease progression, despite increased collagen content. Tg26 podocytes had disordered cytoskeletons, markedly abnormal focal adhesions, and weaker adhesion; they failed to respond to mechanical signals and exerted minimal traction force in three-dimensional collagen gels. Protamine treatment had similar but milder effects on glomeruli and podocytes.
Conclusions Reduced structural integrity of Tg26 podocytes causes increased deformability of glomerular capillaries and limits the ability of capillaries to counter hemodynamic force, possibly leading to further podocyte injury. Loss of normal podocyte mechanical integrity could injure neighboring podocytes due to the absence of normal biophysical signals required for podocyte maintenance. The severe defects in podocyte mechanical behavior in the Tg26 model may explain why Tg26 glomeruli soften progressively, despite increased collagen deposition, and may be the basis for the rapid course of glomerular diseases associated with severe podocyte injury. In milder injury (protamine), similar processes occur but over a longer time.
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Genome-Wide Association Studies of Metabolites in Patients with CKD Identify Multiple Loci and Illuminate Tubular Transport Mechanisms
Background The kidneys have a central role in the generation, turnover, transport, and excretion of metabolites, and these functions can be altered in CKD. Genetic studies of metabolite concentrations can identify proteins performing these functions.
Methods We conducted genome-wide association studies and aggregate rare variant tests of the concentrations of 139 serum metabolites and 41 urine metabolites, as well as their pairwise ratios and fractional excretions in up to 1168 patients with CKD.
Results After correction for multiple testing, genome-wide significant associations were detected for 25 serum metabolites, two urine metabolites, and 259 serum and 14 urinary metabolite ratios. These included associations already known from population-based studies. Additional findings included an association for the uremic toxin putrescine and variants upstream of an enzyme catalyzing the oxidative deamination of polyamines (AOC1, P-min=2.4x10–12), a relatively high carrier frequency (2%) for rare deleterious missense variants in ACADM that are collectively associated with serum ratios of medium-chain acylcarnitines (P-burden=6.6x10–16), and associations of a common variant in SLC7A9 with several ratios of lysine to neutral amino acids in urine, including the lysine/glutamine ratio (P=2.2x10–23). The associations of this SLC7A9 variant with ratios of lysine to specific neutral amino acids were much stronger than the association with lysine concentration alone. This finding is consistent with SLC7A9 functioning as an exchanger of urinary cationic amino acids against specific intracellular neutral amino acids at the apical membrane of proximal tubular cells.
Conclusions Metabolomic indices of specific kidney functions in genetic studies may provide insight into human renal physiology.
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Characterization of Coding/Noncoding Variants for SHROOM3 in Patients with CKD
Background Interpreting genetic variants is one of the greatest challenges impeding analysis of rapidly increasing volumes of genomic data from patients. For example, SHROOM3 is an associated risk gene for CKD, yet causative mechanism(s) of SHROOM3 allele(s) are unknown.
Methods We used our analytic pipeline that integrates genetic, computational, biochemical, CRISPR/Cas9 editing, molecular, and physiologic data to characterize coding and noncoding variants to study the human SHROOM3 risk locus for CKD.
Results We identified a novel SHROOM3 transcriptional start site, which results in a shorter isoform lacking the PDZ domain and is regulated by a common noncoding sequence variant associated with CKD (rs17319721, allele frequency: 0.35). This variant disrupted allele binding to the transcription factor TCF7L2 in podocyte cell nuclear extracts and altered transcription levels of SHROOM3 in cultured cells, potentially through the loss of repressive looping between rs17319721 and the novel start site. Although common variant mechanisms are of high utility, sequencing is beginning to identify rare variants involved in disease; therefore, we used our biophysical tools to analyze an average of 112,849 individual human genome sequences for rare SHROOM3 missense variants, revealing 35 high-effect variants. The high-effect alleles include a coding variant (P1244L) previously associated with CKD (P=0.01, odds ratio=7.95; 95% CI, 1.53 to 41.46) that we find to be present in East Asian individuals at an allele frequency of 0.0027. We determined that P1244L attenuates the interaction of SHROOM3 with 14–3-3, suggesting alterations to the Hippo pathway, a known mediator of CKD.
Conclusions These data demonstrate multiple new SHROOM3-dependent genetic/molecular mechanisms that likely affect CKD.
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The Most N-Terminal Region of THSD7A Is the Predominant Target for Autoimmunity in THSD7A-Associated Membranous Nephropathy
Background Thrombospondin type 1 domain–containing 7A (THSD7A) has been identified as a pathogenic autoantigen in membranous nephropathy (MN). However, the THSD7A epitopes targeted by patient autoantibodies are unknown.
