PhD Candidate The Hospital for Sick Children Vaughan, Ontario, Canada
Background: Atypical hemolytic uremic syndrome (aHUS) is a rare form of thrombotic microangiopathy (TMA) that affects the kidneys. Patients with hyperactivation of the alternative complement pathway, the most common cause of aHUS, are effectively treated with the complement inhibitor Eculizumab. Recessive variants in diacylglycerol kinase epsilon (DGKE) cause complement-independent aHUS. DGKE-aHUS presents in infancy, with recurrent TMA events triggered by infections until age 5. Most patients develop end-stage kidney disease before adulthood. While there is no clear treatment for these patients, retrospective analyses suggest plasma infusion and/or exchange may be effective. The benefits of plasma-based therapies have not been investigated prospectively. Objective: Determine the effectiveness of early administration of plasma-based therapies in reducing acute and chronic kidney pathology in a patient diagnosed with DGKE-aHUS in utero. Design/Methods: Using exome sequencing, we diagnosed a 12-month old female with DGKE-aHUS (homozygous, c.A494G;p.D165G). On that basis, her younger sister was diagnosed antenatally. This unique scenario allowed us to prescribe plasma-based therapy within 24 hours of proteinuria emergence monitored regularly by the parents using dipsticks. Plasma exchange would be used if no improvements were noted with infusions. Results: The older sibling experienced 3 severe TMA episodes which were managed with blood cell transfusions, Eculizumab, plasma infusions, and hemodialysis. At age 10, she exhibits persistent proteinuria. In contrast, early diagnosis via dipstick revealed the younger sibling has experienced 6 distinct TMA episodes. Resolution of renal pathology was observed upon administration of daily plasma infusions. Now age 3, all her kidney parameters remain normal during remission periods. To determine the physiologic impact of the missense variant, transcripts of patient-derived endothelial cells were analyzed. Finding unusually low expression of full-length mRNA transcripts by PCR, we further observed that the exonic c.A494G mutation generates a strong cryptic splice donor leading to production of a truncated DGKE protein.
Conclusion(s): Our data strongly suggest that plasma infusions may be effective as a first-line treatment for DGKE-aHUS. It is unclear if the same benefits would accrue for patients diagnosed after a first severe TMA episode. The inclusion of DGKE testing in newborn screening panels could maximize benefits via early diagnosis. Establishing the mechanism by which plasma infusions abrogate kidney damage in DGKE-aHUS can inform development of innovative therapies.
