Division of Renal Diseases and Hypertension, University of Colorado Anschutz Medical Campus, 12700 East, 19th Ave, Box C281, Aurora, CO, 80045, USA.
Renal Section, Rocky Mountain Regional VA Medical Center, Aurora, CO, USA.
BMC Nephrol. 2022 Jul 23;23(1):264. doi: 10.1186/s12882-022-02873-w.
Glomerular endotheliosis is the pathognomonic glomerular lesion in pre-eclampsia that has also been described in those taking tyrosine kinase inhibitors for cancer treatment. Ibrutinib is a Bruton's tyrosine kinase inhibitor used to treat chronic lymphocytic leukemia (CLL). We report the first known case of glomerular endotheliosis on kidney biopsy in a patient on ibrutinib monotherapy.
The patient presented with acute on chronic kidney disease, proteinuria, low C3 and C4 and a high rheumatoid factor titer. A kidney biopsy was performed to confirm a preliminary diagnosis of membranoproliferative glomerulonephritis (MPGN), the most common glomerular disease in patients with CLL. Unexpectedly, the kidney biopsy showed pre-eclampsia-like lesions on light and electron microscopy: occlusion of glomerular peripheral capillary lumens by swollen reactive endothelial cells. Findings of glomerulonephritis were not seen, and there were no specific glomerular immune deposits by immunofluorescence or electron microscopy.
CLL is known to cause glomerular lesions, mainly MPGN. There is increasing evidence that ibrutinib, a major treatment for CLL, can cause kidney disease, but the precise pathology is not characterized. We present a patient with CLL on ibrutinib with signs of glomerular endotheliosis. Based on the absence of CLL-induced kidney pathologies typically seen on the kidney biopsy and the non-selectivity of ibrutinib, we attributed the glomerular endotheliosis to ibrutinib. In pre-eclampsia, increased soluble fms-like tyrosine kinase 1 (sFlt1) levels induce endothelial dysfunction by decreasing vascular endothelial growth factor (VEGF). Ibrutinib has been demonstrated to have non-selective tyrosine kinase inhibition, including inhibition of VEGF receptor (VEGFR) and epidermal growth factor receptor (EGFR). VEGFR and EGFR inhibitors have recently been described in the literature to cause hypertension, proteinuria, and glomerular endotheliosis. Kidney biopsy should be performed in CLL patients on ibrutinib that present with acute kidney injury (AKI) or proteinuria to determine whether the clinical picture is attributable to the disease itself or a complication of the therapy.
肾小球内皮细胞增多症是子痫前期的特征性肾小球病变，也已在接受癌症酪氨酸激酶抑制剂治疗的患者中描述过。伊布替尼是一种用于治疗慢性淋巴细胞白血病（CLL）的布鲁顿酪氨酸激酶抑制剂。我们报告了首例在接受伊布替尼单药治疗的患者中，通过肾活检发现肾小球内皮细胞增多症的病例。
患者表现为慢性肾脏病急性加重，蛋白尿，C3 和 C4 水平降低，类风湿因子滴度升高。进行肾活检以确认膜增生性肾小球肾炎（MPGN）的初步诊断，这是 CLL 患者最常见的肾小球疾病。出乎意料的是，肾活检显示出类似于子痫前期的病变：肿胀的反应性内皮细胞阻塞肾小球周围毛细血管腔。未见肾小球肾炎的表现，免疫荧光或电子显微镜也未发现特定的肾小球免疫沉积物。
已知 CLL 可引起肾小球病变，主要为 MPGN。越来越多的证据表明，伊布替尼是 CLL 的主要治疗药物，可引起肾脏疾病，但确切的病理特征尚未确定。我们报告了一例接受伊布替尼治疗的 CLL 患者，出现肾小球内皮细胞增多症的迹象。基于肾活检未见 CLL 引起的典型肾脏病变，以及伊布替尼的非选择性，我们将肾小球内皮细胞增多症归因于伊布替尼。在子痫前期，可溶性 fms 样酪氨酸激酶 1（sFlt1）水平升高通过降低血管内皮生长因子（VEGF）而导致内皮功能障碍。伊布替尼已被证明具有非选择性酪氨酸激酶抑制作用，包括抑制血管内皮生长因子受体（VEGFR）和表皮生长因子受体（EGFR）。最近文献中描述了 VEGFR 和 EGFR 抑制剂可引起高血压、蛋白尿和肾小球内皮细胞增多症。对于接受伊布替尼治疗的 CLL 患者，如果出现急性肾损伤（AKI）或蛋白尿，应进行肾活检，以确定临床表现是归因于疾病本身还是治疗的并发症。