Methods We performed an in silico analysis of the THSD7A multidomain structure, expressed the folded domains in HEK293 cells, and tested for domain reactivity with 31 serum samples from patients with THSD7A-associated MN using Western and native blotting. Immunogenicity of the antigen domains was further investigated by cDNA immunization of rabbits and mice.
Results We characterized the extracellular topology of THSD7A as a tandem string of 21 thrombospondin type 1 domains. Overall, 28 serum samples (90%) recognized multiple epitope domains along the molecule. Detailed epitope mapping revealed that the complex consisting of the first and second N-terminal domains (amino acids 48–192) was recognized by 27 of 31 patient serum samples (87%). Serum recognizing one or two epitope domains showed lower anti-THSD7A antibody levels than serum recognizing three or more epitope domains. During follow-up, a loss of epitope recognition was observed in seven of 16 patients, and it was accompanied by decreasing antibody levels and remission of proteinuria. In four of 16 patients, epitope recognition patterns changed during follow-up. Notably, immunization experiments in rabbits and mice revealed that induced antibodies, like patient autoantibodies, preferentially bound to the most N-terminal domains of THSD7A.
Conclusions Our data show that the immune response in THSD7A-associated MN is polyreactive and that autoantibodies predominantly target the most N-terminal part of THSD7A.
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Biomarkers of AKI Progression after Pediatric Cardiac Surgery
Background As children progress to higher stages of AKI, the risk for adverse outcomes dramatically increases. No reliable methods exist to predict AKI progression in hospitalized children. To determine if biomarkers of inflammation and kidney injury can predict AKI progression, we conducted a three-center prospective cohort study of children undergoing cardiopulmonary bypass.
Methods On the first day of serum creatinine–defined AKI, we measured urine biomarkers (neutrophil gelatinase–associated lipocalin [NGAL], IL-18, kidney injury molecule 1, liver fatty acid binding protein [L-FABP], albumin, and cystatin C) and plasma biomarkers (IFN, IL-1, IL-2, IL-4, IL-6, IL-8, IL-10, IL-12, IL-13, TNF-α, NGAL, and cystatin C). We defined AKI progression as a worsening of AKI stage or persisting stage 3 AKI (≥2 consecutive days).
Results In all, 176 of 408 (43%) children developed postoperative AKI. Among the children with AKI, we diagnosed stages 1, 2, and 3 AKI in 145 (82.5%), 25 (14%), and six (3.5%) children, respectively, on the first day of AKI; 28 (7%) children had AKI progression. On the first day of AKI, nine of 17 biomarkers were significantly higher in patients with than without AKI progression. Urine L-FABP (among injury biomarkers) and plasma IL-8 (among inflammatory biomarkers) had the highest discrimination for AKI progression: optimism-corrected area under the curve, 0.70; 95% confidence interval, 0.58 to 0.81 and optimism-corrected area under the curve, 0.80; 95% confidence interval, 0.69 to 0.91, respectively.
Conclusions If validated in additional cohorts, plasma IL-8 could be used to improve clinical care and guide enrollment in therapeutic trials of AKI.
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Diagnostic Accuracy of Biomarkers and Imaging for Bone Turnover in Renal Osteodystrophy
Background Renal osteodystrophy is common in advanced CKD, but characterization of bone turnover status can only be achieved by histomorphometric analysis of bone biopsy specimens (gold standard test). We tested whether bone biomarkers and high-resolution peripheral computed tomography (HR-pQCT) parameters can predict bone turnover status determined by histomorphometry.
Methods We obtained fasting blood samples from 69 patients with CKD stages 4–5, including patients on dialysis, and 68 controls for biomarker analysis (intact parathyroid hormone [iPTH], procollagen type 1 N-terminal propeptide [PINP], bone alkaline phosphatase [bALP], collagen type 1 crosslinked C-telopeptide [CTX], and tartrate-resistant acid phosphatase 5b [TRAP5b]) and scanned the distal radius and tibia of participants by HR-pQCT. We used histomorphometry to evaluate bone biopsy specimens from 43 patients with CKD.
Results Levels of all biomarkers tested were significantly higher in CKD samples than control samples. For discriminating low bone turnover, bALP, intact PINP, and TRAP5b had an areas under the receiver operating characteristic curve (AUCs) of 0.82, 0.79, and 0.80, respectively, each significantly better than the iPTH AUC of 0.61. Furthermore, radius HR-pQCT total volumetric bone mineral density and cortical bone volume had AUCs of 0.81 and 0.80, respectively. For discriminating high bone turnover, iPTH had an AUC of 0.76, similar to that of all other biomarkers tested.
