Clementine Kinderhospital, Theobald-Christ-Strasse 16, 60316, Frankfurt am Main, Germany.
Bürgerhospital, Frankfurt am Main, Germany.
Pediatr Nephrol. 2022 Nov;37(11):2781-2784. doi: 10.1007/s00467-022-05566-6. Epub 2022 May 6.
Atypical hemolytic uremic syndrome (aHUS) is a rare disease characterized by systemic thrombotic microangiopathy mainly in the kidneys and mostly due to genetic disorders leading to uncontrolled activation of the complement system. Severe complications of SARS-CoV2 infection are linked to microvascular injury and complement activation is suspected to play a role in the pathogenesis of endothelial cell damage in severe COVID-19.
We present the first two cases of aHUS triggered by SARS-CoV-2 infection in two unrelated infants with the same mutation in the RNA exosome gene EXOSC3. This mutation is known to cause pontocerebellar hypoplasia type 1b, an autosomal-recessive neurodegenerative disease. So far, no kidney involvement in affected persons was reported.
As eculizumab treatment was unsuccessful and complement-mediated disorders were ruled out, we suppose that the atypical HUS in our two patients is not due to complement-mediated thrombotic microangiopathy but rather due to a dysfunction of the RNA exosome.
The RNA exosome is crucial for the precise processing and degradation of nuclear and cytoplasmatic RNA. We suspect that the SARS-CoV-2 infection led to changes in RNA that could not be offset by the defective RNA exosome in our two patients. The accumulation/wrong processing of the viral RNA must have led to the endothelial cell damage resulting in aHUS. This would be a new - "RNA-induced" - mechanism of aHUS.
非典型溶血尿毒综合征（aHUS）是一种罕见疾病，以全身血栓性微血管病为特征，主要发生在肾脏，主要由导致补体系统失控激活的遗传疾病引起。SARS-CoV2 感染的严重并发症与微血管损伤有关，补体激活被怀疑在严重 COVID-19 中内皮细胞损伤的发病机制中发挥作用。
我们介绍了由 SARS-CoV-2 感染引发的首例两例不相关婴儿的 aHUS，这两例婴儿均存在 RNA 外切体基因 EXOSC3 的相同突变。该突变已知会导致桥脑小脑发育不良 1b 型，一种常染色体隐性神经退行性疾病。迄今为止，受影响者的肾脏未受累。
由于依库珠单抗治疗无效且排除了补体介导的疾病，我们推测我们的两名患者的非典型 HUS 不是由于补体介导的血栓性微血管病引起的，而是由于 RNA 外切体的功能障碍引起的。
RNA 外切体对于核和细胞质 RNA 的精确加工和降解至关重要。我们怀疑 SARS-CoV-2 感染导致了 RNA 的变化，而我们的两名患者的有缺陷的 RNA 外切体无法抵消这些变化。病毒 RNA 的积累/错误处理必定导致了内皮细胞损伤，从而导致 aHUS。这将是 aHUS 的一种新的 -“RNA 诱导”-机制。
