Journal of the American Society of Nephrology : JASN




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This Month's Highlights

doi : 10.1681/ASN.2021060755

JASN August 2021, 32 (8) i

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Transplant Biopsy Assessment in 21st Century

Andrew F. Malone

doi : 10.1681/ASN.2021060804

JASN August 2021, 32 (8) 1827-1828

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Biobanks Linked to Electronic Health Records Accelerate Genomic Discovery

Dana C. Crawford and John R. Sedor

doi : 10.1681/ASN.2021060836

JASN August 2021, 32 (8) 1828-1829

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Novel Insights into Mechanisms of Intestinal Phosphate Absorption in Patients with Chronic Kidney Disease

Kittrawee Kritmetapak and Rajiv Kumar

doi : 10.1681/ASN.2021050610

JASN August 2021, 32 (8) 1830-1832

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Prevention of Post-Transplantation Diabetes: Small Steps, Big Opportunities

Adnan Sharif

doi : 10.1681/ASN.2021060777

JASN August 2021, 32 (8) 1833-1834

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Procurement Biopsies in Kidney Transplantation: More Information May Not Lead to Better Decisions

Krista L. Lentine, Bertram Kasiske and David A. Axelrod

doi : 10.1681/ASN.2021030403

JASN August 2021, 32 (8) 1835-1837

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Current Methodological Challenges of Single-Cell and Single-Nucleus RNA-Sequencing in Glomerular Diseases

Dries Deleersnijder, Jasper Callemeyn, Ingrid Arijs, Maarten Naesens, Amaryllis H. Van Craenenbroeck, Diether Lambrechts and Ben Sprangers

doi : 10.1681/ASN.2021020157

JASN August 2021, 32 (8) 1838-1852

Single-cell RNA sequencing (scRNA-seq) and single-nucleus RNA-seq (snRNA-seq) allow transcriptomic profiling of thousands of cells from a renal biopsy specimen at a single-cell resolution. Both methods are promising tools to unravel the underlying pathophysiology of glomerular diseases. This review provides an overview of the technical challenges that should be addressed when designing single-cell transcriptomics experiments that focus on glomerulopathies. The isolation of glomerular cells from core needle biopsy specimens for single-cell transcriptomics remains difficult and depends upon five major factors. First, core needle biopsies generate little tissue material, and several samples are required to identify glomerular cells. Second, both fresh and frozen tissue samples may yield glomerular cells, although every experimental pipeline has different (dis)advantages. Third, enrichment for glomerular cells in human tissue before single-cell analysis is challenging because no effective standardized pipelines are available. Fourth, the current warm cell-dissociation protocols may damage glomerular cells and induce transcriptional artifacts, which can be minimized by using cold dissociation techniques at the cost of less efficient cell dissociation. Finally, snRNA-seq methods may be superior to scRNA-seq in isolating glomerular cells; however, the efficacy of snRNA-seq on core needle biopsy specimens remains to be proven. The field of single-cell omics is rapidly evolving, and the integration of these techniques in multiomics assays will undoubtedly create new insights in the complex pathophysiology of glomerular diseases.

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Circulating Soluble Fms-like Tyrosine Kinase in Renal Diseases Other than Preeclampsia

Theresa M. Wewers, Annika Schulz, Ingo Nolte, Hermann Pavenst?dt, Marcus Brand and Giovana S. Di Marco

