Kaszyńska Aleksandra, Kępska-Dzilińska Małgorzata, Karakulska-Prystupiuk Ewa, Tomaszewska Agnieszka, Basak Grzegorz Władysław, Żórawski Marcin, Jakubowska Zuzanna, Małyszko Jolanta
Department of Nephrology, Dialysis and Internal Medicine, Medical University of Warsaw, Banacha 1A, 02-097 Warsaw, Poland.
Department of Hematology, Transplantation and Internal Medicine, Medical University of Warsaw, Banacha 1A, 02-097 Warsaw, Poland.
Int J Mol Sci. 2025 Apr 10;26(8):3581. doi: 10.3390/ijms26083581.
Kidney injury encompasses a broad spectrum of structural and functional abnormalities, directly associated with stem cell transplantation. Acute kidney injury and chronic kidney disease represent perilous complications of hematopoietic stem cell transplantation (HSCT), with an elevated risk of mortality and progression to end-stage renal disease. The early detection of these complications is, therefore, paramount, and research is increasingly focused on the identification of novel biomarkers of kidney damage. Recently, proenkephalin (PENK), a monomeric peptide that is freely filtered by the glomerulus and thus reflects glomerular filtration very well, has been shown to be an additional useful predictor of the occurrence of acute kidney injury and heart failure. Dickkopf-3 (DKK3) is a glycoprotein secreted by the renal tubular epithelium in response to stress and has been implicated in the development of interstitial fibrosis. It has therefore been evaluated primarily as a marker of fibrosis in chronic kidney disease (CKD), but may also help predict the development of acute kiney injury. Uromodulin is regarded as a renal marker. Previous studies have examined the potential of PENK, DKK-3 and uromodulin as a biomarker in individuals with preserved renal function. However, the urinary levels of PENK, DKK-3 and uromodulin in patients following HSCT have not yet been established. The objective of the present study was to assess urinary PENK, DKK-3, and uromodulin concentrations in patients who had been under ambulatory care of the Hematology, Transplantation and Internal Medicine Department for a minimum of three months following HSCT, and to investigate their correlations with kidney function, as reflected by serum creatinine and eGFR. The study population comprised 80 patients who had undergone allogeneic HSCT for various reasons, primarily hematological malignancies such as acute leukemias and lymphomas. In addition, 32 healthy volunteers were included in order to establish normal ranges for the biomarkers of interest. Urine concentrations of proenkephalin, DKK-3, and uromodulin were evaluated using a commercially available sandwich ELISA immunoassay. Demographic and clinical data were retrieved from the patients' records. Statistical analyses were conducted using XLSLAT 2022 (Lumivero, Denver, CO, USA) and STATISTICAv13.0 (StatSoft, Tulsa, OH, USA). The results showed that PENK and DKK-3 levels were significantly higher in patients after HSCT compared to healthy volunteers. Furthermore, when patients were divided according to kidney function (below and over 60 mL/min/1.72 m), it was found that the concentration of PENK and DKK-3 were significantly higher in 23 patients with CKD stage 3 relative to patients with eGFR over 60 mL min 1.72 m. In univariate correlations, PENK demonstrated an inverse relationship with eGFR (r: -0.21, < 0.05), while DKK-3 exhibited no significant correlation with creatinine or eGFR.Patients following allogeneic HSCT, despite having normal or near-normal kidney function, exhibited evidence of kidney injury. However, further research is necessary to ascertain the clinical utility of the novel biomarker.
肾损伤包括一系列广泛的结构和功能异常，与干细胞移植直接相关。急性肾损伤和慢性肾病是造血干细胞移植（HSCT）的危险并发症，具有较高的死亡率和进展为终末期肾病的风险。因此，这些并发症的早期检测至关重要，并且研究越来越集中于识别新的肾损伤生物标志物。最近，脑啡肽原（PENK），一种可被肾小球自由滤过从而很好地反映肾小球滤过功能的单体肽，已被证明是急性肾损伤和心力衰竭发生的另一个有用预测指标。Dickkopf-3（DKK3）是肾小管上皮细胞在应激时分泌的一种糖蛋白，与间质纤维化的发生有关。因此，它主要被评估为慢性肾病（CKD）中纤维化的标志物，但也可能有助于预测急性肾损伤的发生。尿调节蛋白被视为一种肾脏标志物。先前的研究已经探讨了PENK、DKK-3和尿调节蛋白作为肾功能正常个体生物标志物的潜力。然而，HSCT患者尿液中PENK、DKK-3和尿调节蛋白的水平尚未确定。本研究的目的是评估HSCT后在血液学、移植和内科门诊护理至少三个月的患者尿液中PENK、DKK-3和尿调节蛋白的浓度，并研究它们与血清肌酐和估算肾小球滤过率（eGFR）所反映的肾功能之间的相关性。研究人群包括80例因各种原因接受异基因HSCT的患者，主要是血液系统恶性肿瘤，如急性白血病和淋巴瘤。此外，纳入了32名健康志愿者以确定所关注生物标志物的正常范围。使用市售的夹心酶联免疫吸附测定法评估脑啡肽原、DKK-3和尿调节蛋白的尿液浓度。从患者记录中获取人口统计学和临床数据。使用XLSLAT 2022（美国科罗拉多州丹佛市Lumivero公司）和STATISTICAv13.0（美国俄亥俄州塔尔萨市StatSoft公司）进行统计分析。结果显示，与健康志愿者相比，HSCT后患者的PENK和DKK-3水平显著更高。此外，当根据肾功能（低于和高于60 mL/min/1.72 m²）对患者进行分组时，发现23例CKD 3期患者的PENK和DKK-3浓度相对于eGFR高于60 mL/min/1.7²m²的患者显著更高。在单变量相关性分析中，PENK与eGFR呈负相关（r：-0.21，P<0.05），而DKK-3与肌酐或eGFR无显著相关性。异基因HSCT后的患者，尽管肾功能正常或接近正常，但仍表现出肾损伤的迹象。然而，需要进一步研究以确定这种新生物标志物的临床实用性。
