Effects of esketamine on perioperative renal injury in paediatric patients undergoing living donor liver transplantation

Abstract

BACKGROUND

Living-donor liver transplantation (LDLT) is the definitive treatment for end-stage paediatric liver disease; however, acute kidney injury (AKI) occurs in 40%-70% of cases and significantly affects mortality and clinical outcomes. Esketamine has demonstrated anti-inflammatory and organ-protective properties in preclinical studies, but its renoprotective effects in paediatric LDLT have not been established.

AIM

To determine whether intraoperative administration of esketamine reduces perioperative AKI and attenuates the inflammatory response in paediatric LDLT.

METHODS

This randomised, double-blind, placebo-controlled trial was conducted at a tertiary transplant centre in China. Sixty paediatric patients (aged 5-15 months) undergoing LDLT were randomly assigned (1:1) to receive intraoperative esketamine (group E; 0.5 mg/kg at induction followed by 0.5 mg/kg/hour infusion) or placebo (group C). Blood samples were collected at five time points to measure serum creatinine (Scr), tumour necrosis factor, interleukin (IL)-18, IL-10, and neutrophil gelatinase-associated lipocalin (NGAL). Between-group comparisons used independent t-tests or Mann-Whitney U tests.

RESULTS

Group E demonstrated lower Scr at 3 hours post-reperfusion (40.56 ± 15.4 μmol/L vs 60.37 ± 15.4 μmol/L, P < 0.05), 24 hours postoperatively (36.35 ± 8.96 μmol/L vs 58.93 ± 12.57 μmol/L, P < 0.05), and 72 hours postoperatively (34.64 ± 5.66 μmol/L vs 53.51 ± 8.69 μmol/L, P < 0.05). Serum tumour necrosis factor, IL-18, and NGAL levels were also reduced in group E at time points T2-T5 (P < 0.05). Mechanical ventilation duration was shorter in group E (168.55 ± 69.64 minutes vs 264.55 ± 73.64 minutes, P < 0.001).

CONCLUSION

Intraoperative administration of esketamine attenuates the increase in Scr levels following ischemia-reperfusion injury and attenuates the systemic inflammatory response in paediatric LDLT recipients.

Key Words: Esketamine; Paediatric living-donor liver transplantation; Acute kidney injury; Ischaemia-reperfusion injury; Renal protection; Inflammatory factors; Paediatric anaesthesia

Core Tip: This randomized controlled trial demonstrates that, compared with the control group, intraoperative esketamine administration significantly attenuates the increase in serum creatinine levels following ischemia-reperfusion injury and attenuates the systemic inflammatory response in pediatric patients undergoing living donor liver transplantation. The renoprotective effects are mediated by the suppression of tumour necrosis factor-α, interleukin-18, and neutrophil gelatinase-associated lipocalin, alongside hemodynamic stabilization. Esketamine may be considered as a component of anesthetic management to mitigate perioperative renal injury in this high-risk population.

INTRODUCTION

Since the late 1980s, paediatric living-donor liver transplantation (LDLT) has been progressively adopted across transplant centres worldwide, as reported by Chan and Fan[1]. And de Ville de Goyet et al[2] and Gondolesi[3] reported significant improvements in long-term postoperative survival in children, attributable to advances in surgical techniques, perioperative management, and immunosuppressive therapy. As the only effective treatment for paediatric end-stage liver disease (PELD), LDLT plays a central role in managing severe hepatic conditions, including cholestatic liver disease, inborn errors of metabolism, fulminant hepatic failure, and hepatic malignancies[4-7]. Thongprayoon et al[8] demonstrated that postoperative acute kidney injury (AKI) is a common complication of liver transplantation, occurring in 40%-70% of cases. Moura et al[9] further showed that postoperative AKI significantly increases paediatric mortality, prolongs hospital stay, and reduces long-term graft survival, thereby worsening overall prognosis. Shekarforoush et al[10] and Luggya et al[11] reported that ketamine, a commonly used anaesthetic in paediatric practice, exerts cardioprotective effects against myocardial ischaemia-reperfusion injury by reducing the release of pro-inflammatory cytokines and attenuating inflammation and apoptosis. Esketamine, the dextrorotatory isomer of ketamine, has recently attracted attention for its potential organ-protective properties. Xian et al[12] demonstrated that esketamine mitigates AKI in a rat sepsis model by suppressing systemic inflammatory responses and reducing tissue inflammatory damage. However, whether esketamine reduces pro-inflammatory cytokine release and confers renoprotective effects in children undergoing LDLT remains unclear. This study aims to evaluate the effects of esketamine on perioperative renal injury in paediatric LDLT and to inform the selection of appropriate anaesthetic agents in clinical practice.

