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Long-term outcomes and response to treatment in diacylglycerol kinase epsilon nephropathy

Recessive mutations in diacylglycerol kinase epsilon (DGKE) display genetic pleiotropy, with pathological features reported as either thrombotic microangiopathy or membranoproliferative glomerulonephritis (MPGN), and clinical features of atypical hemolytic uremic syndrome (aHUS), nephrotic syndrome...

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Autores principales: Brocklebank, Vicky, Kumar, Gurinder, Howie, Alexander J., Chandar, Jayanthi, Milford, David V., Craze, Janet, Evans, Jonathan, Finlay, Eric, Freundlich, Michael, Gale, Daniel P., Inward, Carol, Mraz, Martin, Jones, Caroline, Wong, William, Marks, Stephen D., Connolly, John, Corner, Bronte M., Smith-Jackson, Kate, Walsh, Patrick R., Marchbank, Kevin J., Harris, Claire L., Wilson, Valerie, Wong, Edwin K.S., Malina, Michal, Johnson, Sally, Sheerin, Neil S., Kavanagh, David
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Elsevier 2020
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7242908/
https://www.ncbi.nlm.nih.gov/pubmed/32386968
http://dx.doi.org/10.1016/j.kint.2020.01.045
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author Brocklebank, Vicky
Kumar, Gurinder
Howie, Alexander J.
Chandar, Jayanthi
Milford, David V.
Craze, Janet
Evans, Jonathan
Finlay, Eric
Freundlich, Michael
Gale, Daniel P.
Inward, Carol
Mraz, Martin
Jones, Caroline
Wong, William
Marks, Stephen D.
Connolly, John
Corner, Bronte M.
Smith-Jackson, Kate
Walsh, Patrick R.
Marchbank, Kevin J.
Harris, Claire L.
Wilson, Valerie
Wong, Edwin K.S.
Malina, Michal
Johnson, Sally
Sheerin, Neil S.
Kavanagh, David
author_facet Brocklebank, Vicky
Kumar, Gurinder
Howie, Alexander J.
Chandar, Jayanthi
Milford, David V.
Craze, Janet
Evans, Jonathan
Finlay, Eric
Freundlich, Michael
Gale, Daniel P.
Inward, Carol
Mraz, Martin
Jones, Caroline
Wong, William
Marks, Stephen D.
Connolly, John
Corner, Bronte M.
Smith-Jackson, Kate
Walsh, Patrick R.
Marchbank, Kevin J.
Harris, Claire L.
Wilson, Valerie
Wong, Edwin K.S.
Malina, Michal
Johnson, Sally
Sheerin, Neil S.
Kavanagh, David
author_sort Brocklebank, Vicky
collection PubMed
description Recessive mutations in diacylglycerol kinase epsilon (DGKE) display genetic pleiotropy, with pathological features reported as either thrombotic microangiopathy or membranoproliferative glomerulonephritis (MPGN), and clinical features of atypical hemolytic uremic syndrome (aHUS), nephrotic syndrome or both. Pathophysiological mechanisms and optimal management strategies have not yet been defined. In prospective and retrospective studies of aHUS referred to the United Kingdom National aHUS service and prospective studies of MPGN referred to the National Registry of Rare Kidney Diseases for MPGN we defined the incidence of DGKE aHUS as 0.009/million/year and so-called DGKE MPGN as 0.006/million/year, giving a combined incidence of 0.015/million/year. Here, we describe a cohort of sixteen individuals with DGKE nephropathy. One presented with isolated nephrotic syndrome. Analysis of pathological features reveals that DGKE mutations give an MPGN-like appearance to different extents, with but more often without changes in arterioles or arteries. In 15 patients presenting with aHUS, ten had concurrent substantial proteinuria. Identified triggering events were rare but coexistent developmental disorders were seen in six. Nine with aHUS experienced at least one relapse, although in only one did a relapse of aHUS occur after age five years. Persistent proteinuria was seen in the majority of cases. Only two individuals have reached end stage renal disease, 20 years after the initial presentation, and in one, renal transplantation was successfully undertaken without relapse. Six individuals received eculizumab. Relapses on treatment occurred in one individual. In four individuals eculizumab was withdrawn, with one spontaneously resolving aHUS relapse occurring. Thus we suggest that DGKE-mediated aHUS is eculizumab non-responsive and that in individuals who currently receive eculizumab therapy it can be safely withdrawn. This has important patient safety and economic implications.
