@article{acdda95570044f8299eb6bdc85c004f9,
title = "Long-term outcomes and response to treatment in diacylglycerol kinase epsilon nephropathy",
abstract = "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 In four individuals eculizumab was withdrawn, with one spontaneously resolving aHUS relapse occurring.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aHUS is eculizumab non-responsive and that in individuals who currently receive eculizumab therapy it can be safely withdrawn.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.",
keywords = "atypical hemolytic uremic syndrome, diacylglycerol kinase ε, membranoproliferative glomerulonephritis, thrombotic microangiopathy",
author = "Vicky Brocklebank and Gurinder Kumar and Howie, {Alexander J.} and Jayanthi Chandar and Milford, {David V.} and Janet Craze and Jonathan Evans and Eric Finlay and Michael Freundlich and Gale, {Daniel P.} and Carol Inward and Martin Mraz and Caroline Jones and William Wong and Marks, {Stephen D.} and John Connolly and Corner, {Bronte M.} and Kate Smith-Jackson and Walsh, {Patrick R.} and Marchbank, {Kevin J.} and Harris, {Claire L.} and Valerie Wilson and Wong, {Edwin K.S.} and Michal Malina and Sally Johnson and Sheerin, {Neil S.} and David Kavanagh",
note = "Funding Information: The research was supported/funded by the National Institute for Health Research Newcastle Biomedical Research Centre at Great Ormond Street Hospital for Children NHS Foundation Trust and University College London (SDM) and Newcastle upon Tyne Hospitals NHS Foundation Trust. VB has received funding from the Northern Counties Kidney Research Fund and is a Medical Research Council/Kidney Research UK Clinical Research Training Fellow (MR/R000913/1). PRW was funded by the Wellcome Trust: 4Ward North Academy (RES/0248/7836). KS-J is a Medical Research Council Clinical Research Training Fellow (MR/R001359/1). KJM was also funded by the Northern Counties Kidney Research Fund, the Newcastle Healthcare Charities, and a Kidney Research UK project grant (RP7/2015). EKSW has received funding from the Medical Research Council . DK was funded by the Wellcome Trust, the Medical Research Council, Kidney Research UK, European Union Seventh Framework Programme (EURenOmics) (FP7/2007-2013; grant number 305608 ), and the European Reference Network for Rare Kidney Diseases (ERKNet) (project ID 739532). Funding Information: The research was supported/funded by the National Institute for Health Research Newcastle Biomedical Research Centre at Great Ormond Street Hospital for Children NHS Foundation Trust and University College London (SDM) and Newcastle upon Tyne Hospitals NHS Foundation Trust. VB has received funding from the Northern Counties Kidney Research Fund and is a Medical Research Council/Kidney Research UK Clinical Research Training Fellow (MR/R000913/1). PRW was funded by the Wellcome Trust: 4Ward North Academy (RES/0248/7836). KS-J is a Medical Research Council Clinical Research Training Fellow (MR/R001359/1). KJM was also funded by the Northern Counties Kidney Research Fund, the Newcastle Healthcare Charities, and a Kidney Research UK project grant (RP7/2015). EKSW has received funding from the Medical Research Council. DK was funded by the Wellcome Trust, the Medical Research Council, Kidney Research UK, European Union Seventh Framework Programme (EURenOmics) (FP7/2007-2013; grant number 305608), and the European Reference Network for Rare Kidney Diseases (ERKNet) (project ID 739532). Publisher Copyright: {\textcopyright} 2020 International Society of Nephrology",
year = "2020",
month = jun,
doi = "10.1016/j.kint.2020.01.045",
language = "English (US)",
volume = "97",
pages = "1260--1274",
journal = "Kidney International",
issn = "0085-2538",
publisher = "Nature Publishing Group",
number = "6",
}