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eculizumab was withdrawn, with one spontaneously resolving aHUS relapse occurring.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eculizumab therapy it can be safely withdrawn.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.