Conclusions The biomarkers bALP, intact PINP, and TRAP5b and radius HR-pQCT parameters can discriminate low from nonlow bone turnover. Despite poor diagnostic accuracy for low bone turnover, iPTH can discriminate high bone turnover with accuracy similar to that of the other biomarkers, including CTX.
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Ischemia-Induced DNA Hypermethylation during Kidney Transplant Predicts Chronic Allograft Injury
Background Ischemia during kidney transplant causes chronic allograft injury and adversely affects outcome, but the underlying mechanisms are incompletely understood. In tumors, oxygen shortage reduces the DNA demethylating activity of the ten-11 translocation (TET) enzymes, yielding hypermethylated genomes that promote tumor progression. We investigated whether ischemia similarly induces DNA hypermethylation in kidney transplants and contributes to chronic injury.
Methods We profiled genome-wide DNA methylation in three cohorts of brain-dead donor kidney allograft biopsy specimens: a longitudinal cohort with paired biopsy specimens obtained at allograft procurement (preischemia; n=13), after implantation and reperfusion (postischemia; n=13), and at 3 or 12 months after transplant (n=5 each); a cross-sectional cohort with preimplantation biopsy specimens (n=82); and a cross-sectional cohort with postreperfusion biopsy specimens (n=46).
Results Analysis of the paired preischemia and postischemia specimens revealed that methylation increased drastically in all allografts on ischemia. Hypermethylation was caused by loss of 5-hydroxymethylcytosine, the product of TET activity, and it was stable 1 year after transplant. In the preimplantation cohort, CpG hypermethylation directly correlated with ischemia time and for some CpGs, increased 2.6% per additional hour of ischemia. Hypermethylation preferentially affected and reduced the expression of genes involved in suppressing kidney injury and fibrosis. Moreover, CpG hypermethylation in preimplantation specimens predicted chronic injury, particularly fibrosis and glomerulosclerosis, 1 year after transplant. This finding was validated in the independent postreperfusion cohort, in which hypermethylation also predicted reduced allograft function 1 year after transplant, outperforming established clinical variables.
Conclusions We highlight a novel epigenetic basis for ischemia-induced chronic allograft injury with biomarker potential.
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Antibodies Can Extenuate Polyomavirus Infections
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Studying the Effect of Vitamin D Supplementation on Vascular Function in CKD: A Work in Progress
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The Authors Reply
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The Authors Reply
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FOX NEWS: Court sides with mom to keep boy on life support as she desperately seeks transfer
Court sides with mom to keep boy on life support as she desperately seeks transfer
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Wheelchairs Prohibited in the Last Place You’d Expect
By PAULA SPAN from NYT Health https://ift.tt/2rgfkx9
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Injecting Drugs Can Ruin a Heart. How Many Second Chances Should a User Get?
By ABBY GOODNOUGH from NYT Health https://ift.tt/2I0Wvay
Saturday, April 28, 2018
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Friday, April 27, 2018
The Golden State Killer Is Tracked Through a Thicket of DNA, and Experts Shudder
By GINA KOLATA and HEATHER MURPHY from NYT Health https://ift.tt/2I2fjWS
FOX NEWS: Amid romaine lettuce E. coli outbreak, restaurants aim to soothe customers
Amid romaine lettuce E. coli outbreak, restaurants aim to soothe customers
In the weeks since an E. coli bacteria outbreak on romaine lettuce grown in Yuma, Arizona was announced, restaurants and eateries around the country have worked to assure customers their food is safe.
New C.D.C. Director’s $375,000 Salary Under Scrutiny
By SHEILA KAPLAN from NYT Health https://ift.tt/2r5yvZn
FOX NEWS: Former model 'eaten alive' while in care of Georgia nursing home
Former model 'eaten alive' while in care of Georgia nursing home
Rebecca Zeni’s family said the former model suffered a terrible death after she was eaten alive by a scabies infestation while in the care of Shepherd Hills Nursing Home.
FOX NEWS: Mom dies after battling rare rodent-borne virus for weeks
Mom dies after battling rare rodent-borne virus for weeks
A New Mexico family is mourning the loss of a 27-year-old mother who had spent weeks fighting for her life after contracting a rare rodent-borne virus.
FOX NEWS: More kids have autism, better diagnosis may be the reason
More kids have autism, better diagnosis may be the reason
The government estimates that autism is becoming more common, but it's only a small increase and some experts think it can be largely explained by better diagnosing of minority children.
