Browse
Submit Data
Databases
API
Help

Dataset Information

14 Views

0 Connections

0 Citations

0 Reanalyses

0 Downloads

Omics score: 0

Inherited Renal Tubulopathies-Challenges and Controversies.

ABSTRACT: Electrolyte homeostasis is maintained by the kidney through a complex transport function mostly performed by specialized proteins distributed along the renal tubules. Pathogenic variants in the genes encoding these proteins impair this function and have consequences on the whole organism. Establishing a genetic diagnosis in patients with renal tubular dysfunction is a challenging task given the genetic and phenotypic heterogeneity, functional characteristics of the genes involved and the number of yet unknown causes. Part of these difficulties can be overcome by gathering large patient cohorts and applying high-throughput sequencing techniques combined with experimental work to prove functional impact. This approach has led to the identification of a number of genes but also generated controversies about proper interpretation of variants. In this article, we will highlight these challenges and controversies.

SUBMITTER: Iancu D

PROVIDER: S-EPMC7140864 | biostudies-literature | 2020 Mar

REPOSITORIES: biostudies-literature

ACCESS DATA

Json Xml

Publications

Inherited Renal Tubulopathies-Challenges and Controversies.

Iancu Daniela D Ashton Emma E

Genes 20200305 3

Electrolyte homeostasis is maintained by the kidney through a complex transport function mostly performed by specialized proteins distributed along the renal tubules. Pathogenic variants in the genes encoding these proteins impair this function and have consequences on the whole organism. Establishing a genetic diagnosis in patients with renal tubular dysfunction is a challenging task given the genetic and phenotypic heterogeneity, functional characteristics of the genes involved and the number ...[more]

PMID: 32150856

Similar Datasets

Protective Role of Vitamin D in Renal Tubulopathies.

Project description:Vitamin D is tightly linked with renal tubular homeostasis: the mitochondria of proximal convoluted tubule cells are the production site of 1?,25-dihydroxyvitamin D3. Patients with renal impairment or tubular injury often suffer from chronic inflammation. This alteration comes from oxidative stress, acidosis, decreased clearance of inflammatory cytokines and stimulation of inflammatory factors. The challenge is to find the right formula for each patient to correctly modulate the landscape of treatment and preserve the essential functions of the organism without perturbating its homeostasis. The complexity of the counter-regulation mechanisms and the different axis involved in the Vitamin D equilibrium pose a major issue on Vitamin D as a potential effective anti-inflammatory drug. The therapeutic use of this compound should be able to inhibit the development of inflammation without interfering with normal homeostasis. Megalin-Cubilin-Amnionless and the FGF23-Klotho axis represent two Vitamin D-linked mechanisms that could modulate and ameliorate the damage response at the renal tubular level, balancing Vitamin D therapy with an effect potent enough to contrast the inflammatory cascades, but which avoids potential severe side effects.

| S-EPMC7142711 | biostudies-literature

Inherited salt-losing tubulopathies are associated with immunodeficiency due to impaired IL-17 responses.

Project description:Increased extracellular sodium activates Th17 cells, which provide protection from bacterial and fungal infections. Whilst high salt diets have been shown to worsen autoimmune disease, the immunological consequences of clinical salt depletion are unknown. Here, we investigate immunity in patients with inherited salt-losing tubulopathies (SLT). Forty-seven genotyped SLT patients (with Bartter, Gitelman or EAST Syndromes) are recruited. Clinical features of dysregulated immunity are recorded with a standardised questionnaire and immunological investigations of IL-17 responsiveness undertaken. The effects of altering extracellular ionic concentrations on immune responses are then assessed. Patients are hypokalaemic and hypomagnesaemic, with reduced interstitial sodium stores determined by 23Na-magnetic resonance imaging. SLT patients report increased mucosal infections and allergic disease compared to age-matched controls. Aligned with their clinical phenotype, SLT patients have an increased ratio of Th2:Th17 cells. SLT Th17 and Tc17 polarisation is reduced in vitro, yet STAT1 and STAT3 phosphorylation and calcium flux following T cell activation are unaffected. In control cells, the addition of extracellular sodium (+40 mM), potassium (+2 mM), or magnesium (+1 mM) reduces Th2:Th17 ratio and augments Th17 polarisation. Our results thus show that the ionic environment typical in SLT impairs IL-17 immunity, but the intracellular pathways that mediate salt-driven Th17 polarisation are intact and in vitro IL-17 responses can be reinvigorated by increasing extracellular sodium concentration. Whether better correction of extracellular ions can rescue the immunophenotype in vivo in SLT patients remains unknown.

| S-EPMC7459119 | biostudies-literature

Surgical Therapy of Endometriosis: Challenges and Controversies.

