The Genetic Architecture of Kidney Disease

The kidney is subject to a wide range of abnormalities, many of which have a significant hereditable component. Next generation sequencing is increasingly bringing the genetic drivers of Mendelian disease into focus at the base pair level, whereas inexpensive genotyping arrays have surveyed hundreds of thousands of individuals to identify common variants that predispose to kidney dysfunction. In this first article in a CJASN series on kidney genomics, we review how both rare and common variants contribute to kidney disease, explore how evolution may influence the genetic variants that affect kidney function, consider how genetic information is and will be used in the clinic, and identify some of the most important future directions for kidney disease research. Forthcoming articles in the series will elaborate on many of these themes.

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P0031AURINE METABOLOMICS: AN EMERGING TOOL FOR DISSECTING BIOLOGICAL ABERRATIONS UNDERLYING RENAL DYSFUNCTION IN BARDET-BIEDL SYNDROME

Nephrology Dialysis Transplantation ◽

10.1093/ndt/gfaa142.p0031a ◽

2020 ◽

Vol 35 (Supplement_3) ◽

Author(s):

Miriam Zacchia ◽

Emanuela Marchese ◽

Marianna Caterino ◽

Margherita Ruoppolo ◽

Giovambattista Capasso

Keyword(s):

Lactic Acid ◽

Kidney Disease ◽

Renal Disease ◽

Renal Dysfunction ◽

Metabolic Pathways ◽

Healthy Subjects ◽

Hexadecenoic Acid ◽

Kidney Dysfunction ◽

Bardet Biedl Syndrome ◽

Wide Range

Abstract Background and Aims Bardet Biedl Syndrome (BBS) is a rare genetic disorder characterized by a wide range of organ dysfunction, including kidney disease. The severity of renal dysfunction is highly variable in this setting, ranging from tubular defects to the end stage renal disease, with poor genotype-phenotype correlation. Proteomics and metabolomics are powerful tools able to contribute to the better understanding of molecular basis of disease conditions. Our previous studies demonstrated that the urinary proteomic pattern of BBS patients differed from that of healthy subjects, with a set of deregulated proteins including cell adhesion and extracellular matrix organization proteins (1). The present study aims to characterize urine metabolomic profile of BBS patients, in order to identify both 1) potential disease biomarkers and 2) aberrant metabolic pathways underlying renal disease Method To this end, in the pilot study urine samples have been collected from 14 adult BBS patients and have been compared with healthy volunteers, using an untargeted strategy. In the confirmation study, 24 BBS patients with wide range of kidney dysfunction have been enrolled, and additional control groups, besides healthy subjects, were included: 1) age-gender-matched chronic kidney disease patients by other causes and 2) obese individuals. Results Several metabolites were de-regulated in BBS patients compared with normal subjects (lactic acid, glycolic acid,3-Hydroxypropionic acid, pyruvic acid, 3-hydroxyisobutyric acid, 2-ethyl-3-hydroxy-propionic acid, succinic acid, fumaric acid, erythropentonic acid, 2-hydroxyglutaric acid, 4-hydroxyphenyllactic acid, 3,4-pyridinedicarboxylic acid, retinoic acid, 4-hydroxyphenylacetic acid, palmitic acid, 9-Hexadecenoic acid, oleic acid and 9-Octadecenoic acid). The clusterization performed by MetaboAnalyst tool, revealed a possible deregulation of different metabolic pathways, including glycolysis, TCA cycle, pyruvate metabolism, lipids biosynthesis and glutamate metabolism (p-value <0.01) (figure 1); some of these pathways were described as de-regulated in other ciliopathies (2). In the confirmation study (on-going studies) some metabolites, including lactic acid and intermediates of Krebs cycle, correlated with kidney dysfunction only in the BBS group. Conclusion These findings suggest that urine metabolomic fingerprint of BBS patients is different from that of healthy subjects and indicate a possible deregulation of several metabolic pathways; some urinary molecules correlated with kidney dysfunction only in BBS patients, suggesting the specificity of these results.

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Exome wide association study on Albuminuria identifies a novel rare variant inCUBNand additional genes, in 33985 Europeans with and without diabetes

10.1101/355990 ◽

2018 ◽

Author(s):

Tarunveer S. Ahluwalia ◽

Christina-Alexendra Schulz ◽

Johannes Waage ◽

Tea Skaaby ◽

Niina Sandholm ◽

...

