急性肾损伤患者高尿酸血症与死亡率之间的关系
The Association between Hyperuricemia and Mortality in Patients with Acute Kidney Injury

作者: 李勋亮 :青岛大学,山东 青岛; 栾 弘 , 孙建平 :青岛大学附属医院,山东 青岛;

关键词: 高尿酸血症急性肾损伤预后死亡率Hyperuricemia Acute Kidney Injury Prognosis Mortality

摘要:
目的:探讨急性肾损伤患者高尿酸血症与死亡率的关系。方法:回顾性收集2015年1月1日至2020年7月31日于青岛大学附属医院住院并发生AKI的4646例患者的临床资料。AKI诊断标准依照KDIGO定义与分期进行判断。将血尿酸高于360 μmol/L (女性)、>420 μmol/L (男性以及绝经女性)作为高尿酸血症的确诊依据。使用logistic回归模型对AKI病人血尿酸程度以及住院死亡比例之间的联系进行分析。结果:4646例患者中高尿酸血症患者为1316例(28.3%)。患者总体死亡率为7.7% (n = 358),高尿酸血症组死亡率显著高于非高尿酸血症组(12.8%比5.7%,P < 0.001)。进一步采用logistic回归模型校正年龄、性别、合并症、生化指标及用药等因素后发现,高尿酸血症组患者死亡风险是非高尿酸血症组的1.62倍,当基线血尿酸水平每增加100 μmol/L,患者死亡风险增加38.1% (OR = 1.381, 95%CI 1.304~1.462, P < 0.001)。亚组分析显示,在eGFR ≥ 60 (ml/min)亚组中,两组患者死亡率无统计学意义;而在eGFR < 60 (ml/min)亚组中,高尿酸血症组患者死亡率显著高于非高尿酸血症组(14.6%比8.9%,P < 0.001)。在AKI分期亚组中,和非高尿酸血症组进行比较,高尿酸血症组病人的死亡率有所上升(AKI 1期:11.2%比5.1%,AKI 2期:23.3%比10.6%,AKI 3期:29.8%比10.5%,均P < 0.05)。结论:高尿酸血症和AKI患者病人住院死亡率之间有一定的相关性。高尿酸血症是导致AKI病人死亡的危险因素,在临床的治疗中我们需要重视。

Abstract: Objective: To investigate the association between hyperuricemia and hospital mortality in patients with acute kidney injury. Methods: Clinical data of 4646 patients with AKI in the Affiliated Hospital of Qingdao University from January 1, 2015 to July 31, 2020 were collected. AKI was defined and staged according to the Kidney Disease: Improving Global Outcomes (KDIGO) criteria. Hyperuricemia is defined as serum uric acid > 360 μmol/L (female) and >420 μmol/L (men and postmenopausal women). Logistic regression model was used to evaluate the association between serum uric acid level and hospital mortality in patients with AKI. Results: A total of 4646 patients were included, among whom, 1316 patients were diagnosed with hyperuricemia (28.3%). The overall mortality rate was 7.7% (n = 358). The mortality rate in the hyperuricemia group was significantly higher than that in the non-hyperuricemia group (12.8% vs. 5.7%, P < 0.001). Logistic regression model was used to adjust for age, sex, complications, biochemical indicators and drug use, and it was found that the risk of death in the hyperuricemia group was 1.62 times that in the non-hyperuricemia group. When baseline uric acid level increased by 100 μmol/L, the risk of death in the hyperuricemia group increased by 38.1% (OR = 1.381, 95%CI 1.30~1.462, P < 0.001). Subgroup analysis showed that in the eGFR ≥ 60 (ml/min) subgroup, there was no statistically significant difference in mortality between the two groups. In the eGFR < 60 (ml/min) subgroup, mortality was significantly higher in the hyperuricemia group than in the non-hyperuricemia group (14.6% vs. 8.9%, P < 0.001). In the AKI staging subgroup, mortality was higher in the hyperuricemia group than in the non-hyperuricemia group (all P < 0.05). Conclusion: Hyperuricemia is associated with increased hospital mortality in AKI patients. Hyperuricemia is an independent risk factor for death in patients with AKI.

