Journal
KIDNEY INTERNATIONAL
Volume 97, Issue 6, Pages 1260-1274Publisher
ELSEVIER SCIENCE INC
DOI: 10.1016/j.kint.2020.01.045
Keywords
atypical hemolytic uremic syndrome; diacylglycerol kinase epsilon; membranoproliferative glomerulonephritis; thrombotic microangiopathy
Categories
Funding
- National Institute for Health Research Newcastle Biomedical Research Centre at Great Ormond Street Hospital for Children NHS Foundation Trust
- University College London
- Newcastle upon Tyne Hospitals NHS Foundation Trust
- Northern Counties Kidney Research Fund
- Medical Research Council/Kidney Research UK [MR/R000913/1]
- Wellcome Trust: 4Ward North Academy [RES/0248/7836]
- Medical Research Council [MR/R001359/1]
- Newcastle Healthcare Charities
- Kidney Research UK [RP7/2015]
- Medical Research Council
- Wellcome Trust
- Kidney Research UK
- European Union [305608]
- European Reference Network for Rare Kidney Diseases (ERKNet) [739532]
- MRC [MR/R000913/1, MR/R001359/1, MR/K023519/1] Funding Source: UKRI
- Kidney Research UK [RP7/2015] Funding Source: researchfish
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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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