Department of Pathology, Cedars-Sinai Medical Center, Los Angeles, CA, USA.
Division of Nephrology and Hypertension, Lundquist Institute at Harbor-UCLA Medical Center, Torrance, CA, USA.
BMC Nephrol. 2024 Nov 14;25(1):409. doi: 10.1186/s12882-024-03689-6.
Karyomegalic interstitial nephritis (KIN) is a rare renal diagnosis associated with both genetic and medication etiologies. The primary gene associated with KIN is the FAN1 gene which encodes a protein responsible for DNA interstrand repair. Common medication triggers of KIN are chemotherapeutic agents, especially those which disrupt DNA structure such as carboplatin. Despite overlap between these mechanisms, it has not clearly been established if medication usage requires an underlying genetic predisposition for triggering KIN or if medications alone are sufficient. This ambiguous pathogenesis can make it difficult to appropriately assess risk of KIN development when starting patients on one of the known KIN-inducing therapies. Additionally, brentuximab vedotin, an antibody-drug conjugate directed against CD30, has not been previously implicated in KIN development.
We present a 49-year-old woman previously diagnosed with metastatic Hodgkin's lymphoma who was treated with doxorubicin, bleomycin, vinblastine, and dacarbazine, then 3 cycles of ifosfamide, carboplatin, etoposide, all of which were discontinued due to side effects. Following an episode of acute kidney injury, the serum creatinine was 1.09 mg/dL. She then received 2 doses of brentuximab, the serum creatinine rose, and the drug was discontinued. Kidney biopsy done 2 months after brentuximab and 5 months following ifosfamide therapies showed karyomegalic interstitial nephritis. Genetic evaluation showed no FAN1 gene mutations. The patient was started on pembrolizumab; no steroids were given due to concerns about interference with lymphoma immunotherapy. She remains with stable disease and stable chronic kidney disease.
This case presents a patient who developed KIN with a progressively rising serum creatinine after ifosfamide, carboplatin and brentuximab treatment. Although ifosfamide and carboplatin have known associations with the development of KIN, this case raises the possibility that brentuximab, which has a different mechanism of action, also may be associated with KIN. Additionally, the genetic findings demonstrate that drug-induced KIN can develop in the absence of FAN1 mutations, a finding not previously reported.
巨核细胞性间质性肾炎（KIN）是一种罕见的肾诊断，与遗传和药物病因有关。与 KIN 相关的主要基因是 FAN1 基因，该基因编码一种负责 DNA 链间修复的蛋白质。KIN 的常见药物触发因素是化疗药物，特别是那些破坏 DNA 结构的药物，如卡铂。尽管这些机制有重叠，但尚未明确药物使用是否需要触发 KIN 的潜在遗传易感性，还是仅药物本身就足够了。这种不明确的发病机制使得在开始使用已知的 KIN 诱导疗法之一时，难以适当评估 KIN 发展的风险。此外，靶向 CD30 的抗体药物偶联物 Brentuximab vedotin 以前也没有被牵连到 KIN 的发展中。
我们介绍了一位 49 岁的女性，她先前被诊断患有转移性霍奇金淋巴瘤，曾接受多柔比星、博来霉素、长春碱和达卡巴嗪治疗，然后接受了 3 个周期的异环磷酰胺、卡铂、依托泊苷治疗，但由于副作用而停止了治疗。在发生急性肾损伤后，血清肌酐为 1.09mg/dL。然后她接受了 2 剂 Brentuximab，血清肌酐升高，药物停止使用。在 Brentuximab 后 2 个月和异环磷酰胺治疗后 5 个月进行的肾活检显示巨核细胞性间质性肾炎。基因评估显示没有 FAN1 基因突变。患者开始接受 Pembrolizumab 治疗；由于担心干扰淋巴瘤免疫治疗，没有给予类固醇。她的疾病稳定，慢性肾脏病稳定。
本例患者在接受异环磷酰胺、卡铂和 Brentuximab 治疗后，血清肌酐逐渐升高，发展为 KIN。尽管异环磷酰胺和卡铂与 KIN 的发展有已知的关联，但本例提示作用机制不同的 Brentuximab 也可能与 KIN 有关。此外，基因检测结果表明，在没有 FAN1 突变的情况下，药物诱导的 KIN 也可能发生，这是以前没有报道过的发现。