1. 引言

急性肾损伤(AKI)是一种常见且严重的综合症。它以尿量和血清肌酐作为诊断标准,并有高发病率及高死亡率 [1]。10%~15%的患者会在住院期间发生AKI,其死亡率是非AKI患者的四倍 [1] [2]。此外,幸存者往往不能恢复肾功能,需要长期透析,这带来了巨大的经济负担 [3] [4] [5]。考虑AKI的高发病率和预后较差,一些研究者已经在寻求AKI死亡的危险因素。尿酸是由碳、氮、氧、氢等多种化合物组成的,其化学分子式为C5H4N4O3。高尿酸血症在临床中十分的普遍。现在来看,嘌呤在体内升高和痛风、心血管疾病以及糖尿病等多种代谢性疾病有一定的关系 [6] [7] [8] [9]。它还会增加一些病理状况下的死亡风险,如糖尿病和慢性肾脏疾病 [10] [11] [12]。有相关数据表明,高尿酸血症可导致住院病人的AKI有所增加 [13]。但高尿酸血症与AKI病人预后的关系至今研究较少。因此,本研究拟对本院住院发生AKI的患者进行回顾性分析,评估高尿酸血症与AKI患者死亡率之间的关系。

2. 对象和方法

2.1. 研究对象

选取2015年1月1日至2020年7月31日于青岛大学附属医院住院并发生AKI的患者,所有入选者临床资料完整。纳入标准:1) 2天内血清肌酐绝对值增加达到 ≥ 26.5 μmol/L或在1周内血清肌酐较基础值增加 ≥ 150%;2) 年龄 ≥ 18岁;3) 住院时间 ≥ 24 h;4) 入院2天中发生AKI。排除标准:1) 血清肌酐检测次数小于2次;2) 资料不全;3) 如果患者多次入院,则仅分析首次入院。本次研究经青岛大学附属医院伦理委员会同意批准。

2.2. 相关定义

依照KDIGO诊断,将AKI定义为:1) 2天内血清肌酐绝对值增加达到 ≥ 26.5 μmol/L或在1周内血清肌酐较基础值增加 ≥ 150%;2) 或尿量 < 0.5 mL/kg/h达到6小时以上 [14]。由于本中心尿量为患者自行记录并上报,且存在大量缺失值,故本研究仅以肌酐标准定义AKI。高尿酸血症定义为将血尿酸高于360 μmol/L (女性)、>420 μmol/L (男性以及绝经女性) [15]。

2.3. 数据收集

收集人口学和临床数据的基线资料,包括:年龄、性别、体重指数、高血压、糖尿病、心脑血管疾病、eGFR、血红蛋白、血小板、血白细胞、血白蛋白、谷丙转氨酶、谷草转氨酶、血管紧张素酶抑制剂(Angiotensin converting enzyme inhibitor, ACEI)、血管紧张素II受体抑制剂(angiotensin II type 1 receptor blocke, ARB)、钙离子拮抗剂(Calcium channel blockers, CCB)、利尿剂、住院天数及住院死亡率等信息。所有的实验室检查指标均为入院后48 h内测量的数值。观察主要结局指标是死亡率,次要结果是住院天数。

2.4. 统计学分析

采用SPSS22.0软件对数据进行统计学处理。正态分布的计量资料用x ± s表示,非正态分布计量资料以M (1/4, 3/4)表示,计量资料符合正态分布的组间比较采用t检验,不符合则采用Wilcoxon秩和检验。定性资料以例数(百分比)表示,采用卡方检验或Fisher确切概率法进行两组间比较。运用logistic回归模型评估AKI患者血尿酸水平与死亡率的关系,并以比值比(OR)和95%置信区间(95%CI)表示。在多因素回归分析中运用逐步后退法,校正以下变量:年龄、性别、合并症、生化指标及用药。P < 0.05视为差异有统计学意义。

