Predictive value of serum ceruloplasmin and kidney injury molecule-1 for the occurrence of end-stage renal disease

doi:10.11958/20253013

Abstract

Abstract:

Objective To analyze the predictive value of serum ceruloplasmin (CP) and kidney injury molecule-1 (KIM-1) levels for the progression of elderly patients with chronic kidney disease (CKD) to end-stage renal disease (ESRD). Methods A total of 208 elderly CKD patients were enrolled and divided into the progression group (56 cases) and the non-progression group (152 cases) according to whether they progressed to ESRD. Baseline demographic and clinical data at admission were collected. Serum CP levels were measured by immunoturbidimetry, and KIM-1 levels were detected by enzyme-linked immunosorbent assay (ELISA). Receiver operating characteristic (ROC) curves were plotted to evaluate the predictive efficacy of CP and KIM-1 levels for CKD progression to ESRD. Cox regression analysis was used to assess the relationship between CP and KIM-1 levels and ESRD. Kaplan-Meier (K-M) survival curves were constructed to evaluate the risk correlation. Results Compared with the non-progression group, there were significantly higher age, proportion of CKD stages G4/G5, 24-hour urinary protein quantification (24h-UP), serum creatinine (Scr), urinary albumin-to-creatinine ratio (UACR), blood urea nitrogen (BUN), uric acid (UA), systolic blood pressure (SBP), CP and KIM-1 levels in the progression group, while the estimated glomerular filtration rate (eGFR) was lower (P<0.05). ROC curve analysis showed that when CP and KIM-1 were set at 346.86 mg/L and 3.26 μg/L, respectively, the area under the ROC curve (AUC) was 0.670 (95% CI: 0.601-0.733) for CP and 0.700 (95% CI: 0.633-0.762) for KIM-1. When CP and KIM-1 were combined for prediction, the AUC increased to 0.804 (95% CI: 0.744-0.856), with a sensitivity of 71.43% and specificity of 75.66%. Multivariate Cox regression analysis indicated that both CP and KIM-1 were independent risk factors for progression to ESRD in elderly CKD patients (P<0.05). Kaplan-Meier curve results showed that the 3-year cumulative incidence of ESRD progression in the CP>346.86 mg/L group was significantly higher than that in the CP≤346.86 mg/L group [40.96% (34/83) vs. 17.60% (22/125), Log-rank χ2=22.076, P<0.01]. Similarly, the 3-year cumulative incidence of ESRD in the KIM-1>3.26 μg/L group was significantly higher than that in the KIM-1≤3.26 μg/L group [50.85% (30/59) vs. 17.45% (26/149), Log-rank χ2=46.518, P<0.01]. Conclusion Serum CP and KIM-1 levels are significantly associated with the risk of progression to ESRD in elderly CKD patients. Elevated levels of CP and KIM-1 indicate a higher risk of disease progression.

Key words: renal insufficiency, chronic, kidney failure, chronic, aged, ceruloplasmin, kidney injury molecule-1, forecasting

CLC Number:

R692.5，R446.1

Figures/Tables 6

References 24

[1]	Herrington W G, Judge P K, Grams M E, et al. Chronic kidney disease[J]. Lancet, 2026, 407(10523):90-104. doi:10.1016/S0140-6736(25)01942-7.
[2]	Davis J S, Zuber K. Chronic kidney disease:Updates,priorities,and current challenges[J]. Nursing, 2025, 55(11):17-24. doi:10.1097/NSG.0000000000000284.
[3]	Kovesdy C P. Epidemiology of chronic kidney disease:an update 2022[J]. Kidney Int, Suppl(2011), 2022, 12(1):7-11. doi:10.1016/j.kisu.2021.11.003.
[4]	He J, Wang X, Zhu P, et al. Identification and validation of an explainable early-stage chronic kidney disease prediction model:a multicenter retrospective study[J]. EClinicalMedicine, 2025, 84:103286. doi:10.1016/j.eclinm.2025.103286.
[5]	Tang X, Zhang A, Feng X, et al. Global research trends on the associations between chronic kidney disease and mitochondria:insights from the bibliometric analysis[J]. Int Urol Nephrol, 2025, 57(8):2579-2594. doi:10.1007/s11255-025-04437-x.
[6]	顾芸芸, 仲崇明, 杨海燕. 尿酸/白蛋白比值对慢性肾脏病患者并发冠心病的预测价值[J]. 天津医药, 2024, 52(11):1202-1206.
	Gu Y Y, Zhong C M, Yang H Y. Predictive value of uric acid/albumin ratio for coronary heart disease in patients with chronic kidney disease[J]. Tianjin Med J, 2024, 52(11):1202-1206. doi:10.11958/20240522.
[7]	Jerebtsova M, Saraf S L, Lin X H, et al. Identification of ceruloplasmin as a biomarker of chronic kidney disease in urine of sickle cell disease patients by proteomic analysis[J]. Am J Hematol, 2018, 93(2):E45-E47. doi:10.1002/ajh.24965.
[8]	Batista M N, Cuppari L, De FáTima Campos Pedrosa L, et al. Effect of end-stage renal disease and diabetes on zinc and copper status[J]. Biol Trace Elem Res, 2006, 112(1):1-12. doi:10.1385/bter:112:1:1.
[9]	Mori Y, Ajay A K, Chang J H, et al. KIM-1 mediates fatty acid uptake by renal tubular cells to promote progressive diabetic kidney disease[J]. Cell Metab, 2021, 33(5):1042-1061.e7. doi:10.1016/j.cmet.2021.04.004.
[10]	Han W K, Bailly V, Abichandani R, et al. Kidney injury molecule-1(KIM-1):a novel biomarker for human renal proximal tubule injury[J]. Kidney Int, 2002, 62(1):237-244. doi:10.1046/j.1523-1755.2002.00433.x.
[11]	中华预防医学会肾脏病预防与控制专业委员会. 中国慢性肾脏病早期评价与管理指南[J]. 中华内科杂志, 2023, 62(8):902-930.
	Chinese Preventive Medicine Association for Kidney Disease. Guidelines for the early evaluation and management of chronic kidney disease in China[J]. Chin J Intern Med, 2023, 62(8):902-930. doi:10.3760/cma.j.cn112138-20221013-00755.
[12]	Evans M, Lewis R D, Morgan A R, et al. A narrative review of chronic kidney disease in clinical practice: current challenges and future perspectives[J]. Adv Ther, 2022, 39(1):33-43. doi:10.1007/s12325-021-01927-z.
[13]	Kennedy D J, Fan Y, Wu Y, et al. Plasma ceruloplasmin,a regulator of nitric oxide activity,and incident cardiovascular risk in patients with CKD[J]. Clin J Am Soc Nephrol, 2014, 9(3):462-467. doi:10.2215/CJN.07720713.
[14]	Persichini T, Maio N, Di Patti M C, et al. Interleukin-1β induces ceruloplasmin and ferroportin-1 gene expression via MAP kinases and C/EBPβ,AP-1,and NF-κB activation[J]. Neurosci Lett, 2010, 484(2):133-138. doi:10.1016/j.neulet.2010.08.034.
[15]	Fu Y, Xiang Y, Wang Y, et al. The STAT1/HMGB1/NF-κB pathway in chronic inflammation and kidney injury after cisplatin exposure[J]. Theranostics, 2023, 13(9):2757-2773. doi:10.7150/thno.81406.
[16]	Wu Y, Terekhanova N V, Caravan W, et al. Epigenetic and transcriptomic characterization reveals progression markers and essential pathways in clear cell renal cell carcinoma[J]. Nat Commun, 2023, 14(1):1681. doi:10.1038/s41467-023-37211-7.
[17]	王露. 血清铜蓝蛋白水平预测糖尿病肾病进程[J]. 标记免疫分析与临床, 2016, 23(4):413-417.
	Wang L. Serum ceruloplasmin levels predict the progression of diabetic nephropathy[J]. Labeled Immunoassays Clin Med, 2016, 23(4):413-417. doi:10.11748/bjmy.issn.1006-1703.2016.04.017.
[18]	董小伟, 房勃龙, 齐琳, 等. 尿铜蓝蛋白、肾损伤因子1与糖尿病肾病患者肾功能的关系及对预后不良的预测价值研究[J]. 现代生物医学进展, 2023, 23(11):2083-2088.
	Dong X W, Fang B L, Qi L, et al. Relationship between urinary ceruloplasmin, renal injury factor 1 and renal function in patients with diabetic nephropathy and their predictive value for poor prognosis[J]. Prog Mod Biomed, 2023, 23(11):2083-2088. doi:10.13241/j.cnki.pmb.2023.11.016.
[19]	张霄, 张睿, 吴妍, 等. KIM-1对AGEs诱导的肾小管上皮细胞EMT和凋亡的影响及其机制[J]. 中国病理生理杂志, 2022, 38(11):2005-2013.
	Zhang X, Zhang R, Wu Y, et al. Effects of KIM-1 on EMT and apoptosis of renal tubular epithelial cells induced by AGEs and its mechanisms[J]. Chin J Pathophysiol, 2022, 38(11):2005-2013.
[20]	霍文谦. KIM-1在肾小管上皮细胞缺氧损伤中的保护作用及HIF-1信号通路调节[D]. 重庆: 第三军医大学, 2011:57-68.
	Huo W Q. Protective effects of KIM-1 on renal tubular epithelial cells in hypoxic injury and regulation of the HIF-1 signaling pathway[D]. Chongqing: Third Military Medical University, 2011:57-68.
[21]	李绍梅, 薛雯, 温文龙, 等. 原发性肾病综合征合并急性肾损伤患者尿中性粒细胞明胶酶相关脂质运载蛋白和肾损伤因子1的变化及其意义[J]. 中国综合临床, 2013, 29(12):1287-1290.
	Li S M, Xue W, Wen W L, et al. Changes and significance of neutrophil gelatinase-related lipoprotein and renal injury factor 1 in urine of patients with primary nephrotic syndrome complicated by acute kidney injury[J]. J Clin Med, 2013, 29(12):1287-1290.
[22]	曾信君, 刘平. 糖尿病肾病患者GADA、KIM-1、PTX3、IGF-1的表达及与肾功能指标的相关性[J]. 医学理论与实践, 2024, 37(21):3705-3708.
	Zeng X J, Liu P. Expression of GADA,KIM-1,PTX3,and IGF-1 in diabetic nephropathy patients and their correlation with renal function parameters[J]. J Med Theory Pract, 2024, 37(21):3705-3708. doi:10.19381/j.issn.1001-7585.2024.21.038.
[23]	陈莹莹. 肾损伤指标NGAL、KIM-1、IL-18的研究进展[J]. 中国现代医生, 2024, 62(24):135-140.
	Chen Y Y. Research progress of renal injury markers NGAL,KIM-1,and IL-18[J]. China Mod Doctor, 2024, 62(24):135-140.
[24]	Zhou L T, Lv L L, Pan M M, et al. Are urinary tubular injury markers useful in chronic kidney disease? A systematic review and meta analysis[J]. PLoS One, 2016, 11(12):e0167334. doi:10.1371/journal.pone.0167334.