Keyword(s):

Chronic Kidney Disease ◽

Kidney Disease ◽

Association Study ◽

Genetic Architecture ◽

European Ancestry ◽

Common Variants ◽

Multiple Testing Correction ◽

Meta Analyses ◽

Coding Variants ◽

Prevention Of Diabetes

AbstractIdentifying rare coding variants associated with albuminuria may open new avenues for preventing chronic kidney disease (CKD) and end-stage renal disease which are highly prevalent in patients with diabetes. Efforts to identify genetic susceptibility variants for albuminuria have so far been limited with the majority of studies focusing on common variants.We performed an exome-wide association study to identify coding variants in a two phase (discovery and replication) approach, totaling to 33,985 individuals of European ancestry (15,872 with and 18,113 without diabetes) and further testing in Greenlanders (n = 2,605). We identify a rare (MAF: 0.8%) missense (A1690V) variant inCUBN(rs141640975, β=0.27, p=1.3 × 10−11) associated with albuminuria as a continuous measure in the combined European meta-analyses. Presence of each rare allele of the variant was associated with a 6.4% increase in albuminuria. The rareCUBNvariant had 3 times stronger effect in individuals with diabetes compared to those without(pinteraction:5.4 × 10−4, βDM: 0.69, βnonDM:0.20) in the discovery meta-analyses. Geneaggregate tests based on rare and common variants identify three additional genes associated with albuminuria(HES1, CDC73, andGRM5)after multiple testing correction (P_bonferroni<2.7 × 10−6).The current study identifies a rare coding variant in theCUBNlocus and other potential genes associated with albuminuria in individuals with and without diabetes. These genes have been implicated in renal and cardiovascular dysfunction. These findings provide new insights into the genetic architecture of albuminuria and highlight novel target genes and pathways for prevention of diabetes-related kidney disease.Significance statementIncreased albuminuria is a key manifestation of major health burdens, including chronic kidney disease and/or cardiovascular disease. Although being partially heritable, there is a lack of knowledge on rare genetic variants that contribute to albuminuria. The current study describes the discovery and validation, of a new rare gene mutation (~1%) in theCUBNgene which associates with increased albuminuria. Its effect multiplies 3 folds among diabetes cases compared to non diabetic individuals. The study further uncovers 3 additional genes modulating albuminuria levels in humans. Thus the current study findings provide new insights into the genetic architecture of albuminuria and highlight novel genes/pathways for prevention of diabetes related kidney disease.

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History of the Study of Apocrypha in Early Medieval England

Bulletin for the Study of Religion ◽

10.1558/bsor.37171 ◽

2020 ◽

Vol 48 (3-4) ◽

pp. 13-26

Author(s):

Brandon W. Hawk

Keyword(s):

Old Testament ◽

Medieval England ◽

Medieval Period ◽

Early Medieval ◽

Future Directions ◽

Early Judaism ◽

Wide Range ◽

History Of ◽

The Subject ◽

Early English

Literature written in England between about 500 and 1100 CE attests to a wide range of traditions, although it is clear that Christian sources were the most influential. Biblical apocrypha feature prominently across this corpus of literature, as early English authors clearly relied on a range of extra-biblical texts and traditions related to works under the umbrella of what have been called “Old Testament Pseudepigrapha” and “New Testament/Christian Apocrypha." While scholars of pseudepigrapha and apocrypha have long trained their eyes upon literature from the first few centuries of early Judaism and early Christianity, the medieval period has much to offer. This article presents a survey of significant developments and key threads in the history of scholarship on apocrypha in early medieval England. My purpose is not to offer a comprehensive bibliography, but to highlight major studies that have focused on the transmission of specific apocrypha, contributed to knowledge about medieval uses of apocrypha, and shaped the field from the nineteenth century up to the present. Bringing together major publications on the subject presents a striking picture of the state of the field as well as future directions.

