Charles T. Quinn, MD
Dr. Quinn indicated no relevant conflicts of interest.
Lemaire M, Frémeaux-Bacchi V, Schaefer F, et al. Recessive mutations in DGKE cause atypical hemolytic–uremic
syndrome. Nat Genet. 2013;45:531-536.
Thrombotic microangiopathy (TMA) is the term for a histopathologic lesion of small vessels (arterioles and capillaries) characterized by swelling and detachment of the endothelium, subendothelial accumulation of protein and cellular debris, and obstruction of vessel lumina by fibrin and platelet-rich thrombi. The term TMA is also used for the growing list of rare and once conflated conditions that share the TMA lesion. The clinical phenotype of TMAs includes microangiopathic hemolytic anemia, thrombocytopenia, and ischemia and injury of organs (especially the kidney and the brain). The three “major” TMAs are thrombotic thrombocytopenic purpura (TTP), hemolytic–uremic syndrome caused by Shiga toxin (verocytotoxin) producing Escherichia coli (STEC-HUS), and atypical hemolytic–uremic syndrome (aHUS). TTP can be differentiated from HUS in most cases by a severe reduction in ADAMTS13 activity in the former condition. The terminology is evolving, but aHUS now usually refers to HUS that is not STEC-HUS and not a secondary form of aHUS, such as S. pneumonia-related HUS. The discovery that disordered regulation and abnormal activation of the alternative complement pathway, both genetic and autoimmune, as a cause of aHUS has led to remarkable progress in diagnosis and therapy. Eculizumab, a humanized monoclonal antibody that binds to complement protein C5 and blocks the formation of the membrane attack complex, is an effective life- and kidney-sparing therapy for many patients with aHUS. Given the recent advances in the understanding of the role of the alternative pathway of complement in aHUS, some now use the term aHUS to be synonymous with complement-mediated HUS (complement-HUS).
Just when we thought that the pathophysiology and terminology were becoming clear, Lemaire and colleagues remind us that there is still much to learn. They used exome sequencing to study two unrelated families affected by aHUS who had no pathogenic mutations in known aHUS genes (complement factors and regulators) or auto-antibodies to complement factor H. The affected individuals had aHUS of very early onset (between 4 and 8 months of age), evidenced by microangiopathic hemolytic anemia, thrombocytopenia, acute renal failure, and renal biopsies showing TMA. Lemaire and colleagues discovered homozygous or compound heterozygous variants in DGKE, which encodes diacylglycerol kinase ε, in all affected patients, but not in their relatives (who had no variant or were only heterozygous for one of the variants). The investigators then sequenced DGKE in 83 additional unrelated individuals with aHUS in whom there was no mutation in known aHUS-associated genes or complement factor H antibodies and identified six with homozygous or compound heterozygous DGKE variants. These findings and confirmatory genetic and protein studies allowed the authors to conclude that recessive, loss-of-function mutations in DGKE are a cause of aHUS.
The phenotype of these patients was unique. All presented with aHUS before age 1; had persistent hypertension, hematuria, and proteinuria (sometimes in the nephrotic range) between acute episodes; and developed chronic kidney disease with age. Moreover, no patient had any significant abnormality in the complement system, and two had relapses of aHUS while on anti-complement therapy. Renal transplantation was effective and appeared to prevent relapses of aHUS.
DGKE is the second gene, in addition to thrombomodulin (THBD), implicated in aHUS that is not a canonical component of the complement cascade, so how might it cause aHUS? The investigators infer that loss of DGKE function results in a prothrombotic state. DKGE is an intracellular enzyme that blocks diacylglycerol (DAG) signaling. Arachidonic acid-containing DAGs promote thrombosis by activation of protein kinase C. DGKE is found in endothelium, platelets, and podocytes (which, to remind the hematologist, surround glomerular capillaries), and this expression pattern accords nicely with the triad of microangiopathic hemolytic anemia, thrombocytopenia, and renal injury in aHUS. Mutations in THBD have also been implicated in aHUS. While some experimental data suggest that thrombomodulin has an ancillary role in regulation of the alternative pathway of complement,1 this interpretation has been questioned.2 The current finding of another protein involved in hemostasis (DGKE) argues that mutations in thrombomodulin may induce aHUS as a consequence of aberrant regulation of coagulation rather than as a result of dysregulation of the alternative pathway of complement. There is no evidence linking DGKE to regulation of the complement cascade.
Taking into account the above caveat concerning thrombomodulin, abnormal activation of the alternative pathway of complement is a feature of all previously described, specific causes of primary aHUS, but patients with DKGE-related aHUS have no evidence of complement dysregulation. This form of aHUS may be a primarily pro-thrombotic condition that disproportionately affects the glomerular vasculature. Currently, many advocate that all patients with aHUS be treated with the anti-complement agent, eculizumab. However, anti-complement therapy does not appear to be useful in aHUS caused by DGKE mutations. Renal transplantation does seem to be effective, at least in the small number of patients studied, and there were no post-transplant relapses of aHUS. In contrast, post-transplantation relapses are common in patients with aHUS caused by defective, soluble-phase complement regulatory factors, although renal transplantation is usually effective for aHUS caused by mutant membrane cofactor protein, CD46, a complement regulatory protein expressed on the cell surface. Given that nearly half of patients with primary aHUS currently have no identifiable cause3 and 30 percent have no identifiable complement abnormalities,4 much clearly remains to be learned, and complement may not always be the culprit.
1. Delvaeye M, Noris M, De Vriese A, et al. Thrombomodulin mutations in atypical hemolytic–uremic syndrome. N Engl J Med. 2009;361:345-357.
2. Parker C. Atypical – I’ll Say! The Hematologist. 2009;6:8.
3. Noris M and Remuzzi G. Atypical hemolytic–uremic syndrome. N Engl J Med. 2009;361:1676-1687.
4. Loirat C and Frémeaux-Bacchi V. Atypical hemolytic–uremic syndrome. Orphanet J Rare Dis. 2011;6:60.
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