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AIMS

Early post-transplant complications such as acute graft rejection and infections are associated with high morbidity and mortality of heart and lung transplant recipients who are in vital need of immunosuppressive therapy. MiR-424 is a member of the miR-16 family, which plays an important physiological role in the development of cardiovascular and respiratory pathology, is involved in the regulation of monocyte and macrophage differentiation, and has an immunosuppressive potential. The aim of the study was to determine the diagnostic value of circulating miR-424 as a potential biomarker of post-transplant complications in heart and lung transplant recipients.

METHODS

The study enrolled 83 heart transplant recipients, aged 18 to 70 (48 ± 13) years; 26 lung transplant recipients, aged 10 to 74 (36 ± 16) years. The miR-424 plasma expression was detected by real-time PCR (Qiagen, USA). Significance of miR-424 level was assessed through the ΔCt method. Acute graft rejection was verified by the results of endomyocardial or transbronchial biopsy. Post-transplant infectious complications were verified through microbiological identification of bacteremia from blood cultures.

RESULTS

Our study shows miR-424 upregulation in plasma of patients with chronic heart or respiratory failure in comparison with healthy individuals (p = 0.003 and p = 0.04 resp.). There was a direct correlation of miR-424 expression with red blood cells and hemoglobin levels in patients before heart transplantation (p = 0.01 and p = 0.03 resp.). After transplantation the expression of plasma miR-424 correlated with the level of C-reactive protein (CRP) both in heart (r = 0.75; p = 0.02) and lung (r = 0.50; p = 0.04) transplant recipients. The expression of plasma miR-424 correlated with tacrolimus blood concentration after heart transplantation (r = 0.38; p = 0.04). The miR-424 level didn't differ in heart or lung transplant recipients with and without acute graft rejection (p = 0.47 and p = 0.78 resp.), but was significantly higher in heart and lung transplant recipients with gram-negative bacteremia (p = 0.002). When the miR-424 level is above a threshold value (-5.72 fold change), the relative risk of bacteremia is RR = 3.84 [95% CI 1.94-7.61]; Se = 60.0%; Sp = 89.2%. CRP concentration above 7 mg/L in duplex test with miR-424 improves the diagnostic characteristics of miR-424 for post-transplant gram-negative bacteremia in heart and lung transplant recipients up to RR = 9.17 [95% CI 1.37-61.46]; Se = 83.3% and Sp = 90.1%.

CONCLUSION

MiR-424 plasma expression was upregulated in patients with chronic heart and respiratory failure and in heart and lung transplant recipients in the early post-transplant period. The duplex test, including miR-424 and CRP, has a diagnostic value for detecting the high risk of post-transplant gram-negative bacteremia in heart and lung transplant recipients.

目的

移植后早期并发症，如急性移植物排斥反应和感染，与急需免疫抑制治疗的心脏和肺移植受者的高发病率和死亡率相关。MiR-424是miR-16家族的成员，在心血管和呼吸系统病理发展中发挥重要生理作用，参与单核细胞和巨噬细胞分化的调节，并具有免疫抑制潜力。本研究的目的是确定循环miR-424作为心脏和肺移植受者移植后并发症潜在生物标志物的诊断价值。

方法

本研究纳入了83名年龄在18至70（48±13）岁的心脏移植受者；26名年龄在10至74（36±16）岁的肺移植受者。通过实时PCR（美国Qiagen公司）检测血浆中miR-424的表达。通过ΔCt方法评估miR-424水平的意义。急性移植物排斥反应通过心内膜或经支气管活检结果进行验证。移植后感染并发症通过血培养中细菌血症的微生物鉴定进行验证。

结果

我们的研究表明，与健康个体相比，慢性心力衰竭或呼吸衰竭患者血浆中miR-424上调（分别为p = 0.003和p = 0.04）。心脏移植前患者中miR-424表达与红细胞和血红蛋白水平呈直接相关（分别为p = 0.01和p = 0.03）。移植后，心脏（r = 0.75；p = 0.02）和肺（r = 0.50；p = 0.04）移植受者血浆miR-424的表达与C反应蛋白（CRP）水平相关。心脏移植后血浆miR-424的表达与他克莫司血药浓度相关（r = 0.38；p = 0.04）。有或无急性移植物排斥反应的心脏或肺移植受者中miR-424水平无差异（分别为p = 0.47和p = 0.78），但革兰阴性菌血症的心脏和肺移植受者中miR-424水平显著更高（p = 0.002）。当miR-424水平高于阈值（-5.72倍变化）时，菌血症的相对风险为RR = 3.84 [95% CI 1.94 - 7.61]；敏感性 = 60.0%；特异性 = 89.2%。在与miR-424的双重检测中，CRP浓度高于7mg/L可将心脏和肺移植受者移植后革兰阴性菌血症的miR-424诊断特征提高至RR = 9.17 [95% CI 1.37 - 61.46]；敏感性 = 83.3%，特异性 = 90.1%。