Impact of dexmedetomidine administration on serum creatinine levels following liver transplantation: A systematic review and meta-analysis

Abstract

BACKGROUND

Incidence of acute kidney injury (AKI), reflected by raised serum creatinine level, is a common complication following liver transplant. Dexmedetomidine, an α2-adrenergic agonist, has been proposed as a potential renoprotective agent in the preoperative/perioperative setting. However, its effects on renal outcomes after liver transplantation are relatively understudied.

AIM

To assess the outcomes of preoperative/perioperative dexmedetomidine on serum creatinine level following liver transplant.

METHODS

This systematic review evaluated studies investigating the outcome of preoperative/perioperative systemic dexmedetomidine on postoperative serum creatinine levels following liver transplant. Meta-analysis was performed using random or fixed effects models depending on the degree of statistical heterogeneity. Risk of bias and overall quality of evidence were assessed using standardized methodologies.

RESULTS

A total of four studies involving 535 participants (of whom 270 received dexmedetomidine and 265 served as controls) were included in the meta-analysis. Preoperative/perioperative administration of dexmedetomidine was associated with a statistically significant reduction in postoperative serum creatinine levels (mean difference: -0.06 mg/dL; 95%CI: -0.09 to -0.02; P = 0.002). However, reporting of clinically meaningful renal outcomes was limited, and no consistent reduction in AKI was observed across studies. Heterogeneity among studies was substantial (I² = 75%, P = 0.007).

CONCLUSION

Preoperative/perioperative administration of dexmedetomidine was linked to a modest yet statistically significant decrease in postoperative serum creatinine levels after liver transplantation. Although these results suggest a possible biochemical effect, the clinical relevance remains uncertain, as no consistent improvement in clinically meaningful renal outcomes was demonstrated.

Key Words: Dexmedetomidine; Liver transplantation; Acute kidney injury; Serum creatinine; Renal protection; Preoperative/perioperative care; Systematic review; Meta-analysis

Core Tip: Preoperative/perioperative dexmedetomidine administration was associated with a modest reduction in postoperative serum creatinine following liver transplantation; however, this effect did not translate into a consistent reduction in clinically meaningful renal outcomes such as acute kidney injury. Significant heterogeneity in creatinine measurement timing, outcome definitions, and analytical approaches across studies further limits interpretation, highlighting the need for standardized protocols and trials focused on clinically relevant renal endpoints.

INTRODUCTION

Acute kidney injury (AKI) is a frequent and serious complication following liver transplantation, occurring in approximately 35% of recipients depending on diagnostic criteria and patient risk profiles[1]. The development of postoperative AKI is associated with prolonged intensive care unit stay, increased need for renal replacement therapy, higher healthcare costs, and significantly increased short- and long-term mortality[1,2]. Serum creatinine remains the most commonly used biomarker for renal function assessment in the post–liver transplant period and serves as a key surrogate indicator for AKI development, despite its known limitations in patients with advanced liver disease[3].

The pathophysiology of AKI following liver transplantation is multifactorial and complex. Contributing mechanisms include preoperative/perioperative hemodynamic instability, ischemia-reperfusion injury, systemic inflammatory response, nephrotoxic immunosuppressive agents particularly calcineurin inhibitors and pre-existing renal dysfunction related to cirrhosis[4]. In addition, intraoperative factors such as massive blood loss, prolonged cold and warm ischemia times, and the use of vasopressors further exacerbate renal hypoperfusion and endothelial injury[5]. Given these multiple insults, effective preoperative/perioperative strategies aimed at renal protection remain an important unmet clinical need.

Dexmedetomidine, a highly selective α2-adrenergic receptor agonist, has gained increasing attention for its sedative, anxiolytic, analgesic-sparing, and sympatholytic properties[6]. Beyond its established role in anesthesia and critical care, dexmedetomidine has been proposed to exert organ-protective effects through attenuation of inflammatory responses, reduction of oxidative stress, and modulation of sympathetic nervous system activity[7]. Studies have suggested that dexmedetomidine may preserve renal function by improving renal blood flow, reducing catecholamine-induced vasoconstriction, and limiting ischemia-reperfusion injury[8]. These mechanisms are particularly relevant in the context of liver transplantation, where renal perfusion is often compromised during the preoperative/perioperative period.

