المؤلفون: Katie Wong, David Pitcher, Fiona Braddon, Lewis Downward, Retha Steenkamp, Nicholas Annear, Jonathan Barratt, Coralie Bingham, Constantina Chrysochou, Richard J Coward, David Game, Sian Griffin, Matt Hall, Sally Johnson, Durga Kanigicherla, Fiona Karet Frankl, David Kavanagh, Larissa Kerecuk, Eamonn R Maher, Shabbir Moochhala, Jenny Pinney, John A Sayer, Roslyn Simms, Smeeta Sinha, Shalabh Srivastava, Frederick WK Tam, Andrew Neil Turner, Stephen B Walsh, Aoife Waters, Patricia Wilson, Edwin Wong, Christopher Mark Taylor, Dorothea Nitsch, Moin Saleem, Detlef Bockenhauer, Kate Bramham, Daniel P Gale, Sharirose Abat, Shazia Adalat, Joy Agbonmwandolor, Zubaidah Ahmad, Abdulfattah Alejmi, Rashid Almasarwah, Ellie Asgari, Amanda Ayers, Jyoti Baharani, Gowrie Balasubramaniam, Felix Kpodo, Tarun Bansal, Alison Barratt, Megan Bates, Natalie Bayne, Janet Bendle, Sarah Benyon, Carsten Bergmann, Sunil Bhandari, Preetham Boddana, Sally Bond, Angela Branson, Stephen Brearey, Vicky Brocklebank, Sharanjit Budwal, Conor Byrne, Hugh Cairns, Brian Camilleri, Gary Campbell, Alys Capell, Margaret Carmody, Marion Carson, Tracy Cathcart, Christine Catley, Karine Cesar, Melanie Chan, Houda Chea, James Chess, Chee Kay Cheung, Katy-Jane Chick, Nihil Chitalia, Martin Christian, Tina Chrysochou, Katherine Clark, Christopher Clayton, Rhian Clissold, Helen Cockerill, Joshua Coelho, Elizabeth Colby, Viv Colclough, Eileen Conway, H Terence Cook, Wendy Cook, Theresa Cooper, Sarah Crosbie, Gabor Cserep, Anjali Date, Katherine Davidson, Amanda Davies, Neeraj Dhaun, Ajay Dhaygude, Lynn Diskin, Abhijit Dixit, Eunice Doctolero, Suzannah Dorey, Lewis Downard, Mark Drayson, Gavin Dreyer, Tina Dutt, Kufreabasi Etuk, Dawn Evans, Jenny Finch, Frances Flinter, James Fotheringham, Lucy Francis, Hugh Gallagher, Eva Garcia, Madita Gavrila, Susie Gear, Colin Geddes, Mark Gilchrist, Matt Gittus, Paraskevi Goggolidou, Christopher Goldsmith, Patricia Gooden, Andrea Goodlife, Priyanka Goodwin, Tassos Grammatikopoulos, Barry Gray, Megan Griffith, Steph Gumus, Sanjana Gupta, Patrick Hamilton, Lorraine Harper, Tess Harris, Louise Haskell, Samantha Hayward, Shivaram Hegde, Bruce Hendry, Sue Hewins, Nicola Hewitson, Kate Hillman, Mrityunjay Hiremath, Alexandra Howson, Zay Htet, Sharon Huish, Richard Hull, Alister Humphries, David PJ Hunt, Karl Hunter, Samantha Hunter, Marilyn Ijeomah-Orji, Nick Inston, David Jayne, Gbemisola Jenfa, Alison Jenkins, Caroline A Jones, Colin Jones, Amanda Jones, Rachel Jones, Lavanya Kamesh, Mahzuz Karim, Amrit Kaur, Kelly Kearley, Arif Khwaja, Garry King, Grant King, Ewa Kislowska, Edyta Klata, Maria Kokocinska, Mark Lambie, Laura Lawless, Thomas Ledson, Rachel Lennon, Adam P Levine, Ling Wai Maggie Lai, Graham Lipkin, Graham Lovitt, Paul Lyons, Holly Mabillard, Katherine Mackintosh, Khalid Mahdi, Eamonn Maher, Kevin J Marchbank, Patrick B Mark, Sherry Masoud, Bridgett Masunda, Zainab Mavani, Jake Mayfair, Stephen McAdoo, Joanna Mckinnell, Nabil Melhem, Simon Meyrick, Putnam Morgan, Ann Morgan, Fawad Muhammad, Shona Murray, Kristina Novobritskaya, Albert CM Ong, Louise Oni, Kate Osmaston, Neal Padmanabhan, Sharon Parkes, Jean Patrick, James Pattison, Riny Paul, Rachel Percival, Stephen J Perkins, Alexandre Persu, William G Petchey, Matthew C Pickering, Jennifer Pinney, Lucy Plumb, Zoe Plummer, Joyce Popoola, Frank Post, Albert Power, Guy Pratt, Charles Pusey, Ria Rabara, May Rabuya, Tina Raju, Chadd Javier, Ian SD Roberts, Candice Roufosse, Adam Rumjon, Alan Salama, Richard Sandford, Kanwaljit S Sandu, Nadia Sarween, Neil Sebire, Haresh Selvaskandan, Asheesh Sharma, Edward J Sharples, Neil Sheerin, Harish Shetty, Rukshana Shroff, Manish Sinha, Kerry Smith, Lara Smith, Ian Stott, Katerina Stroud, Pauline Swift, Justyna Szklarzewicz, Fred Tam, Kay Tan, Robert Taylor, Marc Tischkowitz, Kay Thomas, Yincent Tse, Alison Turnbull, A Neil Turner, Kay Tyerman, Miranda Usher, Gopalakrishnan Venkat-Raman, Alycon Walker, Angela Watt, Phil Webster, Ashutosh Wechalekar, Gavin I Welsh, Nicol West, David Wheeler, Kate Wiles, Lisa Willcocks, Angharad Williams, Emma Williams, Karen Williams, Deborah H Wilson, Patricia D Wilson, Paul Winyard, Grahame Wood, Emma Woodward, Len Woodward, Adrian Woolf, David Wright