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A review on aversive Pavlovian-to-Instrumental transfer in humans

10.31234/osf.io/dyz29 ◽

2020 ◽

Author(s):

Anna Gerlicher ◽

Merel Kindt

Keyword(s):

Avoidance Behavior ◽

Neural Circuits ◽

Transfer Effects ◽

Future Directions ◽

Transfer Paradigm ◽

Wide Range ◽

Threat Cues ◽

Imminent Threat ◽

Fear And Anxiety ◽

Pathological Anxiety

A cue that indicates imminent threat elicits a wide range of physiological, hormonal, autonomic, cognitive, and emotional fear responses in humans and facilitates threat-specific avoidance behavior. The occurrence of a threat cue can, however, also have general motivational effects and affect behavior. That is, the encounter with a threat cue can increase our tendency to engage in general avoidance behavior that does neither terminate nor prevent the threat-cue or the threat itself. Furthermore, the encounter with a threat-cue can substantially reduce our likelihood to engage in behavior that leads to rewarding outcomes. Such general motivational effects of threat-cues on behavior can be informative about the transition from normal to pathological anxiety and could also explain the development of comorbid disorders, such as depression and substance abuse. Despite the unmistakable relevance of the motivational effects of threat for our understanding of anxiety disorders, their investigation is still in its infancy. Pavlovian-to-Instrumental transfer is one paradigm that allows us to investigate such motivational effects of threat cues. Here, we review studies investigating aversive transfer in humans and discuss recent results on the neural circuits mediating Pavlovian-to-Instrumental transfer effects. Finally, we discuss potential limitations of the transfer paradigm and future directions for employing Pavlovian-to-Instrumental transfer for the investigation of motivational effects of fear and anxiety.

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Long-term views on chronic kidney disease research priorities among stakeholders engaged in a priority-setting partnership: A qualitative study

Health Expectations ◽

10.1111/hex.12818 ◽

2018 ◽

Vol 21 (6) ◽

pp. 1142-1149 ◽

Cited By ~ 3

Author(s):

Meghan J. Elliott ◽

Joanna E. M. Sale ◽

Zahra Goodarzi ◽

Linda Wilhelm ◽

Andreas Laupacis ◽

...

Keyword(s):

Chronic Kidney Disease ◽

Kidney Disease ◽

Qualitative Study ◽

Priority Setting ◽

Research Priorities ◽

Disease Research ◽

A Priority ◽

Priority Setting Partnership

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Non-Albumin Proteinuria (NAP) as a Complementary Marker for Diabetic Kidney Disease (DKD)

Life ◽

10.3390/life11030224 ◽

2021 ◽

Vol 11 (3) ◽

pp. 224

Author(s):

Jaehyun Bae ◽

Young Jun Won ◽

Byung-Wan Lee

Keyword(s):

Kidney Disease ◽

Filtration Rate ◽

Diabetic Kidney Disease ◽

Estimated Glomerular Filtration Rate ◽

Early Stage ◽

Screening Tools ◽

Tubular Injury ◽

Current Standard ◽

Diabetic Kidney ◽

Wide Range

Diabetic kidney disease (DKD) is one of the most common forms of chronic kidney disease. Its pathogenic mechanism is complex, and it can affect entire structures of the kidney. However, conventional approaches to early stage DKD have focused on changes to the glomerulus. Current standard screening tools for DKD, albuminuria, and estimated glomerular filtration rate are insufficient to reflect early tubular injury. Therefore, many tubular biomarkers have been suggested. Non-albumin proteinuria (NAP) contains a wide range of tubular biomarkers and is convenient to measure. We reviewed the clinical meanings of NAP and its significance as a marker for early stage DKD.

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5 Years (And Counting) of Expanding Access to Kidney Disease Research

Kidney International Reports ◽

10.1016/j.ekir.2021.04.039 ◽

2021 ◽

Author(s):

R. McLean ◽

S. Mohan ◽

J. Radhakrishnan

Keyword(s):

Kidney Disease ◽

Disease Research

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Automatic Vulnerability Detection in Embedded Devices and Firmware

ACM Computing Surveys ◽

10.1145/3432893 ◽

2021 ◽

Vol 54 (2) ◽

pp. 1-42

Author(s):

Abdullah Qasem ◽

Paria Shirani ◽

Mourad Debbabi ◽

Lingyu Wang ◽

Bernard Lebel ◽

...