However, the evidence regarding its renoprotective effects in liver transplantation remains limited and inconsistent. Given the high burden of AKI after liver transplantation and the potential biological plausibility of dexmedetomidine as a renoprotective agent, a systematic synthesis of the available evidence is warranted. Therefore, this systematic review and meta-analysis aimed to evaluate the effect of preoperative/perioperative dexmedetomidine administration on postoperative serum creatinine levels in patients undergoing liver transplantation. By quantitatively summarizing existing data, this study seeks to clarify the extent of renal benefit, assess the consistency of findings, and identify gaps that warrant further investigation in future large-scale, well-designed clinical trials.

MATERIALS AND METHODS

Study design

This study was conducted as a systematic review and meta-analysis in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines (Figure 1). The protocol was designed a priori to evaluate the effect of preoperative/perioperative dexmedetomidine administration on postoperative renal function, as measured by serum creatinine levels, in patients undergoing liver transplantation.

Figure 1  PRISMA Flow diagram depicting the flow of information in this meta-analysis.

Search strategy

A comprehensive literature search was performed across multiple electronic databases, including PubMed, EMBASE, Scopus, Web of Science, Google Scholar, Cochrane Library searched from inception to October 2025. The search combined the MeSH term “liver transplantation” with the keywords “liver” or “hepatic” and “transplant*” or “graft*”, connected using the Boolean operator OR. Dexmedetomidine-related studies were identified using the MeSH terms “Dexmedetomidine” and “Adrenergic alpha - Agonists”, as well as the text words “Precedex” or “Dexmedetomidin*” and the expression “(adrenergic OR alpha) NEAR agonist*”, combined with OR. The two concepts liver transplantation and dexmedetomidine were then linked using AND. A similar strategy was applied for MEDLINE and EMBASE using appropriate subject headings and text words, while ClinicalTrials.gov and WHO ICTRP were searched using “liver transplantation” and “Dexmedetomidine”. No restrictions were applied based on language, and reference lists of retrieved articles were screened to identify additional eligible studies. Duplicate records were removed before screening titles and abstracts.

Eligibility criteria

Studies were included if they met the following criteria: (1) Patients undergoing liver transplantation; (2) Preoperative/perioperative systemic administration of dexmedetomidine; (3) A comparator group receiving placebo or standard care without dexmedetomidine; and (4) Reporting postoperative serum creatinine levels or sufficient data to calculate effect estimates. Randomized controlled trials and observational studies were eligible for inclusion. Exclusion criteria were animal or in vitro studies, case reports, reviews, editorials, conference abstracts without full-text availability, and studies lacking relevant renal outcome data.

Data extraction

Two independent reviewers screened titles and abstracts for eligibility, followed by full-text review of potentially relevant studies. Data extraction was performed independently using a standardized data collection form. Extracted variables included study characteristics (author, year, study design), sample size, dexmedetomidine dosing and timing, comparator details, follow-up duration (Table 1). Discrepancies between reviewers were resolved through discussion or consultation with a third reviewer when necessary.

Table 1 Details of the studies included in this meta-analysis.

Ref.	Number of patients		Intervention	Control	Study type
	Dexmedetomidine	Control
Fayed et al[9], 2016	20	20	A continuous intraoperative infusion of dexmedetomidine was administered at a rate of 0.8 µg/kg/hour, initiated following the induction of anesthesia and maintained throughout the surgical procedure until its completion	Placebo	RCT
Zhang et al[11], 2021	28	26	Dexmedetomidine was administered as a continuous infusion at a rate of 0.4 µg/kg/hour, commencing at the time of surgical incision and continued until completion of the operative procedure	None	Cohort study
Zhang et al[12], 2022	62	59	Dexmedetomidine was administered as a continuous intraoperative infusion at a rate of 0.4 µg/kg/hour without a loading dose, beginning at the time of surgical incision and maintained until completion of the procedure	None	Cohort study
Yang et al[10], 2024	165	165	After induction of anesthesia, a loading dose of dexmedetomidine (1 μg/kg) was administered over 10 minutes, followed by a continuous infusion at 0.5 μg/kg/hour maintained throughout the surgical procedure until its completion	An equivalent volume loading dose of 0.9% saline was administered following induction of anesthesia, followed by a continuous infusion of an equal volume maintained until completion of the surgical procedure	RCT

Yang et al[10] enrolled 165/165 but 160/160 completed surgery and contributed to the creatinine analysis, which is the n used in the meta-analysis. RCT: Randomised controlled trial.