doi : 10.1681/ASN.2020111579

JASN August 2021, 32 (8) 1853-1863

Soluble Fms-like tyrosine kinase (sFlt-1/sVEGFR1) is a naturally occurring antagonist of vascular endothelial growth factor (VEGF). Despite being a secreted, soluble protein lacking cytoplasmic and transmembrane domains, sFlt-1 can act locally and be protective against excessive microenvironmental VEGF concentration or exert autocrine functions independently of VEGF. Circulating sFlt-1 may indiscriminately affect endothelial function and the microvasculature of distant target organs. The clinical significance of excess sFlt-1 in kidney disease was first shown in preeclampsia, a major renal complication of pregnancy. However, circulating sFlt-1 levels appear to be increased in various diseases with varying degrees of renal impairment. Relevant clinical associations between circulating sFlt-1 and severe outcomes (e.g., endothelial dysfunction, renal impairment, cardiovascular disease, and all-cause mortality) have been observed in patients with CKD and after kidney transplantation. However, sFlt-1 appears to be protective against renal dysfunction-associated aggravation of atherosclerosis and diabetic nephropathy. Therefore, in this study, we provide an update on sFlt-1 in several kidney diseases other than preeclampsia, discuss clinical findings and experimental studies, and briefly consider its use in clinical practice.

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Presence of SARS-CoV-2 Antibodies in Spent Peritoneal Dialysate

Xiaoling Wang, Nadja Grobe, Amrish Patel, Shuchita Sharma, Jaime Uribarri and Peter Kotanko

doi : 10.1681/ASN.2021020161

JASN August 2021, 32 (8) 1865-1867

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Race-Free Equations for eGFR: Comparing Effects on CKD Classification

James A. Diao, Neil R. Powe and Arjun K. Manrai

doi : 10.1681/ASN.2021020224

JASN August 2021, 32 (8) 1868-1870

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A Biallelic Frameshift Mutation in Nephronectin Causes Bilateral Renal Agenesis in Humans

Lei Dai, Jingzhi Li, Liangqun Xie, Weinan Wang, Yang Lu, Mingkun Xie, Jingrui Huang, Kuifang Shen, Hui Yang, Chenlin Pei, Yanhua Zhao and Weishe Zhang

doi : 10.1681/ASN.2020121762

JASN August 2021, 32 (8) 1871-1879

Background Bilateral renal agenesis (BRA) is a lethal con genital anomaly caused by the failure of normal development of both kidneys early in embryonic development. Oligohydramnios on fetal ultrasonography reveals BRA. Although the exact causes are not clear, BRA is associated with mutations in many renal development genes. However, molecular diagnostics do not pick up many clinical patients. Nephronectin (NPNT) may be a candidate protein for widening diagnosis. It is essential in kidney development, and knockout of Npnt in mice frequently leads to kidney agenesis or hypoplasia.

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Antibody Status, Disease History, and Incidence of SARS-CoV-2 Infection Among Patients on Chronic Dialysis

Dena E. Cohen, Scott Sibbel, Gilbert Marlowe, Kelsey Bludorn, Dawn Miller, Tara Kelley, Jeffrey Connaire, Amy Young, Francesca Tentori and Steven M. Brunelli

doi : 10.1681/ASN.2021030387

JASN August 2021, 32 (8) 1880-1886

Background Although reinfection with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is rare among individuals with few coronavirus disease 2019 (COVID-19) risk factors, the ability of naturally acquired immunity to prevent reinfection among patients with ESKD is not known.

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Laminin-521 is a Novel Target of Autoantibodies Associated with Lung Hemorrhage in Anti-GBM Disease

Cong-rong Shen, Xiao-yu Jia, Wentian Luo, Florina Olaru, Zhao Cui, Ming-hui Zhao and Dorin-Bogdan Borza

doi : 10.1681/ASN.2020101431

JASN August 2021, 32 (8) 1887-1897

Background Antiglomerular basement membrane (anti-GBM) disease is characterized by GN and often pulmonary hemorrhage, mediated by autoantibodies that typically recognize cryptic epitopes within ?345(IV) collagen—a major component of the glomerular and alveolar basement membranes. Laminin-521 is another major GBM component and a proven target of pathogenic antibodies mediating GN in animal models. Whether laminin-521 is a target of autoimmunity in human anti-GBM disease is not yet known.