3. 结果

3.1. 基线资料对比

本研究共纳入4646例患者,年龄(56.6 ± 18.3)岁,男性2941例(63.3%),合并高血压者2316例(49.8%),合并糖尿病者1151例(24.8%),合并慢性肾脏病者809例(17.4%)。其中高尿酸血症组3330例(71.7%),非高尿酸血症组1316例(28.3%)。结果表明:和非高尿酸血症组进行比较,高尿酸血症组病人的年龄基数较高[(59.3 (42.5, 72.3)比57.2 (40.3, 69.7)岁,P < 0.01],男性占比较高(57.2%比52.2%,P < 0.05),体重指数较高[24.2 (23.0, 27.1)比24.2 (22.1, 25.7) kg/m2,P < 0.001],合并高血压、糖尿病及心脑血管疾病患者比例较高(均P < 0.01),白细胞与谷草转氨酶指标有所上升(均P < 0.01),eGFR、血红蛋白和血小板在体内的水平均减少(均P < 0.05),应用ACEI、ARB、CCB及利尿剂药物者比例较高(均P < 0.001)。病人死亡率达到7.7% (n = 358),高尿酸血症组该指标明显大于非高尿酸血症组(12.8%与5.7%,P < 0.001)。其余血白蛋白、谷丙转氨酶和在院时间等指标两组比较无差异性。见表1

Table 1. Comparison of baseline conditions between hyperuricemia group and non-hyperuricemia group

表1. 高尿酸血症组与非高尿酸血症组患者基线情况比较

ACEI:血管紧张素转化酶抑制剂,ARB:血管紧张素II受体抑制剂,CCB:钙离子拮抗剂。

3.2. 血尿酸水平对死亡率的影响

使用logistic回归模型来量化血尿酸水平与死亡率之间的关系。在连续线性模型关系下,未校正logistic回归模型中,较高的血尿酸水平与病人的高死亡率呈正比例关系。将年龄、性别、合并症、生化指标以及药物对上述模型进行校正,能够将其中混杂因素排除,后发现死亡风险角度上来看,血尿酸水平每加大100 μmol/L,OR = 1.381,95%CI 1.304~1.462,P < 0.001;而高尿酸血症组病人其死亡风险已经达到了1.62倍。见表2

3.3. 亚组分析

在eGFR ≥ 60 (ml/min)亚组中,两组患者死亡率及住院时间差异无统计学意义;而在eGFR < 60 (ml/min)亚组中,高尿酸血症组患者死亡率显著高于非高尿酸血症组(14.6%比8.9%,P < 0.001),高尿酸组患者住院时间短于非高尿酸血症组[(9.7 ± 9.8)比(13.1 ± 10.3)天,P < 0.01]。见表3。在AKI分期亚组中,与非高尿酸血症组进行比较,高尿酸血症组病人的死亡比例相对来说比较高(均P < 0.05),在院治疗时间短(均P < 0.05)。见表4

Table 2. Relationship between hyperuricemia and death in AKI patients

表2. AKI患者高尿酸血症与死亡的关系

Table 3. The prognosis of AKI patients was analyzed by EGFR subgroup

表3. eGFR亚组分析AKI患者的预后

Table 4. The prognosis of AKI patients was analyzed in the AKI staging subgroup

表4. AKI分期亚组分析AKI患者的预后

4. 讨论

我们观察到高尿酸血症与AKI患者的住院死亡率增加相关。而且,在对年龄、性别、合并症、生化指标及用药进行校正后,我们发现高尿酸血症仍然与较高AKI患者的住院死亡率相关。一些研究数据证实,高尿酸血症和很多代谢性疾病有一定的关系,本次研究表明,高尿酸血症是住院AKI患者死亡的危险因素之一。AKI患者高尿酸血症具有较高的危险性,在治疗过程中需密切注意AKI病人的血清尿酸变化。

AKI是一种常见的危险并发症,死亡率较高 [16]。它与局部和全身性炎症有关 [17]。这些炎症介质包含白细胞、嗜中性粒细胞、淋巴细胞、巨噬细胞、成纤维细胞、血小板、内皮细胞和肥大细胞 [18] [19]。许多数据结果证实体内高尿酸和炎症反应、氧化应激、NS系统激活之间呈现一定的关联性 [20]。因此,全身性炎症反应可能有助于解释高尿酸血症与AKI患者死亡率之间的潜在联系。但是,这些关系的确切机制仍然未知。

