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Long-term outcomes and response to treatment in DGKE nephropathy

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 In four individuals eculizumab was withdrawn, with one spontaneously resolving aHUS relapse occurring.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aHUS is eculizumab non-responsive and that in individuals who currently receive eculizumab therapy it can be safely withdrawn.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.

Publication metadata

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


DOI: 10.1016/j.kint.2020.01.045


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Funder referenceFunder name
European Reference Network for Rare Kidney Diseases (ERKNet)
Medical Research Council
MR/R000913/1Medical Research Council (MRC)
MR/R001359/1Medical Research Council (MRC)
Kidney Research UK
National Institute for Health Research Newcastle Biomedical Research Centre at Great Ormond Street Hospital for Children NHS Foundation Trust
Newcastle Healthcare Charities
Newcastle upon Tyne Hospitals NHS Foundation Trust
Northern Counties Kidney Research Fund
RP7/2015Kidney Research UK (was National Kidney Research Fund)
University College London(SDM)
Wellcome Trust