مصطلحات موضوعية: Uncategorized, RaDaR consortium

الوصف: Individuals with rare kidney diseases account for 5-10% of people with chronic kidney disease, but constitute more than 25% of patients receiving kidney replacement therapy. The National Registry of Rare Kidney Diseases (RaDaR) gathers longitudinal data from patients with these conditions, which we used to study disease progression and outcomes of death and kidney failure.People aged 0-96 years living with 28 types of rare kidney diseases were recruited from 108 UK renal care facilities. The primary outcomes were cumulative incidence of mortality and kidney failure in individuals with rare kidney diseases, which were calculated and compared with that of unselected patients with chronic kidney disease. Cumulative incidence and Kaplan-Meier survival estimates were calculated for the following outcomes: median age at kidney failure; median age at death; time from start of dialysis to death; and time from diagnosis to estimated glomerular filtration rate (eGFR) thresholds, allowing calculation of time from last eGFR of 75 mL/min per 1·73 m 2 or more to first eGFR of less than 30 mL/min per 1·73 m 2 (the therapeutic trial window).Between Jan 18, 2010, and July 25, 2022, 27 285 participants were recruited to RaDaR. Median follow-up time from diagnosis was 9·6 years (IQR 5·9-16·7). RaDaR participants had significantly higher 5-year cumulative incidence of kidney failure than 2·81 million UK patients with all-cause chronic kidney disease (28% vs 1%; p<0·0001), but better survival rates (standardised mortality ratio 0·42 [95% CI 0·32-0·52]; p<0·0001). Median age at kidney failure, median age at death, time from start of dialysis to death, time from diagnosis to eGFR thresholds, and therapeutic trial window all varied substantially between rare diseases.Patients with rare kidney diseases differ from the general population of individuals with chronic kidney disease: they have higher 5-year rates of kidney failure but higher survival than other patients with chronic kidney disease stages 3-5, and so are ...