Risk of bias assessment and exploration of heterogeneity

The methodological quality of the included studies was assessed using established risk-of-bias frameworks appropriate for each study design. Randomized controlled trials were evaluated using the Cochrane Risk of Bias Tool 2, while observational cohort studies were assessed using the Newcastle-Ottawa Scale. Two independent reviewers evaluated the studies across predefined domains, and disagreements were resolved through consensus.

Risk of bias in randomized controlled trials

The randomized trials by Fayed et al[9] and Yang et al[10] demonstrated generally acceptable methodological quality. In the trial conducted by Fayed et al[9], the process of random sequence generation was reported. Blinding of participants and personnel was described using placebo infusion, suggesting low risk of performance bias, although reporting of outcome assessor blinding was limited. Additionally, the relatively small sample size (n = 40) raises concerns regarding imprecision and potential small-study effects. The study by Yang et al[10] incorporated a placebo control with equivalent saline infusion and clearly described randomization and blinding procedures. Allocation concealment and outcome assessment appeared adequately addressed, resulting in an overall low risk of bias across most domains. Attrition and selective outcome reporting were not evident in either randomized study.

Risk of Bias in Observational Studies

The cohort studies by Zhang et al[11] and Zhang et al[12] were assessed using the Newcastle-Ottawa Scale. Both studies[11,12] demonstrated moderate methodological quality, with adequate patient selection and clear exposure definition for dexmedetomidine administration. However, the absence of randomization and lack of a placebo control group introduce a risk of confounding and selection bias. Although baseline characteristics were partially adjusted for in the analyses, residual confounding cannot be excluded. Outcome ascertainment was clearly defined, and follow-up was adequate in both studies.

Exploration of heterogeneity

Potential sources of heterogeneity across studies were examined qualitatively. Several factors likely contributed to inter-study variability. First, differences in dexmedetomidine dosing protocols were observed, including variations in loading dose administration and maintenance infusion rates ranging from 0.4 µg/kg/hour to 0.8 µg/kg/hour. Second, study design differences including randomized controlled trials vs retrospective cohort analyses may have influenced effect estimates due to varying susceptibility to confounding. Third, sample size disparities were notable, with cohort studies including larger patient populations compared with smaller randomized trials. Clinical heterogeneity may also arise from variations in surgical procedures, preoperative/perioperative anesthetic management, and patient characteristics across studies. These factors should be considered when interpreting pooled estimates in the meta-analysis. Sensitivity analyses stratified by study design and dexmedetomidine dosing strategy may help further clarify the contribution of these variables to overall heterogeneity. Risk-of-bias assessments for the included studies are summarized in Table 2.

Table 2 Risk-of-bias summary.

Ref.	Randomization	Deviations	Missing data	Outcome measurement	Selective reporting	Overall
Fayed et al[9], 2016	Unclear risk	Low risk	Low risk	Some concerns	Low risk	Some concerns
Yang et al[10], 2024	Low risk	Low risk	Low risk	Low risk	Low risk	Low risk
Zhang et al[11], 2021	Not applicable1	Not applicable1	Not applicable1	Not applicable1	Not applicable1	Moderate risk
Zhang et al[12], 2022	Not applicable1	Not applicable1	Not applicable1	Not applicable1	Not applicable1	Moderate risk

¹Risk of bias for observational studies was assessed using the Newcastle-Ottawa Scale.

Outcome measures

The primary outcome was postoperative serum creatinine level following liver transplantation, expressed as a continuous variable. When multiple postoperative time points were reported, the earliest clinically relevant postoperative measurement was used for analysis. Serum creatinine was selected as the primary endpoint because it remains the most widely reported and standardized measure of postoperative renal function in the liver transplant literature, despite recognized limitations in cirrhotic and peri-transplant populations such as reduced muscle mass and delayed biomarker responsiveness.

