Sun Andrew Y, Hinck Bryan, Cohen Benjamin R, Keslar Karen, Fairchild Robert L, Monga Manoj
1 Glickman Urological and Kidney Institute , Cleveland Clinic, Cleveland, Ohio.
2 Department of Immunology, Cleveland Clinic , Cleveland, Ohio.
J Endourol. 2018 Mar;32(3):236-244. doi: 10.1089/end.2017.0699. Epub 2018 Feb 28.
Intrarenal inflammation has been implicated in the pathogenesis of nephrolithiasis, with prior work showing increased urine levels of IL-6, IL-8, and CCL-2 in stone patients. However, no studies have assessed for inflammation in the renal papillae. We sought to characterize novel papillary tip and urinary biomarkers in stone patients.
Ninety-two patients with nephrolithiasis undergoing percutaneous nephrolithotomy were enrolled. Papillary tip biopsies, kidney urine, and bladder urine were collected, as well as voided urine from eight healthy volunteers. Quantitative polymerase chain reaction was performed to measure inflammatory gene expression.
Initial 84-gene polymerase chain reaction array revealed significant elevation of several cytokines in stone patients vs controls (fold change 2.3-694). Twenty-four genes were selected for final analysis. In 41 pairs of urine samples, levels of CCL5, CD40, FasL, RIPK2, SELE, TLR3, and IL-15 were significantly elevated in kidney vs bladder urine (p0.0001-0.04). In 23 triplets of samples, expression of these cytokines plus CCL2, CCL7, CCR2, CSF1, CXCL9, and CXCL10, was significantly greater in papillary tips vs urine samples (p0.001-0.05). Cytokine elevation was independent of maximum postoperative heart rate, respiratory rate, temperature, leukocyte count, urinary tract infection in the past year, presence or absence of antibiotics at the time of surgery, and stone composition (all p > 0.05).
Expression of CCL-2, CCL-5, CCL-7, CCR-2, CD40, CSF1, CXCL-9, CXCL-10, Fas-L, RIPK2, SELE, and TLR-3 is markedly elevated in the papillary tips, kidney urine, and bladder urine of nephrolithiasis patients. Cytokine elevation was independent of signs of systemic inflammation. These findings further support the role of inflammation in nephrolithiasis and imply that the inflammatory process likely begins at the renal papillae. These may represent novel biomarkers of stone disease, which may be useful in basic nephrolithiasis research, disease diagnosis, and prognosis.
肾内炎症与肾结石的发病机制有关，先前的研究表明结石患者尿液中白细胞介素-6（IL-6）、白细胞介素-8（IL-8）和趋化因子配体2（CCL-2）水平升高。然而，尚无研究评估肾乳头中的炎症情况。我们试图确定结石患者新的乳头尖端和尿液生物标志物。
纳入92例接受经皮肾镜取石术的肾结石患者。采集乳头尖端活检组织、肾尿液、膀胱尿液，以及8名健康志愿者的晨尿。采用定量聚合酶链反应检测炎症基因表达。
最初的84基因聚合酶链反应芯片显示，与对照组相比，结石患者中几种细胞因子显著升高（倍数变化为2.3 - 694）。选择24个基因进行最终分析。在41对尿液样本中，肾尿液中趋化因子配体5（CCL5）、肿瘤坏死因子受体超家族成员40（CD40）、凋亡诱导配体（FasL）、受体相互作用丝氨酸/苏氨酸蛋白激酶2（RIPK2）、内皮细胞选择素（SELE）、Toll样受体3（TLR3）和白细胞介素-15（IL-15）水平显著高于膀胱尿液（p<0.0001 - 0.04）。在23组三联样本中，这些细胞因子加上CCL2、CCL7、趋化因子受体2（CCR2）、集落刺激因子1（CSF1）、CXC趋化因子配体9（CXCL9）和CXC趋化因子配体10（CXCL10）在乳头尖端的表达显著高于尿液样本（p<0.001 - 0.05）。细胞因子升高与术后最高心率、呼吸频率、体温、白细胞计数、过去一年的尿路感染、手术时是否使用抗生素以及结石成分无关（所有p>0.05）。
趋化因子配体2（CCL-2）、趋化因子配体5（CCL-5）、趋化因子配体7（CCL-7）、趋化因子受体2（CCR-2）、肿瘤坏死因子受体超家族成员40（CD40）、集落刺激因子1（CSF1）、CXC趋化因子配体9（CXCL-9）、CXC趋化因子配体10（CXCL-10）、凋亡诱导配体（Fas-L）、受体相互作用丝氨酸/苏氨酸蛋白激酶2（RIPK2）、内皮细胞选择素（SELE）和Toll样受体3（TLR-3）在肾结石患者的乳头尖端、肾尿液和膀胱尿液中的表达显著升高。细胞因子升高与全身炎症体征无关。这些发现进一步支持了炎症在肾结石发病中的作用，并表明炎症过程可能始于肾乳头。这些可能代表结石疾病的新型生物标志物，可能有助于肾结石基础研究、疾病诊断和预后评估。