MATERIALS AND METHODS

General data

This study was a randomised controlled clinical trial. Sample size was calculated using PASS 15.0 software, with serum creatinine (Scr) levels at 3 hours in the neohepatic phase as the primary endpoint. In a pilot study of five paediatric patients, the mean Scr levels in the esketamine and control groups were 40.56 μmol/L and 60.37 μmol/L, respectively. Assuming a between-group difference of 19.81 μmol/L and a pooled standard deviation of 15.4 μmol/L, 24 patients per group were required to detect a statistically significant difference using a two-sided test with 80% power and a significance level of α = 0.05. Allowing for a 20% attrition rate, including loss to follow-up and withdrawal, a total of 60 patients (n = 30 per group) were planned for enrolment, which met the statistical requirements. Sixty paediatric patients scheduled for elective LDLT were enrolled without sex restriction. Participants were aged 5-15 months, weighed 5.5-10.0 kg, and were classified as American Society of Anesthesiologists (ASA) physical status II or III. All patients had no cardiac, pulmonary, renal, or cerebral dysfunction and no congenital heart disease, such as atrial or ventricular septal defects. Patients were randomly assigned to the esketamine group (group E, n = 30) or the control group (group C, n = 30). A research coordinator who was not involved in clinical management prepared the study medications. Esketamine (50 mg) was diluted with normal saline to a total volume of 20 mL, and 20 mL of normal saline served as the placebo. Both solutions were prepared in identical, indistinguishable syringes. Randomisation was performed in a 1:1 ratio using a computer-generated random number table. Allocation sequences were placed in sequentially numbered, opaque, sealed envelopes. Upon enrolment, the coordinator opened the next envelope and provided the corresponding syringe to the attending anaesthesiologist, who remained blinded to group allocation. Patients in group E received 0.5 mg/kg esketamine (batch No. 200411BL; Jiangsu Hengrui Pharmaceutical Co., Ltd.) during anaesthetic induction, followed by a continuous infusion of 0.5 mg/kg/hour until the end of surgery. Group C received an equivalent volume of 0.9% sodium chloride solution during induction and maintenance. Group allocation was concealed from patients, anaesthesiologists, data collectors, and outcome assessors. The study was approved by the Ethics Committee of the Tianjin First Central Hospital (Approval no. KYAP2025-26), and written informed consent was obtained from the legal guardians of all participants prior to study enrolment.