FOX NEWS: Halsey announces she plans to freeze her eggs due to endometriosis
Halsey announces she plans to freeze her eggs due to endometriosis
Halsey announced she plans to freeze her eggs due to her recent diagnosis of endometriosis.
FOX NEWS: Teacher who smells 'like a fish' due to rare disorder finds relief
Teacher who smells 'like a fish' due to rare disorder finds relief
A mother with an extremely rare condition that makes her smell like fish has finally found relief after years of being humiliated by the odor.
FOX NEWS: Hog farm's neighbors awarded $50M after suing over smells, spraying
Hog farm's neighbors awarded $50M after suing over smells, spraying
Families who live near a hog farm in Bladen County, N.C., have been complaining for decades about bad smells, flies and excessive chemical spraying.
Thursday, April 26, 2018
Trump’s Doctor Accused of Handing Out Ambien. D.E.A. Calls the Practice Illegal
By GINA KOLATA from NYT Health https://ift.tt/2Fk9j6s
FOX NEWS: A doctor who can feel his patient's pain
A doctor who can feel his patient's pain
What if a doctor could physically feel the pain their patients were experiencing? Dr. Joel Salinas, a neurologist and clinical researcher at Massachusetts General Hospital, can do just that. He has a neurological trait called mirror-touch, a medical mystery that causes him to feel the emotional and physical experiences of other people.
FOX NEWS: Woman claims she watched YouTube clips on childbirth before delivering own baby in hotel room during overseas layover
Woman claims she watched YouTube clips on childbirth before delivering own baby in hotel room during overseas layover
A Tennessee woman’s birth story has gone viral after she claimed on Twitter that she gave birth by herself in her hotel room during a layover in Turkey while on her way to Germany.
FOX NEWS: Mom claims son's 'hidden' unborn twin gave her cancer
Mom claims son's 'hidden' unborn twin gave her cancer
A mother-of-four is claiming that was left fighting for life when she developed cancer stemming from her baby son's hidden unborn twin.
FOX NEWS: Alfie Evans' parents to meet with doctors to discuss taking terminally ill tot home
Alfie Evans' parents to meet with doctors to discuss taking terminally ill tot home
The parents of Alfie Evans plan to meet with his doctors on Thursday to discuss bringing the terminally ill boy home.
FOX NEWS: Abandoned dog with one eye undergoes incredible transformation
Abandoned dog with one eye undergoes incredible transformation
A dreadlocked dog that was "one big mat" when he was rescued from the streets has undergone a stunning transformation - and is now looking for a home.
‘Desperation Oncology’: When Patients Are Dying, Some Cancer Doctors Turn to Immunotherapy
By GINA KOLATA from NYT Health https://ift.tt/2Hwgv5t
Wednesday, April 25, 2018
FOX NEWS: Missouri pediatrician slams 'selfish' anti-vaxers after measles Facebook post sparks debate
Missouri pediatrician slams 'selfish' anti-vaxers after measles Facebook post sparks debate
A Missouri pediatrician is not planning to apologize for his facility's Facebook post encouraging Kansas City-area residents to be "responsible" and get vacinated amid a measles outbreak in the area.
A Lifesaving Pump for Cancer Patients Is Being Phased Out
By DENISE GRADY and SHEILA KAPLAN from NYT Health https://ift.tt/2HQ1ieM
Infant Deaths Fall Sharply in Africa With Routine Antibiotics
By DONALD G. McNEIL Jr. from NYT Health https://ift.tt/2vNkmWj
FOX NEWS: Alfie Evans' parents lose attempt to overturn ruling that barred terminally ill British boy from traveling to Rome
Alfie Evans' parents lose attempt to overturn ruling that barred terminally ill British boy from traveling to Rome
Alfie Evans parents' attempt to overturn their appeal was rejected by the Court of Appeal on Wednesday.
FOX NEWS: Florida mom gets 'blood boiling' letter from neighbors regarding 'hefty' teen with autism
Florida mom gets 'blood boiling' letter from neighbors regarding 'hefty' teen with autism
When Leah Solomon's husband forwarded her a letter he found under their front door, the Florida mother was shocked.
FOX NEWS: Mom has foot amputated after discovering cancerous tumor during pedicure
Mom has foot amputated after discovering cancerous tumor during pedicure
A North Carolina mother’s decision to amputate her right foot in hopes of preventing a cancerous tumor from spreading did not come easy, but she said it was her love of life and her kids that ultimately helped her make it.