العلاقة: 2381/25499611.v1; https://figshare.com/articles/journal_contribution/Effects_of_rare_kidney_diseases_on_kidney_failure_a_longitudinal_analysis_of_the_UK_National_Registry_of_Rare_Kidney_Diseases_RaDaR_cohort/25499611Test

الإتاحة: https://figshare.com/articles/journal_contribution/Effects_of_rare_kidney_diseases_on_kidney_failure_a_longitudinal_analysis_of_the_UK_National_Registry_of_Rare_Kidney_Diseases_RaDaR_cohort/25499611Test

المؤلفون: Debbie S. Gipson, Chia-shi Wang, Eloise Salmon, Rasheed Gbadegesin, Abhijit Naik, Simone Sanna-Cherchi, Alessia Fornoni, Matthias Kretzler, Sandra Merscher, Paul Hoover, Kelley Kidwell, Moin Saleem, Leonardo Riella, Lawrence Holzman, Annette Jackson, Opeyemi Olabisi, Paolo Cravedi, Benjamin Solomon Freedman, Jonathan Himmelfarb, Marina Vivarelli, Jennifer Harder, Jon Klein, George Burke, Michelle Rheault, Cathie Spino, Hailey E. Desmond, Howard Trachtman

المصدر: Glomerular Diseases, Pp 1-1 (2023)

مصطلحات موضوعية: Diseases of the endocrine glands. Clinical endocrinology, RC648-665

الوصف: Since it was first described more than 50 years ago, recurrence of FSGS in kidney allografts has frustrated the transplant community. This rare condition is associated with considerable morbidity, and it is the most common cause of graft loss in patients with CKD stage 5 due to FSGS. However, the problem remains insufficiently studied. It is an ultra-orphan disease and incidence rates at individual centers are often very low and unpredictable. The published literature contains conflicting reports in basic epidemiologic data. Progress in defining the mechanisms of disease and advancing therapeutic options has been limited. The treatment options that are currently available are limited and largely ineffective. The range in time to recurrence and variability in responsiveness to treatment suggest that recurrence is not a single entity, but rather multiple phenotypes resulting from diverse pathogenetic mechanisms grouped under a larger umbrella. There is an urgent need for innovative basic science and translational research to [1] better understand FSGS recurrence from a mechanistic perspective; [2] improve risk stratification to predict this outcome; and [3] develop effective therapies. In this conference report, we describe the work of investigators whose state-of-the-art research paves the way for innovative approaches to diagnosis and treatment of the problem and provides hope that we can achieve these objectives for affected patients.

وصف الملف: electronic resource

العلاقة: https://beta.karger.com/Article/FullText/535138Test; https://doaj.org/toc/2673-3633Test

الوصول الحر: https://doaj.org/article/9bd7d704a73d447f997a7ecb9b5f8d94Test

المؤلفون: Leticia Cuarental, Lara Valiño-Rivas, Luis Mendonça, Moin Saleem, Sergio Mezzano, Ana Belen Sanz, Alberto Ortiz, Maria Dolores Sanchez-Niño

المصدر: Journal of Clinical Medicine; Volume 9; Issue 7; Pages: 2178

مصطلحات موضوعية: podocyte, nephrotic syndrome, membranous nephropathy, Fn14, TWEAK, tacrolimus, PLA2R