Anaesthetic method

Intravenous access was established before the patient entered the operating theatre. The patients did not eat or drink for 6 hours before surgery. Upon entering the operating theatre, heart rate (HR), electrocardiogram, blood pressure, and blood oxygen saturation (SPO₂) were monitored. An intravenous infusion of paediatric electrolyte solution was administered at a rate of 10-20 mL/kg/hour. Anaesthetic induction included intravenous administration of 0.15-0.2 mg/kg midazolam, 0.15 mg/kg etomidate, 2-5 µg/kg fentanyl, and 0.3-0.6 mg/kg rocuronium bromide. Following tracheal intubation, mechanical ventilation was initiated with an inspired oxygen concentration of 50%-60%, a respiratory rate of 20-25 breaths/minute, a tidal volume: Inspired gas ratio of 1:1.5, and maintenance of end-tidal carbon dioxide pressure at 30-40 mmHg (1 mmHg = 0.133 kPa). Both groups of paediatric recipients received combined intravenous and inhalation anaesthesia with propofol and sevoflurane during surgery. Anaesthesia maintenance involved intermittent intravenous injections of fentanyl at 1-2 µg/kg, continuous infusion of cisatracurium besylate at 1-2 µg/kg/minute, inhalation of sevoflurane at 0.6-1.5 minimum effective alveolar concentrations, and continuous intravenous infusion of propofol at 9-15 mg/kg to maintain analgesia, sedation, and muscle relaxation. Group E received 0.5 mg/kg esketamine during induction, followed by a continuous infusion of esketamine at 0.5 mg/kg/hour until the end of surgery. Group C received the same dose of 0.9% sodium chloride for induction and maintenance of anaesthesia. Continuous bispectral index (BIS) monitoring was performed, with the BIS values maintained within 40-60 and the anaesthetic drug doses adjusted according to the BIS readings. Ultrasound-guided radial artery puncture and internal jugular vein catheterisation were performed, with continuous monitoring of invasive arterial pressure and central venous pressure (CVP). Intravenous fluid warming was administered throughout surgery, with paediatric inflatable warming blankets maintaining the nasopharyngeal temperature between 36.0 °C and 37.0 °C. During the anhepatic phase and when significant haemodynamic fluctuations occurred after the new liver was opened, intravenous dopamine infusion was administered to maintain circulatory stability. Suspended red blood cells were intravenously administered when the haemoglobin concentration fell below 80 g/L, and fresh frozen plasma was infused on the basis of the coagulation test results. The respiratory rate, oxygen concentration, and fluid infusion volume were adjusted in real time on the basis of intraoperative blood gas analysis, blood loss, urine output, and other factors to maintain the patient’s electrolyte and acid-base balance alongside adequate blood volume. Upon completion of surgery, the patient was transferred to the intensive care unit (ICU) with tracheal intubation and arterial/venous catheters in place for continued management.

Surgical phases

Preanhepatic phase: The period from the commencement of surgery until the occlusion of the inferior vena cava and portal vein.

Anhepatic phase: From removal of the diseased liver and occlusion of the inferior vena cava and portal venous circulation until establishment of blood flow in the transplanted liver.

New liver phase: From opening the inferior vena cava and establishing portal venous circulation until the conclusion of surgery.

Specimen collection and parameter measurement

Specimen collection: Blood samples were collected 5 minutes after anaesthetic induction (T1), 30 minutes into the no-liver phase (T2), 3 hours into the new-liver phase (T3), 24 hours postoperatively (T4), and 3 days postoperatively (T5). Blood was centrifuged at 3000 rpm for 15 minutes at room temperature using a centrifuge with a radius of 13 cm. The serum was then transferred to a -80 °C freezer for storage and subsequent analysis.

Indicator assays: Serum cytokine level measurement: Scr concentration was determined using a colorimetric assay, while serum tumour necrosis factor-α (TNF-α), interleukin (IL)-18, IL-10, and neutrophil gelatinase-associated lipocalin (NGAL) concentrations were measured via enzyme-linked immunosorbent assay.

Paediatric patient general conditions: Preoperative data included age, sex, height, weight, PELD score, and laboratory test results. Intraoperative data included the duration of surgery, urine output, blood loss, blood product transfusion volume, and fluid infusion volume. Postoperative data included laboratory test results, length of hospital stay, extubation time, and ICU stay duration.

Renal function assessment: AKI, defined according to the 2012 International Kidney Disease Outcomes Organisation guidelines[13], as follows: An increase in Scr of ≥ 0.3 mg/dL (≥ 26.5 μmol/L) within 48 hours; or an increase in Scr to ≥ 1.5 times the baseline or a urine output < 0.5 mL/kg/hour for 6 consecutive hours.