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Increasing mTORC1 Pathway Activity or Methionine Supplementation during Pregnancy Reverses the Negative Effect of Maternal Malnutrition on the Developing Kidney

Yaniv Makayes, Elad Resnick, Liad Hinden, Elina Aizenshtein, Tomer Shlomi, Raphael Kopan, Morris Nechama and Oded Volovelsky

doi : 10.1681/ASN.2020091321

JASN August 2021, 32 (8) 1898-1912

Background Low nephron number at birth is associated with a high risk of CKD in adulthood because nephrogenesis is completed in utero. Poor intrauterine environment impairs nephron endowment via an undefined molecular mechanism. A calorie-restricted diet (CRD) mouse model examined the effect of malnutrition during pregnancy on nephron progenitor cells (NPCs).

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TWEAK Signaling Pathway Blockade Slows Cyst Growth and Disease Progression in Autosomal Dominant Polycystic Kidney Disease

Adrian Cordido, Laura Nu?ez-Gonzalez, Julio M. Martinez-Moreno, Olaya Lamas-Gonzalez, Laura Rodriguez-Osorio, Maria Vanessa Perez-Gomez, Diego Martin-Sanchez, Patricia Outeda, Marco Chiaravalli, Terry Watnick, Alessandra Boletta, Candido Diaz, Angel Carracedo, Ana B. Sanz, Alberto Ortiz and Miguel A. Garcia-Gonzalez

doi : 10.1681/ASN.2020071094

JASN August 2021, 32 (8) 1913-1932

Background In autosomal dominant polycystic kidney disease (ADPKD), cyst development and enlargement lead to ESKD. Macrophage recruitment and interstitial inflammation promote cyst growth. TWEAK is a TNF superfamily (TNFSF) cytokine that regulates inflammatory responses, cell proliferation, and cell death, and its receptor Fn14 (TNFRSF12a) is expressed in macrophage and nephron epithelia.

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Data-Driven Kidney Transplant Phenotyping as a Histology-Independent Framework for Biomarker Discovery

Konrad Buscher, Barbara Heitplatz, Veerle van Marck, Jian Song, Sophie Loismann, Rebecca Rixen, Birte Hüchtmann, Sunil Kurian, Erik Ehinger, Dennis Wolf, Klaus Ley, Hermann Pavenst?dt and Stefan Reuter

doi : 10.1681/ASN.2020121685

JASN August 2021, 32 (8) 1933-1945

Background In transplant medicine, clinical decision making largely relies on histology of biopsy specimens. However, histology suffers from low specificity, sensitivity, and reproducibility, leading to suboptimal stratification of patients. We developed a histology-independent immune framework of kidney graft homeostasis and rejection.

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Phase Separation of MAGI2-Mediated Complex Underlies Formation of Slit Diaphragm Complex in Glomerular Filtration Barrier

Haijiao Zhang, Lin Lin, Jianping Liu, Lifeng Pan, Zhijie Lin, Mingjie Zhang, Jiong Zhang, Ying Cao, Jinwei Zhu and Rongguang Zhang

doi : 10.1681/ASN.2020111590

JASN August 2021, 32 (8) 1946-1960

Background Slit diaphragm is a specialized adhesion junction between the opposing podocytes, establishing the final filtration barrier to urinary protein loss. At the cytoplasmic insertion site of each slit diaphragm there is an electron-dense and protein-rich cellular compartment that is essential for slit diaphragm integrity and signal transduction. Mutations in genes that encode components of this membrane-less compartment have been associated with glomerular diseases. However, the molecular mechanism governing formation of compartmentalized slit diaphragm assembly remains elusive.

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Uncovering Modifier Genes of X-Linked Alport Syndrome Using a Novel Multiparent Mouse Model

Yuka Takemon, Valerie Wright, Bernard Davenport, Daniel M. Gatti, Susan M. Sheehan, Kelsey Letson, Holly S. Savage, Rachel Lennon and Ron Korstanje

doi : 10.1681/ASN.2020060777

JASN August 2021, 32 (8) 1961-1973

Background Mutations in COL4A5 are responsible for 80% of cases of X-linked Alport Syndrome (XLAS). Although genes that cause AS are well characterized, people with AS who have similar genetic mutations present with a wide variation in the extent of kidney impairment and age of onset, suggesting the activities of modifier genes.