组别		n		年龄/岁			性别（男/女）		BMI/（kg/m²）			吸烟史			饮酒史		用药史
组别		n		年龄/岁			性别（男/女）		BMI/（kg/m²）			吸烟史			饮酒史		RAS抑制剂			SGLT2抑制剂			MRA			利尿剂			他汀类药物
未进展组		152		65.76±3.87			80/72		23.86±2.67			48（31.58）			36（23.68）		115（75.66）			35（23.03）			26（17.11）			72（47.37）			93（61.18）
进展组		56		72.28±4.02			32/24		24.32±2.15			20（35.71）			12（21.43）		43（76.79）			10（17.86）			12（21.43）			30（53.57）			31（55.36）
t或χ²				3.632^＊＊			0.084		0.598			0.198			0.029		0.029			0.645			0.512			0.630			0.577
组别	CKD分期												eGFR/[mL/（min·1.73 m²）]			24 h-UP/（g/d）			Scr/（μmol/L）			UACR/（mg/g）			BUN/（mmol/L）			UA/（μmol/L）
组别	G3a				G3b			G4			G5		eGFR/[mL/（min·1.73 m²）]			24 h-UP/（g/d）			Scr/（μmol/L）			UACR/（mg/g）			BUN/（mmol/L）			UA/（μmol/L）
未进展组	52（34.21）				56（36.84）			35（23.03）			9（5.92）		40.53±5.62			1.35±0.48			213.56±57.21			420.98±65.24			11.64±3.17			410.24±54.68
进展组	14（25.00）				15（26.79）			16（28.57）			11（19.64）		37.42±7.26			1.84±0.63			256.35±76.79			456.45±68.57			16.84±4.23			480.34±75.45
t或χ²	10.833^＊												2.901^＊＊			2.641^＊			2.297^＊			3.352^＊＊			2.532^＊			3.182^＊＊
组别			TC/（mmol/L）			TG/（mmol/L）				FBG/（mmol/L）				SBP/（mmHg）				DBP/（mmHg）			血钾/（mmol/L）			血磷/（mmol/L）			血钙/（mmol/L）
未进展组			5.25±0.84			1.95±0.83				5.91±1.01				137.65±10.42				86.62±7.73			4.84±0.61			1.56±0.25			2.34±0.46
进展组			5.83±1.04			2.34±0.71				6.42±1.25				168.31±10.54				89.45±8.24			5.03±0.63			1.73±0.35			2.13±0.31
t			1.874			1.676				1.371				3.245^＊＊				1.117			1.946			1.667			1.883