Statistical analysis

Analysis was performed using SPSS 23.0 software. Normally distributed continuous data are expressed as the mean ± SD. Between-group comparisons were performed with paired t tests, whereas within-group comparisons were performed with repeated measures analysis of variance. Non-normally distributed data (blood transfusion volume and plasma transfusion volume, presented as medians with interquartile ranges in Table 1) were analyzed using the Mann-Whitney U test for intergroup comparisons. The χ² tests or Fisher’s exact probability test were used for counting data comparisons. P < 0.05 was considered to indicate statistical significance.

Table 1 Comparison of general characteristics between paediatric groups.

Parameter	Group E (n = 30)	Group C (n = 30)	P value
Age (months)	7.56 (6.44-9.09)	8.26 (6.80-10.09)	0.091
Weight (kg)	7.05 ± 0.44	7.18 ± 0.52	0.206
Height (cm)	65.45 ± 5.09	66.38 ± 7.02	0.426
PELD score	16.09 ± 3.40	17.10 ± 3.43	0.055
ASA (II/III)	18/12	17/13	0.586
Preoperative Scr level (μmol/L)	16.88 ± 6.02	17.71 ± 5.42	0.527
Blood loss (mL)	158.02 ± 32.12	155.17 ± 27.21	0.656
Urine output (mL)	455.50 ± 62.46	446.28 ± 59.75	0.494
Infusion volume (mL)	1620.63 ± 443.41	1478.73 ± 510.38	0.255
Blood transfusion volume (units)	3.00 (2.00, 4.00)	2.00 (2.00, 3.76)	0.175
Plasma transfusion volume (mL)	400 (225-400)	400 (200-415)	0.680
Ascites-free period (minute)	41.32 ± 12.53	43.54 ± 14.23	0.596
Surgical time (hour)	8.60 ± 1.20	8.80 ± 1.03	0.361
Anaesthesia duration (hour)	10.12 ± 1.21	9.80 ± 1.06	0.734

Data were showed as median (interquartile range) or mean ± SD. PELD: Paediatric end-stage liver disease; ASA: American Society of Anesthesiologists; Scr: Serum creatinine.

RESULTS

General and intraoperative characteristics of paediatric liver transplant recipients

Comparisons between groups for age, height, weight, PELD score, ASA physical status classification, preoperative Scr level, blood loss, urine output, fluid infusion volume, blood transfusion volume, plasma transfusion volume, anhepatic period duration, operation time, and anaesthesia duration revealed no statistically significant differences (P > 0.05; Table 1).

Comparison of AKI incidence between the two groups

The incidence of AKI was 36.7% in group E and 50.0% in group C, with no statistically significant difference between the two groups (χ² = 1.086, P = 0.435). Compared with those at T1, Scr levels significantly increased at T3-5 in both groups (P < 0.05), peaking at T3. Compared with group C, group E exhibited significantly lower Scr levels at T3-5 (P < 0.05). No significant intergroup differences were observed in the changes in the Scr level between T1 and T2 (P > 0.05; Table 2).

Table 2 Comparison of serum creatinine levels and acute kidney injury incidence between groups.

Time	Group E Scr (μmol/L)	Group C Scr (μmol/L)	P value	Cohen's d
T1	18.84 ± 6.11	20.78 ± 5.67	0.207	-0.329
T2	22.26 ± 7.05	22.59 ± 6.85	0.855	-0.047
T3	40.56 ± 15.4a,b	60.37 ± 15.4b	< 0.05	-1.286
T4	36.35 ± 8.96a,b	58.93 ± 12.57b	< 0.05	-2.069
T5	34.64 ± 5.66a,b	53.51 ± 8.69b	< 0.05	-2.573
AKI	11 (36.7)	15 (50.0)	0.435	-

^aP < 0.05 vs group C.

^bP < 0.05 vs T1.

Data were showed as n (%) or mean ± SD. T1: 5 minutes after anaesthetic induction; T2: 30 minutes during the anhepatic phase; T3: 3 hours during the new liver phase; T4: 24 hours postoperatively; T5: 72 hours postoperatively. Scr: Serum creatinine; AKI: Acute kidney injury.