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REST and Stress Resistance in the Aging Kidney

Sato Magassa, Liviu Aron, Clément Hoguin, Pierre Isnard, Fabiola Terzi, Christophe Legendre, Bruce A. Yankner and Guillaume Canaud

doi : 10.1681/ASN.2021020231

JASN August 2021, 32 (8) 1974-1986

Background CKD is associated with the loss of functional nephr ons, leading to increased mechanical and metabolic stress in the remaining cells, particularly for cells constituting the filtration barrier, such as podocytes. The failure of podocytes to mount an adequate stress response can lead to further nephron loss and disease progression. However, the mechanisms that regulate this degenerative process in the kidney are unknown.

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Progressive Cellular Senescence Mediates Renal Dysfunction in Ischemic Nephropathy

Seo Rin Kim, Amrutesh S. Puranik, Kai Jiang, Xiaojun Chen, Xiang-Yang Zhu, Ian Taylor, Alireza Khodadadi-Jamayran, Amir Lerman, LaTonya J. Hickson, Bennett G. Childs, Stephen C. Textor, Tamara Tchkonia, Timothy B. Niewold, James L. Kirkland and Lilach O. Lerman

doi : 10.1681/ASN.2020091373

JASN August 2021, 32 (8) 1987-2004

Background Peripheral vascular diseases may induce chronic ischemia and cellular injury distal to the arterial obstruction. Cellular senescence involves proliferation arrest in response to stress, which can damage neighboring cells. Renal artery stenosis (RAS) induces stenotic-kidney dysfunction and injury, but whether these arise from cellular senescenceand their temporal pattern remain unknown.

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Long-Term Kidney Outcomes Following Dialysis-Treated Childhood Acute Kidney Injury: A Population-Based Cohort Study

Cal H. Robinson, Nivethika Jeyakumar, Bin Luo, Ron Wald, Amit X. Garg, Danielle M. Nash, Eric McArthur, Jason H. Greenberg, David Askenazi, Cherry Mammen, Lehana Thabane, Stuart Goldstein, Rulan S. Parekh, Michael Zappitelli and Rahul Chanchlani

doi : 10.1681/ASN.2020111665

JASN August 2021, 32 (8) 2005-2019

Background AKI is common during pediatric hospitalizations and associated with adverse short-term outcomes. However, long-term outcomes among survivors of pediatric AKI who received dialysis remain uncertain.

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Serum Biomarkers of Iron Stores Are Associated with Increased Risk of All-Cause Mortality and Cardiovascular Events in Nondialysis CKD Patients, with or without Anemia

Murilo Guedes, Daniel G. Muenz, Jarcy Zee, Brian Bieber, Benedicte Stengel, Ziad A. Massy, Nicolas Mansencal, Michelle M.Y. Wong, David M. Charytan, Helmut Reichel, Sandra Waechter, Ronald L. Pisoni, Bruce M. Robinson and Roberto Pecoits-Filho; CKDopps Investigators

doi : 10.1681/ASN.2020101531

JASN August 2021, 32 (8) 2020-2030

Background Approximately 30%–45% of patients with nondialysis CKD have iron deficiency. Iron therapy in CKD has focused primarily on supporting erythropoiesis. In patients with or without anemia, there has not been a comprehensive approach to estimating the association between serum biomarkers of iron stores, and mortality and cardiovascular event risks.

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Medical Records-Based Genetic Studies of the Complement System

Atlas Khan, Ning Shang, Lynn Petukhova, Jun Zhang, Yufeng Shen, Scott J. Hebbring, Halima Moncrieffe, Leah C. Kottyan, Bahram Namjou-Khales, Rachel Knevel, Soumya Raychaudhuri, Elizabeth W. Karlson, John B. Harley, Ian B. Stanaway, David Crosslin, Joshua C. Denny, Mitchell S.V. Elkind, Ali G. Gharavi, George Hripcsak, Chunhua Weng and Krzysztof Kiryluk

doi : 10.1681/ASN.2020091371

JASN August 2021, 32 (8) 2031-2047

Background Genetic variants in complement genes have been associated with a wide range of human disease states, but well-powered genetic association studies of complement activation have not been performed in large multiethnic cohorts.

