Supplementary Material for: A case of rapidly progressive diabetic nephropathy induced by osimertinib

The number of patients with diabetic nephropathy is increasing worldwide and it is important to understand the underlying pathological mechanisms of the disease. In early-stage diabetic nephropathy, the hyperglycemic environment leads to vascular endothelial cell damage, resulting in overexpression of vascular endothelial growth factor (VEGF) in podocytes and renal pathology of glomerular hypertrophy, glomerular basement membrane thickening, and mesangial hyperplasia. In diabetic nephropathy, renal thrombotic microangiopathy (TMA) develops and the nephropathy progressively worsens in some cases of severe glomerular podocyte damage. Further, receptor tyrosine kinase inhibitors (RTKIs) may suppress VEGF secretion via VEGF receptor-2 tyrosine kinase inhibition in podocytes, which results in renal TMA and rapid deterioration of diabetic nephropathy. Osimertinib, a third-generation irreversible epidermal growth factor receptor (EGFR)-TKI, is approved as a first-line treatment agent for metastatic or locally advanced EGFR mutation-positive non-small cell lung cancer. We encountered a case of a patient with diabetic nephropathy with lung adenocarcinoma treated with osimertinib, whose condition deteriorated from early nephropathy to end-stage renal disease in approximately 4 months. The patient had early diabetic nephropathy, but the use of a RTKI suppressed VEGF expression in podocytes, resulting in the induction of renal TMA and the development of rapidly progressive diabetic nephropathy.

全球糖尿病肾病（diabetic nephropathy）患者数量呈逐年上升趋势，阐明该疾病的潜在病理机制具有重要临床价值。在糖尿病肾病早期阶段，高糖环境会诱发血管内皮细胞损伤，导致足细胞内血管内皮生长因子（vascular endothelial growth factor, VEGF）过表达，并引发肾小球肥大、肾小球基底膜增厚及系膜增生等肾脏病理改变。糖尿病肾病进展过程中可并发肾脏血栓性微血管病（renal thrombotic microangiopathy, TMA），在部分存在严重肾小球足细胞损伤的病例中，肾病可出现进行性恶化。此外，受体酪氨酸激酶抑制剂（receptor tyrosine kinase inhibitors, RTKIs）可通过抑制足细胞内的VEGF受体2酪氨酸激酶活性，减少VEGF分泌，进而诱发肾脏血栓性微血管病，加速糖尿病肾病的恶化进程。奥希替尼（Osimertinib）属于第三代不可逆性表皮生长因子受体（epidermal growth factor receptor, EGFR）-TKI，目前已被批准作为转移性或局部晚期EGFR突变阳性非小细胞肺癌的一线治疗药物。我们曾收治1例合并早期糖尿病肾病的肺腺癌患者，该患者接受奥希替尼治疗后，肾病在约4个月内从早期阶段快速进展至终末期肾病。该患者原本处于糖尿病肾病早期，使用受体酪氨酸激酶抑制剂后，足细胞内VEGF的表达受到抑制，进而诱导肾脏血栓性微血管病，最终引发快速进展性糖尿病肾病。