Comparison of perioperative haemodynamic changes between groups

Compared with that at T1, the mean arterial pressure (MAP) was significantly lower at T2-3 in both groups (P < 0.05). Compared with that in group C, the MAP in group E was increased at T2-3 (P < 0.05). There were no statistically significant differences in HR or CVP between the two groups at any time point (P > 0.05; Table 3).

Table 3 Comparison of mean arterial pressure, heart rate, and central venous pressure between the two groups of paediatric patients.

	Group E			Group C
	MAP (mmHg)	HR (beats/minute)	CVP (mmHg)	MAP (mmHg)	HR (beats/minute)	CVP (mmHg)
T1	55 ± 3.1	119 ± 12	6.4 ± 2.5	54 ± 3.7	126 ± 13	6.9 ± 2.2
T2	44 ± 2.8a,b	128 ± 17	5.2 ± 2.3	34 ± 2.6b	131 ± 16	5.4 ± 3.5
T3	42 ± 2.5a,b	105 ± 16	8.3 ± 2.0	32 ± 2.7b	108 ± 17	8.9 ± 2.8
T4	48 ± 4.8	120 ± 16	9.5 ± 3.4	47 ± 3.8	114 ± 15	8.6 ± 3.0
T5	55 ± 5.1	118 ± 13	8.7 ± 2.6	53 ± 5.4	122 ± 17	8.5 ± 3.2

^aP < 0.05 vs group C.

^bP < 0.05 vs T1.

T1: 5 minutes after anaesthetic induction; T2: 30 minutes during the anhepatic phase; T3: 3 hours during the new liver phase; T4: 24 hours postoperatively; T5: 72 hours postoperatively. MAP: Mean arterial pressure; HR: Heart rate; CVP: Central venous pressure.

Comparison of TNF-α, IL-18, IL-10, and NGAL levels at each time point in both groups

Serum TNF-α, IL-18, IL-10, and NGAL levels peaked at T3 in both groups but subsequently decreased at T4 and T5. Compared with group C, group E exhibited reduced serum levels of TNF-α, IL-18, and NGAL at T2-5 (P < 0.05). No statistically significant differences were observed in the IL-10 levels between the two groups at any time point (P > 0.05; Table 4).

Table 4 Comparison of interleukin-10, interleukin-18, neutrophil gelatinase-associated lipocalin and tumour necrosis factor-α levels at different time points between the two groups.

	Group E				Group C
	IL-10 (pg/mL)	IL-18 (pg/mL)	NGAL (ng/mL)	TNF-α (pg/mL)	IL-10 (pg/mL)	IL-18 (pg/mL)	NGAL (ng/mL)	TNF-α (pg/mL)
T1	89.74 ± 20.32	86.30 ± 15.30	23.45 ± 5.29	80.65 ± 13.80	90.91 ± 16.63	92.32 ± 15.41	25.14 ± 5.37	89.73 ± 16.45
T2	94.23 ± 22.21	123.34 ± 32.44a,b	38.15 ± 6.17a,b	129.50 ± 26.63a,b	91.27 ± 20.33	168.50 ± 35.60b	60.53 ± 5.46b	163.76 ± 31.26b
T3	93.78 ± 19.25	145.55 ± 34.47a,b	62.16 ± 8.39a,b	147.62 ± 32.12a,b	93.48 ± 21.33	191.27 ± 39.92b	102.22 ± 6.77b	199.22 ± 29.43b
T4	90.23 ± 21.21	122.51 ± 23.76a,b	35.54 ± 5.26a,b	130.90 ± 25.51a,b	94.21 ± 22.56	150.33 ± 25.37b	96.32 ± 5.54b	172.30 ± 29.43b
T5	92.31 ± 30.21	108.26 ± 22.90a,b	34.65 ± 8.19a,b	97.23 ± 23.45a,b	93.32 ± 26.54	141.32 ± 22.43b	71.43 ± 6.18b	156.29 ± 26.65b

^aP < 0.05 vs group C.

^bP < 0.05 vs T1.

