Conroy Andrea L, Datta Dibyadyuti, Opoka Robert O, Batte Anthony, Bangirana Paul, Gopinadhan Adnan, Mellencamp Kagan A, Akcan-Arikan Ayse, Idro Richard, John Chandy C
Ryan White Center for Pediatric Infectious Disease and Global Health, Indiana University School of Medicine, Indianapolis, IN, United States.
Department of Paediatrics and Child Health, Makerere University College of Health Sciences, Kampala, Uganda.
Front Hum Neurosci. 2023 May 2;17:1177242. doi: 10.3389/fnhum.2023.1177242. eCollection 2023.
Cerebral malaria is one of the most severe manifestations of malaria and is a leading cause of acquired neurodisability in African children. Recent studies suggest acute kidney injury (AKI) is a risk factor for brain injury in cerebral malaria. The present study evaluates potential mechanisms of brain injury in cerebral malaria by evaluating changes in cerebrospinal fluid measures of brain injury with respect to severe malaria complications. Specifically, we attempt to delineate mechanisms of injury focusing on blood-brain-barrier integrity and acute metabolic changes that may underlie kidney-brain crosstalk in severe malaria.
We evaluated 30 cerebrospinal fluid (CSF) markers of inflammation, oxidative stress, and brain injury in 168 Ugandan children aged 18 months to 12 years hospitalized with cerebral malaria. Eligible children were infected with and had unexplained coma. Acute kidney injury (AKI) on admission was defined using the Kidney Disease: Improving Global Outcomes criteria. We further evaluated blood-brain-barrier integrity and malaria retinopathy, and electrolyte and metabolic complications in serum.
The mean age of children was 3.8 years (SD, 1.9) and 40.5% were female. The prevalence of AKI was 46.3% and multi-organ dysfunction was common with 76.2% of children having at least one organ system affected in addition to coma. AKI and elevated blood urea nitrogen, but not other measures of disease severity (severe coma, seizures, jaundice, acidosis), were associated with increases in CSF markers of impaired blood-brain-barrier function, neuronal injury (neuron-specific enolase, tau), excitatory neurotransmission (kynurenine), as well as altered nitric oxide bioavailability and oxidative stress ( < 0.05 after adjustment for multiple testing). Further evaluation of potential mechanisms suggested that AKI may mediate or be associated with CSF changes through blood-brain-barrier disruption ( = 0.0014), ischemic injury seen by indirect ophthalmoscopy ( < 0.05), altered osmolality ( = 0.0006) and through alterations in the amino acids transported into the brain.
In children with cerebral malaria, there is evidence of kidney-brain injury with multiple potential pathways identified. These changes were specific to the kidney and not observed in the context of other clinical complications.
脑型疟疾是疟疾最严重的表现形式之一，是非洲儿童后天神经残疾的主要原因。最近的研究表明，急性肾损伤（AKI）是脑型疟疾脑损伤的一个危险因素。本研究通过评估脑损伤脑脊液指标相对于严重疟疾并发症的变化，来评估脑型疟疾脑损伤的潜在机制。具体而言，我们试图阐明损伤机制，重点关注血脑屏障完整性以及可能是重症疟疾肾脑串扰基础的急性代谢变化。
我们评估了168名18个月至12岁因脑型疟疾住院的乌干达儿童的30种脑脊液（CSF）炎症、氧化应激和脑损伤标志物。符合条件的儿童感染了疟原虫且出现无法解释的昏迷。入院时的急性肾损伤（AKI）根据改善全球肾脏病预后组织（KDIGO）标准定义。我们进一步评估了血脑屏障完整性、疟疾视网膜病变以及血清中的电解质和代谢并发症。
儿童的平均年龄为3.8岁（标准差1.9），40.5%为女性。AKI的患病率为46.3%，多器官功能障碍很常见，76.2%的儿童除昏迷外至少有一个器官系统受累。AKI和血尿素氮升高，但不是其他疾病严重程度指标（严重昏迷、癫痫发作、黄疸、酸中毒），与血脑屏障功能受损、神经元损伤（神经元特异性烯醇化酶、tau蛋白）、兴奋性神经传递（犬尿氨酸）以及一氧化氮生物利用度改变和氧化应激的脑脊液标志物增加相关（多重检验校正后P<0.05）。对潜在机制的进一步评估表明，AKI可能通过血脑屏障破坏（P = 0.0014）、间接检眼镜检查所见的缺血性损伤（P<0.05）、渗透压改变（P = 0.0006）以及通过进入大脑的氨基酸改变来介导或与脑脊液变化相关。
在脑型疟疾儿童中，有证据表明存在肾脑损伤，并确定了多种潜在途径。这些变化是肾脏特有的，在其他临床并发症的情况下未观察到。