Project description:Endometriosis is one of the most common disorders encountered in surgical gynaecology. The laparoscopic technique, the planning of the surgical intervention, the extent of information provided to patients and the interdisciplinary coordination make it a challenging intervention. Complete resection of all visible foci of disease offers the best control of symptoms. However, the possibility of achieving this goal is limited by the difficulty of detecting all foci and the risks associated with radical surgical strategies. Thus, the excision of ovarian endometrioma can result in a significant impairment of ovarian function, while damage to nerve structures during resection of the uterosacral ligaments, the parametrium, the rectovaginal septum or the vaginal cuff to treat deep infiltrating endometriosis can lead to serious functional impairments such as voiding disorders. A detailed risk-benefit analysis is therefore necessary, and patients must be treated using an individual approach.

| S-EPMC3858988 | biostudies-literature

Selenium and at-risk pregnancy: challenges and controversies.

Project description:Selenium (Se), an essential trace element, is inserted as selenocysteine into an array of functional proteins and forms the core of various enzymes that play a cardinal role in antioxidant defense mechanisms, in redox regulation, and in thyroid hormone metabolism. Variations in plasma Se are due to nutritional habits, geographic and ethnic differences, and probably to genetic polymorphisms, the latter still to be conclusively established. Se concentrations were reported to be low in women of reproductive age in the UK, decreasing further during pregnancy, this resulting in low plasma and placental antioxidant enzyme activities. Since low serum Se levels have been found in women with preeclampsia, it has been hypothesized that low maternal Se status during early gestation may be an indicator of preterm birth. Moreover, it is documented that Se administration during pregnancy tendentially reduced the markers of thyroid autoimmunity and the incidence of maternal hypothyroidism in the postpartum period. Importantly, low Se levels in pregnant women affect fetal growth and augment the risk of delivering a small-for-gestational age infant by reducing placental antioxidant defense, while low Se in the third trimester is thought to indicate increased demands by the placenta, an issue which requires further confirmation. There is evidently a need for double-blind, placebo-controlled studies to better determine the efficacy and safety of Se supplementation in pregnancy at high risk for complications, and for measurement of Se levels or of selenoprotein P, the most reliable parameter of Se status, particularly in selenopenic regions.

| S-EPMC7528225 | biostudies-literature

Recent controversies on comparative effectiveness research investigations: Challenges, opportunities, and pitfalls.

Project description:The purpose of comparative effectiveness research (CER) is to improve health outcomes by developing and disseminating evidence-based information about which currently available interventions and practices are most effective for patients. Randomized Controlled Trials (RCT) are the hallmark of scientific proof, and have been used to compare interventions used in variable ways by different clinicians (comparative effectiveness RCTs, CER-RCTs). But such CER-RCTs have at times generated controversy. Usually the background for the CER-RCT is a range of "standard therapy" or "standard of care." This may have been adopted on observational data alone, or pilot data. At times, such prior data may derive from populations that differ from the population in which the widely variable standard approach is being applied. We believe that controversies related to these CER-RCTs result from confusing "accepted" therapies and "rigorously evaluated therapies." We first define evidence-based medicine and consider how well neonatology conforms to that definition. We then contrast the approach of testing new therapies and those already existing and widely adopted, as in CER-RCTs. We next examine a central challenge in incorporating the control arm within CER-RCTs and aspects of the "titrated" trial. We finally briefly consider some ethical issues that have arisen, and discuss the wide range of neonatology practices that could be tested by CER-RCTs or alternative CER-based strategies that might inform practice. Throughout, we emphasize the lack of awareness of the lay community, and indeed many researchers or commentators, in appreciating the wide variation of standard of care. There is a corresponding need to identify the best uses of available resources that will lead to the best outcomes for our patients. We conclude that CER-RCTs are an essential methodology in modern neonatology to address many unanswered questions and test unproven therapies in newborn care.

| S-EPMC5222533 | biostudies-literature

Challenges and Controversies in the Genetic Diagnosis of Hereditary Spastic Paraplegia.

Project description:Purpose of reviewThe hereditary spastic paraplegias (HSPs) are a group of disorders characterised by progressive lower limb weakness and spasticity. We address the challenges and controversies involved in the genetic diagnosis of HSP.Recent findingsThere is a large and rapidly expanding list of genes implicated in HSP, making it difficult to keep gene testing panels updated. There is also a high degree of phenotypic overlap between HSP and other disorders, leading to problems in choosing the right panel to analyse. We discuss genetic testing strategies for overcoming these diagnostic hurdles, including the use of targeted sequencing gene panels, whole-exome sequencing and whole-genome sequencing. Personalised treatments for HSP are on the horizon, and a genetic diagnosis may hold the key to access these treatments. Developing strategies to overcome the challenges and controversies in HSP may hold the key to a rapid and accurate genetic diagnosis.

| S-EPMC7921051 | biostudies-literature

Brain barriers and brain fluid research in 2016: advances, challenges and controversies.

