Rosner Grace M, Goswami Himanshu B, Sessions Katherine, Mendyka Lindsay K, Kerin Brenna, Vlasac Irma, Mellinger Diane, Gwilt Lorraine, Hampton Thomas H, Graber Martha, Ashare Alix, Harris William T, Christensen Brock, Stanton Bruce A, Swiatecka-Urban Agnieszka, Skopelja-Gardner Sladjana
Department of Microbiology and Immunology, Geisel School of Medicine at Dartmouth, Lebanon, NH, USA.
Department of Medicine, Dartmouth Hitchcock Medical Center, Lebanon, NH, USA.
medRxiv. 2024 Sep 19:2023.11.10.23298378. doi: 10.1101/2023.11.10.23298378.
Adult people with cystic fibrosis (PwCF) have a higher risk of end-stage kidney disease than the general population. The nature and mechanism of kidney disease in CF are unknown. This study quantifies urinary kidney injury markers and examines the hypothesis that neutrophil activation and lung infection are associated with early kidney injury in CF.
Urinary total protein, albumin, and markers of kidney injury and neutrophil activation, normalized to creatinine, as well as urinary immune cells, were quantified in CF (n = 48) and healthy (n = 33) cohorts. Infection burden and chronicity were defined by sputum culture and serum titers of anti-bacterial antibodies.
PwCF had increased urinary protein levels, consisting of low-molecular-weight tubular injury markers, independent of glomerular filtration rate (eGFR). This finding suggests subclinical renal injury processes. Urinary analysis of the CF cohort identified different associations of urinary injury markers with aminoglycoside exposure, lung function, and neutrophil activation. High urinary KIM-1 levels and increased prevalence of neutrophils among urine immune cells correlated with decreased lung function in PwCF. The relationship between tubular injury and decreased lung function was most prominent in patients harboring chronic infection.
Increased urinary tubular injury markers in PwCF suggest early subclinical renal injury not readily detected by eGFR. The strong association of high urinary KIM-1 and neutrophils with diminished lung function and high burden suggests that pulmonary disease may contribute to renal injury in CF.
成年囊性纤维化患者（PwCF）发生终末期肾病的风险高于普通人群。囊性纤维化患者肾病的性质和机制尚不清楚。本研究对尿肾损伤标志物进行定量分析，并检验中性粒细胞活化和肺部感染与囊性纤维化患者早期肾损伤相关的假设。
对囊性纤维化队列（n = 48）和健康队列（n = 33）的尿总蛋白、白蛋白、肾损伤和中性粒细胞活化标志物（以肌酐进行标准化）以及尿免疫细胞进行定量分析。通过痰培养和抗菌抗体血清滴度确定感染负担和慢性程度。
PwCF患者的尿蛋白水平升高，包括低分子量肾小管损伤标志物，且与肾小球滤过率（eGFR）无关。这一发现提示存在亚临床肾损伤过程。对囊性纤维化队列的尿液分析发现，尿损伤标志物与氨基糖苷类药物暴露、肺功能和中性粒细胞活化之间存在不同的关联。PwCF患者尿KIM-1水平升高以及尿免疫细胞中中性粒细胞比例增加与肺功能下降相关。在患有慢性感染的患者中，肾小管损伤与肺功能下降之间的关系最为显著。
PwCF患者尿肾小管损伤标志物升高提示存在早期亚临床肾损伤，而eGFR不易检测到这种损伤。尿KIM-1水平升高和中性粒细胞与肺功能降低及高负担之间的强烈关联表明，肺部疾病可能导致囊性纤维化患者的肾损伤。