الوصف: Primary membranous nephropathy is usually caused by antibodies against the podocyte antigen membrane M-type phospholipase A2 receptor (PLA2R). The treatment of membranous nephropathy is not fully satisfactory. The calcineurin inhibitor tacrolimus is used to treat membranous nephropathy, but recurrence upon drug withdrawal is common. TNF superfamily members are key mediators of kidney injury. We have now identified key TNF receptor superfamily members in podocytes and explored the regulation of PLA2R expression and the impact of tacrolimus. Data mining of single cell transcriptomics and glomerular transcriptomics data identified TNFRSF12a/Fn14 as the highest expressed TNF receptor superfamily gene in human membranous nephropathy, and this was confirmed by immunohistochemistry that also identified NFκB activation in membranous nephropathy podocytes. Additionally, glomerular transcriptomics identified PLA2R1 expression as being increased in membranous nephropathy in the parenteral administration of the Fn14 ligand TWEAK increased podocyte PLA2R expression in mice. Furthermore, in cultured human podocytes, TWEAK increased the expression of PLA2R as well as the expression of other genes recently identified by GWAS as linked to membranous nephropathy: NFKB1 and IRF4. Interestingly, IRF4 encodes the FK506-binding protein 52 (FKBP52), a protein associated with tacrolimus. Tacrolimus prevented the increased expression of PLA2R, NFKB1 and IRF4 induced by TWEAK in cultured podocytes. In conclusion, TWEAK upregulates the expression of PLA2R and of other genes linked to membranous nephropathy in podocytes, and this is prevented by tacrolimus. An impact of tacrolimus on the expression of PLA2R and other genes in podocytes may underlie its efficacy in treating the disease as well as the frequent recurrence of nephrotic syndrome upon tacrolimus withdrawal.

وصف الملف: application/pdf

العلاقة: Nephrology & Urology; https://dx.doi.org/10.3390/jcm9072178Test

الإتاحة: https://doi.org/10.3390/jcm9072178Test

المؤلفون: Kushani Jayasinghe, Cathy Quinlan, Zornitza Stark, Chirag Patel, Matthew G. Sampson, Moin Saleem, Andrew J. Mallett, on behalf of the KidGen Collaborative

المصدر: Human Genomics, Vol 12, Iss 1, Pp 1-6 (2018)

مصطلحات موضوعية: Inherited kidney disease, Nephrogenetics, Renal genetics, Medicine, Genetics, QH426-470

الوصف: Abstract The 2017 KidGen Renal Genetics Symposium was held at the Royal Children’s Hospital and Murdoch Children’s Research Institute, Melbourne, from 6 to 8 December 2017. This meeting addressed clinical, diagnostic, and research aspects of inherited kidney disease. More than 100 clinicians, researchers, and patient representatives attended the conference. The overall goal was to improve the understanding and direction of genomics in renal medicine in Australia and discuss barriers to the use of genomic testing within this area. It also aimed to strengthen collaborations between local, state, and global research and diagnostic and clinical groups.

وصف الملف: electronic resource

العلاقة: http://link.springer.com/article/10.1186/s40246-018-0137-7Test; https://doaj.org/toc/1479-7364Test

الوصول الحر: https://doaj.org/article/d2c1d2e666b04a488ca3a4c56d921f2dTest

المؤلفون: Irena Audzeyenka, Patrycja Rachubik, Marlena Typiak, Tomasz Kulesza, Daria Kalkowska, Dorota Rogacka, Michał Rychłowski, Stefan Angielski, Moin Saleem, Agnieszka Piwkowska

المصدر: Journal of Molecular Medicine. 100:903-915

مصطلحات موضوعية: Podocytes, PTEN Phosphohydrolase, Permeability, Glucose, Albumins, Hyperglycemia, Drug Discovery, Humans, Insulin, Molecular Medicine, Diabetic Nephropathies, Protein Kinases, Genetics (clinical), Signal Transduction