Keyword(s):

Embedded Systems ◽

Symbolic Execution ◽

Vital Role ◽

Security And Privacy ◽

Embedded Devices ◽

Security Vulnerabilities ◽

Future Directions ◽

Hybrid Approaches ◽

Wide Range ◽

The Internet Of Things

In the era of the internet of things (IoT), software-enabled inter-connected devices are of paramount importance. The embedded systems are very frequently used in both security and privacy-sensitive applications. However, the underlying software (a.k.a. firmware) very often suffers from a wide range of security vulnerabilities, mainly due to their outdated systems or reusing existing vulnerable libraries; which is evident by the surprising rise in the number of attacks against embedded systems. Therefore, to protect those embedded systems, detecting the presence of vulnerabilities in the large pool of embedded devices and their firmware plays a vital role. To this end, there exist several approaches to identify and trigger potential vulnerabilities within deployed embedded systems firmware. In this survey, we provide a comprehensive review of the state-of-the-art proposals, which detect vulnerabilities in embedded systems and firmware images by employing various analysis techniques, including static analysis, dynamic analysis, symbolic execution, and hybrid approaches. Furthermore, we perform both quantitative and qualitative comparisons among the surveyed approaches. Moreover, we devise taxonomies based on the applications of those approaches, the features used in the literature, and the type of the analysis. Finally, we identify the unresolved challenges and discuss possible future directions in this field of research.

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Re-Evaluation of the Podosphaera tridactyla Species Complex in Australia

Journal of Fungi ◽

10.3390/jof7030171 ◽

2021 ◽

Vol 7 (3) ◽

pp. 171

Author(s):

Reannon L. Smith ◽

Tom W. May ◽

Jatinder Kaur ◽

Tim I. Sawbridge ◽

Ross C. Mann ◽

...

Keyword(s):

Phylogenetic Analysis ◽

Powdery Mildew ◽

Species Complex ◽

Taxonomic Revision ◽

Stone Fruit ◽

Prunus Species ◽

Wide Range ◽

Unidentified Species ◽

The Rose ◽

Generation Sequencing

The Podosphaera tridactyla species complex is highly variable morphologically and causes powdery mildew on a wide range of Prunus species, including stone fruit. A taxonomic revision of the Po. tridactyla species complex in 2020 identified 12 species, seven of which were newly characterised. In order to clarify which species of this complex are present in Australia, next generation sequencing was used to isolate the fungal ITS+28S and host matK chloroplast gene regions from 56 powdery mildew specimens of stone fruit and ornamental Prunus species accessioned as Po. tridactyla or Oidium sp. in Australian reference collections. The specimens were collected in Australia, Switzerland, Italy and Korea and were collected from 1953 to 2018. Host species were confirmed using matK phylogenetic analysis, which identified that four had been misidentified as Prunus but were actually Malusprunifolia. Podosphaera species were identified using ITS+28S phylogenetic analysis, recognising three Podosphaera species on stone fruit and related ornamental Prunus hosts in Australia. These were Po.pannosa, the rose powdery mildew, and two species in the Po. tridactyla species complex: Po. ampla, which was the predominant species, and a previously unidentified species from peach, which we describe here as Po. cunningtonii.

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Current Development and Applications of Super-Resolution Ultrasound Imaging

Sensors ◽

10.3390/s21072417 ◽

2021 ◽

Vol 21 (7) ◽

pp. 2417

Author(s):

Qiyang Chen ◽

Hyeju Song ◽

Jaesok Yu ◽

Kang Kim

Keyword(s):

Kidney Disease ◽

Ultrasound Imaging ◽

Atherosclerotic Plaque ◽

Super Resolution ◽

Emerging Technology ◽

Diffraction Limit ◽

Disease Models ◽

Current Development ◽

Future Directions ◽

Acoustic Diffraction

Abnormal changes of the microvasculature are reported to be key evidence of the development of several critical diseases, including cancer, progressive kidney disease, and atherosclerotic plaque. Super-resolution ultrasound imaging is an emerging technology that can identify the microvasculature noninvasively, with unprecedented spatial resolution beyond the acoustic diffraction limit. Therefore, it is a promising approach for diagnosing and monitoring the development of diseases. In this review, we introduce current super-resolution ultrasound imaging approaches and their preclinical applications on different animals and disease models. Future directions and challenges to overcome for clinical translations are also discussed.

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