组别		n		年龄/岁			性别（男/女）		BMI/（kg/m²）			吸烟史			饮酒史		用药史
组别		n		年龄/岁			性别（男/女）		BMI/（kg/m²）			吸烟史			饮酒史		RAS抑制剂			SGLT2抑制剂			MRA			利尿剂			他汀类药物
未进展组		152		65.76±3.87			80/72		23.86±2.67			48（31.58）			36（23.68）		115（75.66）			35（23.03）			26（17.11）			72（47.37）			93（61.18）
进展组		56		72.28±4.02			32/24		24.32±2.15			20（35.71）			12（21.43）		43（76.79）			10（17.86）			12（21.43）			30（53.57）			31（55.36）
t或χ²				3.632^＊＊			0.084		0.598			0.198			0.029		0.029			0.645			0.512			0.630			0.577
组别	CKD分期												eGFR/[mL/（min·1.73 m²）]			24 h-UP/（g/d）			Scr/（μmol/L）			UACR/（mg/g）			BUN/（mmol/L）			UA/（μmol/L）
组别	G3a				G3b			G4			G5		eGFR/[mL/（min·1.73 m²）]			24 h-UP/（g/d）			Scr/（μmol/L）			UACR/（mg/g）			BUN/（mmol/L）			UA/（μmol/L）
未进展组	52（34.21）				56（36.84）			35（23.03）			9（5.92）		40.53±5.62			1.35±0.48			213.56±57.21			420.98±65.24			11.64±3.17			410.24±54.68
进展组	14（25.00）				15（26.79）			16（28.57）			11（19.64）		37.42±7.26			1.84±0.63			256.35±76.79			456.45±68.57			16.84±4.23			480.34±75.45
t或χ²	10.833^＊												2.901^＊＊			2.641^＊			2.297^＊			3.352^＊＊			2.532^＊			3.182^＊＊
组别			TC/（mmol/L）			TG/（mmol/L）				FBG/（mmol/L）				SBP/（mmHg）				DBP/（mmHg）			血钾/（mmol/L）			血磷/（mmol/L）			血钙/（mmol/L）
未进展组			5.25±0.84			1.95±0.83				5.91±1.01				137.65±10.42				86.62±7.73			4.84±0.61			1.56±0.25			2.34±0.46
进展组			5.83±1.04			2.34±0.71				6.42±1.25				168.31±10.54				89.45±8.24			5.03±0.63			1.73±0.35			2.13±0.31
t			1.874			1.676				1.371				3.245^＊＊				1.117			1.946			1.667			1.883

组别	n	CP/（mg/L）	KIM-1/（μg/L）
未进展组	152	296.89±96.28	3.05±0.96
进展组	56	387.94±111.99	3.82±1.34
t		2.946^＊＊	2.868^＊＊

组别	n	CP/（mg/L）	KIM-1/（μg/L）
未进展组	152	296.89±96.28	3.05±0.96
进展组	56	387.94±111.99	3.82±1.34
t		2.946^＊＊	2.868^＊＊

指标	AUC	95%CI	截断值	敏感度/%	特异度/%	约登指数
CP	0.670	0.601~0.733	346.86 mg/L	60.71	68.42	0.291
KIM-1	0.700	0.633~0.762	3.26 μg/L	60.71	72.37	0.331
二者联合	0.804	0.744~0.856		71.43	75.66	0.471