T1: 5 minutes after anaesthetic induction; T2: 30 minutes during the anhepatic phase; T3: 3 hours during the new liver phase; T4: 24 hours postoperatively; T5: 72 hours postoperatively. IL: Interleukin; NGAL: Neutrophil gelatinase-associated lipocalin; TNF-α: Tumour necrosis factor-α.

Comparison of hospitalisation duration, extubation time, and ICU stay between groups

Compared with that in group C, the duration of mechanical ventilation in group E was significantly shorter, with statistically significant intergroup differences (P < 0.05; Table 5). No statistically significant differences were observed between the groups regarding the duration of ICU stay or hospitalisation (P > 0.05; Table 5).

Table 5 Comparison of hospitalisation duration, extubation time, and intensive care unit stay between groups.

Parameter	Group E	Group C	P value
Tube withdrawal time (minute)	168.55 ± 69.64	264.55 ± 73.64	< 0.001
Hospitalisation duration (day)	23.25 ± 5.44	24.29 ± 5.52	0.268
ICU stay duration (day)	3.25 ± 0.84	3.58 ± 1.22	0.087

ICU: Intensive care unit.

DISCUSSION

Renal injury and inflammatory factors in paediatric liver transplantation

Liver transplantation is an established treatment for end-stage liver disease in children. Nicolau-Raducu et al[14] and Hilmi et al[15] reported that intraoperative hepatic ischaemia-reperfusion not only impairs graft function but also induces distal organ injury, particularly renal damage. Lee et al[16] attributed postoperative renal injury after liver transplantation to ischaemia-reperfusion-mediated release of pro-inflammatory cytokines, including tumour necrosis factor and IL-18. Selimoğlu et al[17] further identified renal dysfunction as an independent risk factor for mortality, with a significant adverse impact on prognosis in liver transplant recipients. In addition, Xie and Liu[18] highlighted that structural and functional immaturity of infant kidneys, combined with limited renal reserve, increases susceptibility to AKI under pathological stress. Early detection of organ injury therefore carries substantial clinical importance in paediatric liver transplantation, as emphasised by Che et al[19].

In this study, Scr levels increased significantly 30 minutes after portal vein clamping and peaked at 3 hours after reperfusion, reaching 1.5 times baseline, indicating renal impairment during the reperfusion phase. Niemann et al[20] demonstrated that NGAL is markedly upregulated during ischaemia and expressed in renal tissue, serving as a sensitive early marker of tubular injury. Consistent with these findings, serum NGAL levels in the present study also peaked at 3 hours after reperfusion, coinciding with the maximal elevation in Scr. Serum pro-inflammatory cytokines remained elevated from 30 minutes after portal vein occlusion through 72 hours postoperatively, supporting the role of excessive inflammatory mediator release in the pathogenesis of renal injury in paediatric liver transplant recipients.

Esketamine and inflammatory modulation

Esketamine, the S-enantiomer of ketamine, exerts anti-inflammatory effects through multiple molecular mechanisms. Huang et al[21] reported that ketamine attenuates cisplatin-induced renal injury by activating the brain-derived neurotrophic factor-tropomyosin receptor kinase B pathway and downstream extracellular signal-regulated kinase-cAMP response element-binding protein signalling, providing mechanistic insight into the anti-inflammatory properties of esketamine. In a rat sepsis model, Xian et al[12] demonstrated that esketamine suppresses activation of the Toll-like receptor 4/nuclear factor-kappa B (NF-κB) signalling pathway, enhances renal autophagy as evidenced by an increased LC3-II/LC3-I ratio, upregulated Beclin-1 expression, and reduced p62 expression, and inhibits activation of the NLR family pyrin domain containing 3 inflammasome. These effects reduce downstream pro-inflammatory cytokines, including IL-1β and IL-18, and alleviate renal histopathological injury. Collectively, these findings indicate that esketamine mediates renal anti-inflammatory effects through multi-target mechanisms involving modulation of signalling pathways, regulation of autophagy, and suppression of inflammasome activation rather than through a single pathway. The precise mechanisms by which esketamine reduces pro-inflammatory cytokine release in hepatic ischaemia-reperfusion-induced renal injury, however, remain to be clarified.