Project description:This editorial highlights some of the advances that occurred in relation to brain barriers and brain fluid research in 2016. It also aims to raise some of the attendant controversies and challenges in such research.

| S-EPMC5288882 | biostudies-literature

Making urinary extracellular vesicles a clinically tractable source of biomarkers for inherited tubulopathies using a small volume precipitation method: proof of concept.

Project description:Biomarkers of inherited tubulopathies would be useful for clarifying diagnoses in patients where genetic screening is not readily available or where disease-attributable mutations are not found. Urinary extracellular vesicles (uEVs) obtained by ultracentrifugation can be used as a source of biomarkers for inherited tubulopathies such as Gitelman Syndrome (GS), however, ultracentrifugation requires costly equipment and is thus not usually accessible. In contrast, precipitation methods can extract uEVs using standard laboratory centrifuges, thus making uEVs extracted by this method clinically tractable as a source of biomarkers for GS and other inherited tubulopathies. Here we optimise a precipitation method for extracting urinary extracellular vesicles (uEVs) and provide proof of concept that these uEVs are a source of biomarkers using GS an exemplar tubulopathy. For method optimisation, uEVs were precipitated from fresh and frozen (for up to 6 years), small volume (1-2 mL) urine samples from healthy volunteers and GS patients. Nanoparticle tracking analysis was used to calculate the concentration of uEVs. Thiazide sensitive sodium-chloride cotransporter (NCC) content was determined by densitometry of Western blots. NCC content of uEVs was lower in GS patients (n = 11) than healthy volunteers (n = 12; P = 0.001). Three of four patients clinically suspected for GS, in whom only a single SLC12A3 mutation was identified, had lower uEV NCC content than all healthy volunteers tested. In the clinical setting, sufficient uEVs can be extracted from frozen, small volume urine samples using precipitation methods to distinguish patients with GS from healthy volunteers, and thus this source of uEVs could be utilised as an additional diagnostic test for GS and similar disorders.

| S-EPMC7118034 | biostudies-literature

Rare inherited kidney diseases: challenges, opportunities, and perspectives.

Project description:At least 10% of adults and nearly all children who receive renal-replacement therapy have an inherited kidney disease. These patients rarely die when their disease progresses and can remain alive for many years because of advances in organ-replacement therapy. However, these disorders substantially decrease their quality of life and have a large effect on health-care systems. Since the kidneys regulate essential homoeostatic processes, inherited kidney disorders have multisystem complications, which add to the usual challenges for rare disorders. In this review, we discuss the nature of rare inherited kidney diseases, the challenges they pose, and opportunities from technological advances, which are well suited to target the kidney. Mechanistic insights from rare disorders are relevant for common disorders such as hypertension, kidney stones, cardiovascular disease, and progression of chronic kidney disease.

| S-EPMC4135047 | biostudies-literature

Gene therapy of inherited retinal degenerations: prospects and challenges.

Project description:Because of its favorable anatomical and immunological characteristics, the eye has been at the forefront of translational gene therapy. Dozens of promising proofs of concept have been obtained in animal models of inherited retinal degenerations (IRDs), and some of them have been relayed to the clinic. The results from the first clinical trials for a congenital form of blindness have generated great interest and have demonstrated the safety and efficacy of intraocular administrations of viral vectors in humans. However, this progress has also generated new questions and posed challenges that need to be addressed to further expand the applicability of gene therapy in the eye, including safe delivery of viral vectors to the outer retina, treatment of dominant IRDs as well as of IRDs caused by mutations in large genes, and, finally, selection of the appropriate IRDs and patients to maximize the efficacy of gene transfer. This review summarizes the strategies that are currently being exploited to overcome these challenges and drive the clinical development of retinal gene therapy.

| S-EPMC4410187 | biostudies-literature

OmicsDI is part of the ELIXIR infrastructure

OmicsDI is an Elixir interoperability service. Learn more ›

OmicsDI Databases

PRIDE
PeptideAtlas
MassIVE
JPOST Repository
Physiome Model Repository

EGA
EVA
ENA
LINCS
PAXDB
Cell Collective

MetaboLights
Metabolomics Workbench
MetabolomeExpress
GNPS
BioModels
FAIRDOMHub

ArrayExpress
dbGaP
ExpressionAtlas
GEO
NODE

Information

Databases
Help
API
Contact us
Code on GitHub
Terms of use
Submit Data