الوصف: Alterations of insulin signaling in diabetes are associated with podocyte injury, proteinuria, and renal failure. Insulin stimulates glucose transport to cells and regulates other intracellular processes that are linked to cellular bioenergetics, such as autophagy, gluconeogenesis, fatty acid metabolism, and mitochondrial homeostasis. The dysfunction of mitochondrial dynamics, including mitochondrial fusion, fission, and mitophagy, has been observed in high glucose-treated podocytes and renal cells from patients with diabetes. Previous studies showed that prolonged hyperglycemia is associated with the development of insulin resistance in podocytes, and high glucose-treated podocytes exhibit an increase in mitochondrial fission and decrease in markers of mitophagy. In the present study, we found that deficiency of the main mitophagy protein PTEN-induced kinase 1 (PINK1) significantly increased albumin permeability and hampered glucose uptake to podocytes. We suggest that PINK1 inhibition impairs the insulin signaling pathway, in which lower levels of phosphorylated Akt and membrane fractions of the insulin receptor and glucose transporter-4 were observed. Moreover, PINK1-depleted podocytes exhibited lower podocin and nephrin expression, thus identifying a potential mechanism whereby albumin leakage increases under hyperglycemic conditions when mitophagy is inhibited. In conclusion, we found that PINK1 plays an essential role in insulin signaling and the maintenance of proper permeability in podocytes. Therefore, PINK1 may be a potential therapeutic target for the treatment or prevention of diabetic nephropathy.

الوصول الحر: https://explore.openaire.eu/search/publication?articleId=doi_dedup___::84521cc634c02cbb4a3b76337aa43f0aTest
https://doi.org/10.1007/s00109-022-02204-4Test

المؤلفون: Howard Trachtman, Rosanna Coppo, Moin Saleem, Alex Mercer, Radko Komers

المصدر: Journal of Nephrology.

مصطلحات موضوعية: Nephrology

الوصول الحر: https://explore.openaire.eu/search/publication?articleId=doi_dedup___::3d1b0cc362e4efe93fdd9878b40c4923Test
https://doi.org/10.1007/s40620-022-01542-3Test

المؤلفون: Howard Trachtman, Moin Saleem, Rosanna Coppo, Michelle Rheault, Ping He, Radko Komers

المصدر: British Association for Community Child Health.

الوصول الحر: https://explore.openaire.eu/search/publication?articleId=doi_________::a7c3013738c283bae4b58e0ed1c231c6Test
https://doi.org/10.1136/archdischild-2022-rcpch.157Test

المؤلفون: Agnieszka Bierzynska, Moin Saleem

المصدر: F1000Research, Vol 6 (2017)

مصطلحات موضوعية: Dialysis & Renal Transplantation, Immunopharmacology & Hematologic Pharmacology, Renal Immunology & Pathology (incl. Glomerular Diseases), Renal Pharmacology, Medicine, Science

الوصف: Idiopathic nephrotic syndrome (INS) is one of the most common glomerular diseases in children and adults, and the central event is podocyte injury. INS is a heterogeneous disease, and treatment is largely empirical and in many cases unsuccessful, and steroids are the initial mainstay of therapy. Close to 70% of children with INS have some response to steroids and are labelled as steroid-‘sensitive’, and the rest as steroid-‘resistant’ (also termed focal segmental glomerulosclerosis), and single-gene mutations underlie a large proportion of the latter group. The burden of morbidity is enormous, both to patients with lifelong chronic disease and to health services, particularly in managing dialysis and transplantation. The target cell of nephrotic syndrome is the glomerular podocyte, and podocyte biology research has exploded over the last 15 years. Major advances in genetic and biological understanding now put clinicians and researchers at the threshold of a major reclassification of the disease and testing of targeted therapies both identified and novel. That potential is based on complete genetic analysis, deep clinical phenotyping, and the introduction of mechanism-derived biomarkers into clinical practice. INS can now be split off into those with a single-gene defect, of which currently at least 53 genes are known to be causative, and the others. Of the others, the majority are likely to be immune-mediated and caused by the presence of a still-unknown circulating factor or factors, and whether there is a third (or more) mechanistic group or groups remains to be discovered. Treatment is therefore now being refined towards separating out the monogenic cases to minimise immunosuppression and further understanding how best to stratify and appropriately direct immunosuppressive treatments within the immune group. Therapies directed specifically towards the target cell, the podocyte, are in their infancy but hold considerable promise for the near future.