Esketamine and haemodynamic stability

The renoprotective effects of esketamine may also relate to haemodynamic stabilisation. Leithead et al[22] reported that perioperative haemodynamic fluctuations and surgical stress responses are associated with the development of AKI in transplant recipients. Renal tissue demonstrates high sensitivity to changes in vascular compliance and perfusion pressure, which explains the high incidence of AKI after liver transplantation. In the present study, the esketamine group maintained MAP within ± 9% of baseline during the anhepatic phase and showed significantly higher values than the control group at the T2 and T3 time points. Peltoniemi et al[23] attributed this haemodynamic stability to the sympathomimetic properties of ketamine derivatives. These agents stimulate central sympathetic activity, inhibit neuronal catecholamine re-uptake, and enhance the release of norepinephrine, dopamine, and serotonin from noradrenergic neurons, thereby preserving cardiac output and perfusion pressure during periods of haemodynamic stress.

Clinical implications and limitations

Esketamine is widely used as an intravenous anaesthetic in paediatric practice. It has a rapid onset, short recovery time, and minimal respiratory depression, which confer important clinical advantages. Liu et al[24] and Tang et al[25] reported that esketamine also exerts anti-inflammatory, antioxidant, and haemodynamic-stabilising effects. In the present study, children in the esketamine group showed significantly lower serum NGAL and creatinine levels from 3 hours after portal vein reperfusion through 72 hours postoperatively compared with the control group. Serum tumour necrosis factor and IL-18 levels were also reduced from 30 minutes after portal vein occlusion through 72 hours postoperatively. In addition, the duration of postoperative mechanical ventilation was shorter in the esketamine group. Although no statistically significant differences were observed between the groups regarding the duration of ICU stay or hospitalisation, it possibly due to the multifactorial nature of postoperative recovery in this complex patient population. These findings support the inclusion of esketamine in anaesthetic management strategies aimed at reducing perioperative renal injury in this high-risk population.

Several limitations warrant consideration. First, although the incidence of postoperative AKI was lower in the esketamine group than in the control group, the difference between the two groups did not reach statistical significance. This may be attributed to the limited sample size of the present study, which resulted in insufficient statistical power. Second, intraoperative use of other anaesthetic agents, including propofol, opioids, and inhalational agents, was not prospectively quantified. Although retrospective review of anaesthetic records showed no significant between-group differences, documentation bias and residual confounding cannot be excluded. The effects of esketamine on dosing requirements of other anaesthetic agents therefore require confirmation in rigorously designed prospective trials. Third, follow-up was limited to 72 hours after surgery, and longer-term renal outcomes, including progression to chronic kidney disease, were not assessed. Fourth, mechanistic analyses, such as measurement of oxidative stress markers or assessment of NF-κB pathway activation, were not performed. Finally, unmeasured confounders may have influenced the observed renoprotective effects, and the underlying molecular mechanisms require further investigation in experimental models.

Future studies should consider incorporating urinary biomarkers such as kidney injury molecule-1, which offers a non-invasive diagnostic strategy for AKI and may provide complementary information to serum markers. Additionally, longer follow-up periods, multi-center validation, and mechanistic investigations including oxidative stress markers and NF-κB pathway activation assessment would further elucidate the renoprotective effects of esketamine in this population.

CONCLUSION

Intraoperative esketamine administration attenuates the increase in Scr levels following ischemia-reperfusion injury and attenuates inflammatory responses in paediatric LDLT recipients. Its renoprotective effects appear to be associated with improved haemodynamic stability and suppression of pro-inflammatory cytokines. Esketamine may therefore be considered as part of the anaesthetic regimen to reduce perioperative renal injury in this high-risk population.

ACKNOWLEDGEMENTS

The authors thank the following individuals for their contributions to this study: Ying-Ying Kang for technical support in laboratory assays and Xin-Chang Guo for clinical coordination.