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Lookup NU author(s): Dr Vicky Brocklebank, Dr Kate Smith-Jackson, Dr Patrick Walsh, Professor Kevin MarchbankORCiD, Professor Claire Harris, Dr Valerie Wilson, Dr Edwin Wong, Dr Michal Malina, Dr Sally Johnson, Professor Neil SheerinORCiD, Professor David KavanaghORCiD
This work is licensed under a Creative Commons Attribution 4.0 International License (CC BY 4.0).
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 haemolytic uraemic syndrome (aHUS), nephrotic syndrome or both. The pathophysiological mechanisms and optimal management strategies have not yet been defined. In prospective and retrospective studies of aHUS referred to the UK national aHUS service and prospective studies of MPGN referred to the UK National Registry of Rare Kidney Diseases (RaDaR) for MPGN we defined the incidence of DGKE aHUS as 0.009 per million per year and so-called DGKE MPGN as 0.006 per million per year, giving a combined incidence of 0.015 per million per year for DGKE nephropathy.We describe a cohort of sixteen individuals with DGKE nephropathy. One presented with isolated nephrotic syndrome. Analysis of pathological features reveals thatDGKE mutations give an MPGN-like appearance to different extents, with or more often without changes in arterioles or arteries. In 15 patients presenting with aHUS, 10 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 In four individuals eculizumab was withdrawn, with one spontaneously resolving aHUS relapse occurring. Based on our experience 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aHUS is eculizumab non-responsive and that in individuals who currently receive eculizumab therapy it can be safely withdrawn.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.
Author(s): Brocklebank V, Kumar G, Howie AJ, Chandar J, Milford DV, Craze J, Evans J, Finlay E, Freundlich M, Gale DP, Inward C, Mraz M, Jones C, Wong W, Marks SD, Connolly J, Corner BM, Smith-Jackson K, Walsh PR, Marchbank KJ, Harris C, Wilson V, Wong EKS, Malina M, Johnson S, Sheerin NS, Kavanagh D
Publication type: Article
Publication status: Published
Journal: Kidney International
Year: 2020
Volume: 97
Issue: 6
Pages: 1260-1274
Print publication date: 01/06/2020
Online publication date: 28/02/2020
Acceptance date: 31/01/2020
Date deposited: 14/05/2020
ISSN (print): 0085-2538
ISSN (electronic): 1523-1755
Publisher: Elsevier
URL: https://doi.org/10.1016/j.kint.2020.01.045
DOI: 10.1016/j.kint.2020.01.045
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