Rhode Heidrun, Lüse Alexandra, Tautkus Bärbel, Nabity Mary, John-Kroegel Ulrike, Weigel Friederike, Dost Axel, Schitke Julia, Metzing Oliver, Böckhaus Jan, Rubel Diana, Kiess Wieland, Gross Oliver
Institute of Biochemistry I, Jena University Hospital, Jena, Germany.
Department of Veterinary Pathobiology, College of Veterinary Medicine, Texas A&M University, College Station, Texas, USA.
Kidney Int Rep. 2023 Sep 29;8(12):2778-2793. doi: 10.1016/j.ekir.2023.09.028. eCollection 2023 Dec.
Alport syndrome (AS) is a hereditary type IV collagen disease. It starts shortly after birth, without clinical symptoms, and progresses to end-stage kidney disease early in life. The earlier therapy starts, the more effectively end-stage kidney disease can be delayed. Clearly then, to ensure preemptive therapy, early diagnosis is an essential prerequisite.
To provide early diagnosis, we searched for protein biomarkers (BMs) by mass spectrometry in dogs with AS stage 0. At this very early stage, we identified 74 candidate BMs. Of these, using commercial enzyme-linked immunosorbent assays (ELISAs), we evaluated 27 in dogs and 28 in children, 50 with AS and 104 healthy controls.
Most BMs from blood appeared as fractions of multiple variants of the same protein, as shown by their chromatographic distribution before mass spectrometry. Blood samples showed only minor differences because ELISAs rarely detect disease-specific variants. However, in urine , several proteins, individually or in combination, were promising indicators of very early and preclinical kidney injury. The BMs with the highest sensitivity and specificity were collagen type XIII, hyaluronan binding protein 2 (HABP2), and complement C4 binding protein (C4BP).
We generated very strong candidate BMs by our approach of first examining preclinical AS in dogs and then validating these BMs in children at early stages of disease. These BMs might serve for screening purposes for AS before the onset of kidney damage and therefore allow preemptive therapy.
奥尔波特综合征（AS）是一种遗传性IV型胶原疾病。它在出生后不久就开始发病，起初没有临床症状，并在生命早期发展为终末期肾病。治疗开始得越早，终末期肾病就能得到越有效的延缓。显然，为了确保早期治疗，早期诊断是必不可少的前提条件。
为了实现早期诊断，我们通过质谱法在处于0期的AS犬中寻找蛋白质生物标志物（BMs）。在这个非常早期的阶段，我们鉴定出了74种候选BMs。其中，我们使用商业酶联免疫吸附测定（ELISA），在犬中评估了27种，在儿童中评估了28种，包括50例AS患者和104例健康对照。
血液中的大多数BMs表现为同一蛋白质多种变体的组分，这在质谱分析前的色谱分布中得到了体现。血液样本显示出的差异很小，因为ELISA很少能检测到疾病特异性变体。然而，在尿液中，几种蛋白质单独或联合使用时，是非常早期和临床前肾损伤的有前景的指标。敏感性和特异性最高的BMs是 XIII型胶原、透明质酸结合蛋白2（HABP2）和补体C4结合蛋白（C4BP）。
我们通过先在犬中检查临床前AS，然后在疾病早期的儿童中验证这些BMs的方法，生成了非常强大的候选BMs。这些BMs可能用于在肾损伤发生前对AS进行筛查，从而实现早期治疗。