在一些研究中,已经提出了这些机制的几种可能的解释。首先,在AKI患者中,铁的代谢和骨髓功能受到炎症的抑制 [21]。促炎细胞因子也抑制红细胞的成熟和增殖 [22]。此外,炎症程度对AKI患者的生存也有负面影响 [23]。而且,AKI的发生和发展与炎症反应密切相关。AKI中发生的肾血管和血管收缩机制的根本变化与高尿酸血症相似,包括肾素–血管紧张素–醛固酮系统激活,氧化应激,一氧化氮减少和炎症 [20]。这些揭示了高尿酸血症与AKI之间的紧密联系。

约30%的尿酸经过肾脏排除体外,在肾小球滤过的90%~95%的尿酸会在近端肾小管被重吸收回体内 [24]。血液中尿酸水平的高低和肾小球滤过以及肾小管重吸收之间有着不可分割的联系,所以高尿酸血症的原因之一可能是因为肾小球滤过率减少、肾小管尿酸分泌减少或肾小管重吸收能力加强所导致的,也可能因为肾脏出现疾病所导致血液中尿酸升高 [25]。考虑到肾小球滤过率下降对血尿酸浓度的影响,我们使用eGFR和AKI分期进行了亚组分析来分析AKI患者高尿酸血症对死亡率的影响。在AKI分期亚组中,我们发现在AKI各期的AKI高尿酸血症患者与AKI非高尿酸血症患者相比,死亡率均明显升高。在eGFR亚组中,eGFR大于60 mL/min组中,AKI高尿酸血症患者与AKI非高尿酸血症患者相比,死亡率无明显差异。越来越多的证据表明,AKI患者伴有CKD的预后与没有CKD的AKI患者不同。Ali等 [26] 研究报道AKI患者伴有CKD的住院死亡率显著高于不伴有CKD的AKI患者。Wu等 [27] 发现无CKD的AKI病人的肾脏恢复比例显著大于患有CKD的AKI病人。高尿酸血症与肾脏疾病密切相关。高尿酸血症不仅被认为是肾功能不全的重要指标,也是CKD进展的重要因素。因此,在低eGFR的AKI患者中更应该积极监测血清尿酸水平。

最关键的临床问题是高尿酸血症的治疗是否会降低AKI患者的死亡风险。有研究表明,应用别嘌醇降低血尿酸水平可以改善全身性炎症反应和氧化应激 [28]。两项小型研究报告表明,应用别嘌呤醇降低血尿酸可以预防造影剂诱发的AKI的发生 [29] [30]。Kanbay等 [31] 证明了在无症状的高尿酸血症患者中,应用别嘌呤醇治疗可以导致eGFR升高。而研究人员Tallaat以及El-Sheikh的其他实验证实了在CKD 3以及4期病人中,不使用别嘌呤醇进行治疗可导致AKI的发生 [32]。在Focus一项研究中证实,使用非布索坦可对CKD病人的肾功能起到改善作用,血尿酸减少1 mg/dL,eGFR指标会增加1 mL/min [33]。综上所述,我们在临床中应监测基线血清尿酸水平,如果尿酸水平较高,降尿酸药物可能会降低AKI患者的死亡率,但降尿酸药物对于AKI患者高尿酸血症的作用应通过前瞻性随机对照试验来证实。

本研究也有一些局限性。首先,我们的研究是单中心回顾性研究,且排除了部分无血肌酐、血尿酸数据或者其他数据资料不完整的患者,导致可能会受到选择偏倚的影响。其次,由于本研究只应用肌酐标准定义AKI,缺少尿量标准,AKI的检测灵敏度和特异性可能与以前的研究不同。并且,本次实验只使用死亡率作为指标进行分析可能对导致预后评估产生影响。最后,本研究并没有将药物对体内尿酸产生的影响进行混杂因素的分析,因此实验结果最终可能出现一定的出入。

5. 结论

综上,我们的研究表明,AKI患者高尿酸血症与死亡率增高相关。但这些研究结果尚需要进一步的研究,特别是大型的前瞻性研究,以确认高尿酸血症与不良临床结果之间的关系。此外,尚需进一步的基础研究来明确研究结果背后的确切机制。

NOTES

*第一作者。

#通讯作者。

文章引用: 李勋亮 , 栾 弘 , 孙建平 (2021) 急性肾损伤患者高尿酸血症与死亡率之间的关系。 临床医学进展, 11, 1695-1702. doi: 10.12677/ACM.2021.114243

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