Division of Nephrology, Cliniques universitaires Saint-Luc, Brussels, Belgium.
Institut de Recherche Expérimentale et Clinique, UCLouvain, Brussels, Belgium.
Clin J Am Soc Nephrol. 2023 Jul 1;18(7):881-891. doi: 10.2215/CJN.0000000000000182. Epub 2023 Apr 21.
BACKGROUND: The identification of complement defects as major drivers of primary atypical hemolytic uremic syndrome (HUS) has transformed the landscape of thrombotic microangiopathies (TMAs), leading to the development of targeted therapies and better patient outcomes. By contrast, little is known about the presentation, genetics, and outcomes of TMA associated with specific diseases or conditions, also referred to as secondary TMA. METHODS: In this study, we assessed the relative incidence, clinical and genetic spectra, and long-term outcomes of secondary TMA versus other TMAs in consecutive patients hospitalized with a first episode of TMA from 2009 to 2019 at two European reference centers. RESULTS: During the study period, 336 patients were hospitalized with a first episode of TMA. Etiologies included atypical HUS in 49 patients (15%), thrombotic thrombocytopenic purpura (TTP) in 29 (9%), shigatoxin-associated HUS in 70 (21%), and secondary TMA in 188 (56%). The main causes of secondary TMA were hematopoietic stem-cell transplantation ( n =56, 30%), solid-organ transplantation ( n =44, 23%), and malignant hypertension ( n =25, 13%). Rare variants in complement genes were identified in 32 of 49 patients (65%) with atypical HUS and eight of 64 patients (13%) with secondary TMA; pathogenic or likely pathogenic variants were found in 24 of 49 (49%) and two of 64 (3%) of them, respectively ( P < 0.001). After a median follow-up of 1157 days, death or kidney failure occurred in 14 (29%), eight (28%), five (7%), and 121 (64%) patients with atypical HUS, TTP, shigatoxin-associated HUS, and secondary TMA, respectively. Unadjusted and adjusted Cox regressions showed that patients with secondary TMA had the highest risk of death or kidney failure (unadjusted hazard ratio [HR], 3.35; 95% confidence interval [CI], 1.85 to 6.07; P < 0.001; adjusted HR, 4.11; 95% CI, 2.00 to 8.46; P < 0.001; considering atypical HUS as reference). CONCLUSIONS: Secondary TMAs represent the main cause of TMA and are independently associated with a high risk of death and progression to kidney failure.
背景：补体缺陷被确定为原发性非典型溶血尿毒症综合征（HUS）的主要驱动因素，这改变了血栓性微血管病（TMA）的格局，导致了靶向治疗的发展和患者预后的改善。相比之下，对于与特定疾病或病症相关的 TMA（也称为继发性 TMA）的表现、遗传学和结局知之甚少。
方法：在这项研究中，我们评估了 2009 年至 2019 年期间在欧洲两个参考中心连续住院的首例 TMA 患者中，继发性 TMA 与其他 TMA 的相对发病率、临床和遗传谱以及长期结局。
结果：在研究期间，336 例患者因首次发生 TMA 住院。病因包括非典型 HUS 49 例（15%）、血栓性血小板减少性紫癜（TTP）29 例（9%）、志贺毒素相关性 HUS 70 例（21%）和继发性 TMA 188 例（56%）。继发性 TMA 的主要病因是造血干细胞移植（n=56，30%）、实体器官移植（n=44，23%）和恶性高血压（n=25，13%）。在 49 例非典型 HUS 患者中有 32 例（65%）和 64 例继发性 TMA 患者中有 8 例（13%）发现补体基因的罕见变异；在其中 24 例（49%）和 2 例（3%）中发现了致病性或可能致病性变异（P<0.001）。中位随访 1157 天后，非典型 HUS、TTP、志贺毒素相关性 HUS 和继发性 TMA 患者的死亡或肾衰竭发生率分别为 14（29%）、8（28%）、5（7%）和 121（64%）。未调整和调整后的 Cox 回归显示，继发性 TMA 患者的死亡或肾衰竭风险最高（未调整的危险比[HR]，3.35；95%置信区间[CI]，1.85 至 6.07；P<0.001；调整后的 HR，4.11；95% CI，2.00 至 8.46；P<0.001；以非典型 HUS 为参照）。
结论：继发性 TMA 是 TMA 的主要病因，与死亡和进展为肾衰竭的高风险独立相关。
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