وصف الملف: electronic resource

العلاقة: https://f1000research.com/articles/6-121/v1Test; https://doaj.org/toc/2046-1402Test

الوصول الحر: https://doaj.org/article/4ec95e38239d40488bb128bb0d8b6d38Test

المؤلفون: Musleeha Chesor, Jack Tuffin, Carl May, Irene Ghobrial, Melissa Little, Gavin Welsh, Moin Saleem

الوصف: Recurrence of steroid-resistant nephrotic syndrome (SRNS) is thought to be due to an unknown “circulating factor”, the identity of which has so far remained elusive. Our previous work suggests a signaling role for protease-activated receptor-1 (PAR-1), leading to impaired podocyte function. Here, we show that relapse nephrotic plasma (NP), but not paired remission plasma, induced a pro-fibrotic response. This change was inhibited by PAR-1 inhibitors, but not by TGF-β1 inhibition. Four PAR-1 inhibitors demonstrated distinct antagonistic properties. The phosphorylation of VASP and JNK in a 3D spheroid model (GlomSpheres) and kidney organoids corroborated the finding from a 2D ciPods model. Functionally, relapse NP induced podocyte motility, and podocyte loss from spheroids both of which were also selectively rescued by PAR-1 inhibitors. Also, it induced the loss of podocyte-specific markers in kidney organoids. We propose that the circulating factor acts as a pro-fibrotic effector by activating PAR-1, leading to increased podocyte injury.

الوصول الحر: https://explore.openaire.eu/search/publication?articleId=doi_________::bec5cbf9af712e73c86c9a71a2b74f9bTest
https://doi.org/10.21203/rs.3.rs-1226619/v1Test

المؤلفون: Brandon M, Lane, Susan, Murray, Katherine, Benson, Agnieszka, Bierzynska, Megan, Chryst-Stangl, Liming, Wang, Guanghong, Wu, Gianpiero, Cavalleri, Brendan, Doyle, Neil, Fennelly, Anthony, Dorman, Shane, Conlon, Virginia, Vega-Warner, Damian, Fermin, Poornima, Vijayan, Mohammad Azfar, Qureshi, Shirlee, Shril, Moumita, Barua, Friedhelm, Hildebrandt, Martin, Pollak, David, Howell, Matthew G, Sampson, Moin, Saleem, Peter J, Conlon, Robert, Spurney, Rasheed, Gbadegesin

المصدر: J Am Soc Nephrol

مصطلحات موضوعية: Basic Research

الوصف: BACKGROUND: Podocyte dysfunction is the main pathologic mechanism driving the development of FSGS and other morphologic types of steroid-resistant nephrotic syndrome (SRNS). Despite significant progress, the genetic causes of most cases of SRNS have yet to be identified. METHODS: Whole-genome sequencing was performed on 320 individuals from 201 families with familial and sporadic NS/FSGS with no pathogenic mutations in any known NS/FSGS genes. RESULTS: Two variants in the gene encoding regulator of calcineurin type 1 (RCAN1) segregate with disease in two families with autosomal dominant FSGS/SRNS. In vitro, loss of RCAN1 reduced human podocyte viability due to increased calcineurin activity. Cells expressing mutant RCAN1 displayed increased calcineurin activity and NFAT activation that resulted in increased susceptibility to apoptosis compared with wild-type RCAN1. Treatment with GSK-3 inhibitors ameliorated this elevated calcineurin activity, suggesting the mutation alters the balance of RCAN1 regulation by GSK-3β, resulting in dysregulated calcineurin activity and apoptosis. CONCLUSIONS: These data suggest mutations in RCAN1 can cause autosomal dominant FSGS. Despite the widespread use of calcineurin inhibitors in the treatment of NS, genetic mutations in a direct regulator of calcineurin have not been implicated in the etiology of NS/FSGS before this report. The findings highlight the therapeutic potential of targeting RCAN1 regulatory molecules, such as GSK-3β, in the treatment of FSGS.

الوصول الحر: https://explore.openaire.eu/search/publication?articleId=pmid________::1d95e7504da5a59402f4476a3474174dTest
https://pubmed.ncbi.nlm.nih.gov/33863784Test