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 In four individuals eculizumab was withdrawn, with one spontaneously resolving aHUS relapse occurring.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aHUS is eculizumab non-responsive and that in individuals who currently receive eculizumab therapy it can be safely withdrawn.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.
Highlights
I n 2013 recessive mutations in DGKE, which encodes diacylglycerol kinase epsilon (DGKE), were first reported to cause atypical hemolytic uremic syndrome[1] and nephrotic syndrome, with glomerular microangiopathy said to resemble membranoproliferative glomerulonephritis (MPGN)[2] (Online Mendelian Inheritance in Man #615008), though the pathophysiological mechanisms remain poorly understood
AHUS is characterized by a clinical presentation with thrombocytopenia, microangiopathic hemolytic anemia, and organ injury.[3] atypical hemolytic uremic syndrome (aHUS) is a broad term that has been used to refer to cases of thrombotic microangiopathy (TMA), in Kidney International (2020) 97, 1260–1274
Incidence of DGKE-mediated aHUS and MPGN Sixteen individuals (5 boys, 11 girls) with DGKE nephropathy were identified by systematic genetic analysis of 5 cohorts referred to the National Renal Complement Therapeutics Centre (NRCTC, http://www.atypicalhus.co.uk/), Newcastle upon Tyne, UK
Summary
I n 2013 recessive mutations in DGKE, which encodes diacylglycerol kinase epsilon (DGKE), were first reported to cause atypical hemolytic uremic syndrome (aHUS)[1] and nephrotic syndrome, with glomerular microangiopathy said to resemble membranoproliferative (mesangiocapillary) glomerulonephritis (MPGN)[2] (Online Mendelian Inheritance in Man #615008), though the pathophysiological mechanisms remain poorly understood. AHUS is characterized by a clinical presentation with thrombocytopenia, microangiopathic hemolytic anemia, and organ injury.[3] aHUS is a broad term that has been used to refer to cases of thrombotic microangiopathy (TMA), in Kidney International (2020) 97, 1260–1274. Most individuals with aHUS in whom all secondary causes of TMA have been excluded[3] have complement-mediated aHUS—in w50% an inherited or acquired complement abnormality is identified,[4] and others will improve concurrent with complement-inhibiting therapy despite no complement abnormality being detected. MPGN-type lesions, which can manifest in a diverse range of conditions, including aHUS, are characterized by a histopathological pattern recognized by light microscopy, comprising an increase in mesangial cellularity and matrix with thickening of glomerular capillary walls secondary to subendothelial deposition of immune complexes and/or complement factors, cellular entrapment, and new basement membrane formation.
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