FOX NEWS: Former classmate donates life-saving kidney to man nearly 50 years after graduating
Former classmate donates life-saving kidney to man nearly 50 years after graduating
A pair of former classmates who hardly knew each other while in school 50 years ago reunited recently, but it wasn’t to reminisce or catch up -- it was for a life-saving transplant that has bonded the pair for life.
FOX NEWS: 7-year-old boy recovering after 5-organ transplant surgery
7-year-old boy recovering after 5-organ transplant surgery
A seven-year-old boy is one of the youngest patients in Britain to undergo a multi-transplant operation to successfully replace five organs.
FOX NEWS: Chicago baby fitted with world's tiniest mechanical heart valve
Chicago baby fitted with world's tiniest mechanical heart valve
A Chicago baby is thriving after she became one of the first to receive a mechanical heart valve.
FOX NEWS: Alfie Evans' parents to appeal ruling that barred terminally ill British boy from traveling to Rome
Alfie Evans' parents to appeal ruling that barred terminally ill British boy from traveling to Rome
Alfie Evans’ parents will appeal to overturn a ruling Wednesday that barred the terminally ill child from being taken to Rome for care.
FOX NEWS: Alfie Evans' parents to appeal ruling that barred terminally ill British teen from traveling to Rome
Alfie Evans' parents to appeal ruling that barred terminally ill British teen from traveling to Rome
Alfie Evans’ parents will appeal to overturn a ruling Wednesday that barred the terminally ill child from being taken to Rome for care.
Tuesday, April 24, 2018
FOX NEWS: Alfie Evans' dad giving toddler mouth-to-mouth resuscitation to 'keep him alive'
Alfie Evans' dad giving toddler mouth-to-mouth resuscitation to 'keep him alive'
Alfie Evans' parents are tonight giving him mouth-to-mouth resuscitation in a desperate bid to keep him alive after a court ruled he cannot be flown to Italy for treatment.
With George H.W. Bush Hospitalized, the World Wonders: Is It a Broken Heart?
By GINA KOLATA and BENEDICT CAREY from NYT Health https://ift.tt/2FhjCsg
FOX NEWS: Sorority grants World War II vet's final wish to dance with a beautiful woman
Sorority grants World War II vet's final wish to dance with a beautiful woman
A bedridden 92-year-old World War II veteran had a dying wish fulfilled thanks to a Mississippi sorority-- to dance with a beautiful woman.
FOX NEWS: Alfie Evans' family loses appeal to transport terminally ill British toddler to Rome
Alfie Evans' family loses appeal to transport terminally ill British toddler to Rome
The family of Alfie Evans, the terminally ill British toddler who was taken off life support Monday, lost their legal challenge Tuesday to transport the boy to Rome.
FOX NEWS: 1 dead, another recovering after 2 men suffer heart attacks at same train station
1 dead, another recovering after 2 men suffer heart attacks at same train station
Officers called to a medical emergency at an Atlanta train station last week were called back to the same station an hour later, for the same emergency but with a different patient.
FOX NEWS: Alfie Evans, severely ill British toddler, may be transported to Rome for care if appeal succeeds
Alfie Evans, severely ill British toddler, may be transported to Rome for care if appeal succeeds
Alfie Evans, the terminally ill British toddler who was taken off life support Monday, may be transported to Rome for care if a last-ditch appeal succeeds in court.
FOX NEWS: 'QLaser' TV infomercial doc gets 12 years in prison for selling scam device
'QLaser' TV infomercial doc gets 12 years in prison for selling scam device
A former dentist-turned convicted con-man and his two cohorts were sentenced to prison on Friday for their roles in a multi-million-dollar fraud case that primarily preyed on the elderly.
F.D.A. Cracks Down on Sales of E-Cigarettes to Minors
By KATE ZERNIKE and SHEILA KAPLAN from NYT Health https://ift.tt/2qYcqMe
FOX NEWS: Ice pops recalled over possible listeria contamination
Ice pops recalled over possible listeria contamination
A West Virginia-based company has issued a voluntary recall for 3,000 cases of ice pops sold under two different brands over concerns about listeria contamination.
FOX NEWS: Veteran diagnosed with skin cancer after dentist spots mark on face
Veteran diagnosed with skin cancer after dentist spots mark on face
A routine trip to the dentist last year may have played a key role in saving an Oregon veteran’s life.
FOX NEWS: Woman has leg amputated after break wouldn't heal
Woman has leg amputated after break wouldn't heal
A young woman decided to have her leg amputated after a simple stress fracture she suffered walking down a street wouldn't heal.