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Racial and Neighborhood-Level Disparities in COVID-19 Incidence among Patients on Hemodialysis in New York City

Sri Lekha Tummalapalli, Jeffrey Silberzweig, Daniel Cukor, Jonathan T. Lin, Tarek Barbar, Yao Liu, Kwan Kim, Thomas S. Parker, Daniel M. Levine and Said A. Ibrahim

doi : 10.1681/ASN.2020111606

JASN August 2021, 32 (8) 2048-2056

Background The coronavirus disease 2019 (COVID-19) pandemic has disproportionately affected socially disadvantaged populations. Whether disparities in COVID-19 incidence related to race/ethnicity and socioeconomic factors exist in the hemodialysis population is unknown.

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Intestinal Phosphorus Absorption in Moderate CKD and Healthy Adults Determined Using a Radioisotopic Tracer

Elizabeth R. Stremke, Gretchen N. Wiese, Sharon M. Moe, Meryl E. Wastney, Ranjani N. Moorthi and Kathleen M. Hill Gallant

doi : 10.1681/ASN.2020091340

JASN August 2021, 32 (8) 2057-2069

Background Reducing intestinal phosphorus absorption is a cornerstone in CKD-MBD management. Yet, knowledge gaps include how CKD pathophysiology affects intestinal phosphorus absorption. In vivo rodent studies suggest that intestinal phosphorus absorption remains inappropriately normal in early-moderate CKD, despite declining 1,25-dihydroxyvitamin D (1,25D). We measured intestinal phosphorus absorption in patients with moderate CKD versus healthy adults using a direct radiotracer method.

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Missing Self–Induced Microvascular Rejection of Kidney Allografts: A Population-Based Study

Jasper Callemeyn, Aleksandar Senev, Maarten Coemans, Evelyne Lerut, Ben Sprangers, Dirk Kuypers, Alice Koenig, Olivier Thaunat, Marie-Paule Emonds and Maarten Naesens

doi : 10.1681/ASN.2020111558

JASN August 2021, 32 (8) 2070-2082

Background Circulating anti-HLA donor-specific antibodies (HLA-DSA) are often absent in kidney transplant recipients with microvascular inflammation (MVI). Missing self, the inability of donor endothelial cells to provide HLA I–mediated signals to inhibitory killer cell Ig-like receptors (KIRs) on recipient natural killer cells, can cause endothelial damage in vitro, and has been associated with HLA-DSA–negative MVI. However, missing self’s clinical importance as a nonhumoral trigger of allograft rejection remains unclear.

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Early Postoperative Basal Insulin Therapy versus Standard of Care for the Prevention of Diabetes Mellitus after Kidney Transplantation: A Multicenter Randomized Trial

Elisabeth Schwaiger, Simon Krenn, Amelie Kurnikowski, Leon Bergfeld, Mar?a José Pérez-S?ez, Alexander Frey, David Topitz, Michael Bergmann, Sebastian H?dlmoser, Friederike Bachmann, Fabian Halleck, Susanne Kron, Hildegard Hafner-Giessauf, Kathrin Eller, Alexander R. Rosenkranz, Marta Crespo, Anna Faura, Andrea Tura, Peter X. K. Song, Friedrich K. Port, Julio Pascual, Klemens Budde, Robin Ristl, Johannes Werzowa and Manfred Hecking

doi : 10.1681/ASN.2021010127

JASN August 2021, 32 (8) 2083-2098

Background Post-transplantation diabetes mellitus (PTDM) might be preventable.

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Considerations in Comparing Proximal Tubule Cell Culture Models

Ora A. Weisz

doi : 10.1681/ASN.2021040510

JASN August 2021, 32 (8) 2099-2100

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Correction: Long-Term Exposure to Ambient PM2.5 and Increased Risk of Chronic Kidney Disease Prevalence in China

doi : 10.1681/ASN.2021050692

JASN August 2021, 32 (8) 2101

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