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spelling pubmed-72429082020-06-01 Long-term outcomes and response to treatment in diacylglycerol kinase epsilon nephropathy Brocklebank, Vicky Kumar, Gurinder Howie, Alexander J. Chandar, Jayanthi Milford, David V. Craze, Janet Evans, Jonathan Finlay, Eric Freundlich, Michael Gale, Daniel P. Inward, Carol Mraz, Martin Jones, Caroline Wong, William Marks, Stephen D. Connolly, John Corner, Bronte M. Smith-Jackson, Kate Walsh, Patrick R. Marchbank, Kevin J. Harris, Claire L. Wilson, Valerie Wong, Edwin K.S. Malina, Michal Johnson, Sally Sheerin, Neil S. Kavanagh, David Kidney Int Article Recessive mutations in diacylglycerol kinase epsilon (DGKE) display genetic pleiotropy, with pathological features reported as either thrombotic microangiopathy or membranoproliferative glomerulonephritis (MPGN), and clinical features of atypical hemolytic uremic syndrome (aHUS), nephrotic syndrome or both. Pathophysiological mechanisms and optimal management strategies have not yet been defined. In prospective and retrospective studies of aHUS referred to the United Kingdom National aHUS service and prospective studies of MPGN referred to the National Registry of Rare Kidney Diseases for MPGN we defined the incidence of DGKE aHUS as 0.009/million/year and so-called DGKE MPGN as 0.006/million/year, giving a combined incidence of 0.015/million/year. Here, we describe a cohort of sixteen individuals with DGKE nephropathy. One presented with isolated nephrotic syndrome. Analysis of pathological features reveals that DGKE mutations give an MPGN-like appearance to different extents, with but more often without changes in arterioles or arteries. In 15 patients presenting with aHUS, ten had concurrent substantial proteinuria. Identified triggering events were rare but coexistent developmental disorders were seen in six. Nine with aHUS experienced at least one relapse, although in only one did a relapse of aHUS occur after age five years. Persistent proteinuria was seen in the majority of cases. Only two individuals have reached end stage renal disease, 20 years after the initial presentation, and in one, renal transplantation was successfully undertaken without relapse. Six individuals received eculizumab. Relapses on treatment occurred in one individual. In four individuals eculizumab was withdrawn, with one spontaneously resolving aHUS relapse occurring. Thus we suggest that DGKE-mediated aHUS is eculizumab non-responsive and that in individuals who currently receive eculizumab therapy it can be safely withdrawn. This has important patient safety and economic implications. Elsevier 2020-06 /pmc/articles/PMC7242908/ /pubmed/32386968 http://dx.doi.org/10.1016/j.kint.2020.01.045 Text en © 2020 International Society of Nephrology. Published by Elsevier Inc. http://creativecommons.org/licenses/by/4.0/ This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/).
spellingShingle Article
Brocklebank, Vicky
Kumar, Gurinder
Howie, Alexander J.
Chandar, Jayanthi
Milford, David V.
Craze, Janet
Evans, Jonathan
Finlay, Eric
Freundlich, Michael
Gale, Daniel P.
Inward, Carol
Mraz, Martin
Jones, Caroline
Wong, William
Marks, Stephen D.
Connolly, John
Corner, Bronte M.
Smith-Jackson, Kate
Walsh, Patrick R.
Marchbank, Kevin J.
Harris, Claire L.
Wilson, Valerie
Wong, Edwin K.S.
Malina, Michal
Johnson, Sally
Sheerin, Neil S.
Kavanagh, David
Long-term outcomes and response to treatment in diacylglycerol kinase epsilon nephropathy
title Long-term outcomes and response to treatment in diacylglycerol kinase epsilon nephropathy
title_full Long-term outcomes and response to treatment in diacylglycerol kinase epsilon nephropathy
title_fullStr Long-term outcomes and response to treatment in diacylglycerol kinase epsilon nephropathy
title_full_unstemmed Long-term outcomes and response to treatment in diacylglycerol kinase epsilon nephropathy
title_short Long-term outcomes and response to treatment in diacylglycerol kinase epsilon nephropathy
title_sort long-term outcomes and response to treatment in diacylglycerol kinase epsilon nephropathy
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7242908/
https://www.ncbi.nlm.nih.gov/pubmed/32386968
http://dx.doi.org/10.1016/j.kint.2020.01.045
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