Statistical analysis

Meta-analysis was performed using pooled mean differences (MDs) with corresponding 95% confidence intervals (CIs) for continuous outcomes. Statistical heterogeneity was assessed using the Cochran Q test and quantified using the I² statistic. A fixed-effects model was applied when heterogeneity was low (I² < 50%), while a random-effects model was used in cases of substantial heterogeneity. Publication bias was evaluated through visual inspection of funnel plots. A two-sided P value < 0.05 was considered statistically significant. Additional data extraction was performed to characterize heterogeneity in renal outcome reporting across studies, including creatinine measurement timing, outcome definitions, baseline renal function reporting, and adjustment strategies. Given variability in reporting and low event rates, clinically meaningful renal outcomes such as AKI and renal replacement therapy (RRT) were not pooled quantitatively. AKI definitions were extracted when available and described qualitatively across studies.

RESULTS

A total of four eligible studies involving 535 patients who underwent liver transplantation were included in the meta-analysis[9-12]. Among these, 270 patients received preoperative/perioperative dexmedetomidine, while 265 patients were managed with standard care or placebo. Postoperative serum creatinine levels were reported for all included studies and were suitable for quantitative synthesis.

The pooled analysis demonstrated a statistically significant difference in postoperative serum creatinine levels between the two groups. Patients who received dexmedetomidine had lower postoperative serum creatinine values compared with controls, with a mean difference of -0.06 mg/dL (95%CI: -0.09 to -0.02; P = 0.002). Owing to the presence of between-study variability, a random-effects model was applied (Figure 2).

Figure 2  Forest plot showing the effect of dexmedetomidine on serum creatinine level following transplant.

Statistical assessment revealed substantial heterogeneity across the included studies (I² = 75%; P = 0.007). Evaluation of publication bias using funnel plot analysis showed a visually symmetrical distribution of studies around the pooled effect estimate (Figure 3). However, the reliability of this assessment was limited by the small number of studies included in the analysis.

Figure 3 Funnel plot showing the effect of dexmedetomidine on serum creatinine level following transplant. MD: Mean difference.

Reporting of clinically meaningful renal outcomes was heterogeneous across included studies (Supplementary Tables 1-4). AKI, defined using Kidney Disease: Improving Global Outcomes (KDIGO) criteria, was reported in three studies. In the randomized controlled trial by Yang et al[10], AKI occurred in 30.0% of patients receiving dexmedetomidine compared with 37.5% in the control group (P = 0.16), indicating no statistically significant difference. The observational studies by Zhang et al[11] and Zhang et al[12] also assessed AKI using KDIGO criteria, with no significant differences observed between groups.

RRT was not reported as an outcome in any of the included studies. Baseline renal function was inconsistently reported, with only two studies providing preoperative/perioperative creatinine values. Substantial heterogeneity was also observed in the measurement of postoperative creatinine. Fayed et al[9] reported serial creatinine measurements at fixed postoperative timepoints, similarly, Zhang et al[11] reported peak serum creatinine values within the first postoperative week, consistent with the approach used in the companion cohort study by the same group. Yang et al[10] reported serial creatinine trends without a single extractable timepoint for analysis. This variability in outcome measurement likely contributed to the observed statistical heterogeneity (I² = 75%) and limits direct comparability across studies.

DISCUSSION

This systematic review and meta-analysis evaluated the effect of preoperative/perioperative dexmedetomidine administration on postoperative renal function in patients undergoing liver transplantation, using serum creatinine as the primary outcome measure. The pooled analysis of four studies involving 535 patients demonstrated a statistically significant reduction in postoperative serum creatinine levels among patients who received dexmedetomidine compared with controls. Although the absolute magnitude of reduction was modest, these findings suggest a potential role for dexmedetomidine in mitigating early postoperative renal dysfunction following liver transplantation.

AKI remains one of the most frequent and clinically significant complications after liver transplantation, contributing to increased morbidity, prolonged hospitalization, need for renal replacement therapy, and reduced graft and patient survival[13]. Therefore, strategies aimed at preserving renal function, even if associated with relatively small biochemical improvements, may have important implications when applied across high-risk populations[4].

The observed reduction in postoperative serum creatinine may be explained by several proposed mechanisms of dexmedetomidine-mediated renal protection. As a highly selective α2-adrenergic agonist, dexmedetomidine reduces sympathetic outflow and circulating catecholamine levels, leading to improved renal perfusion and decreased renal vasoconstriction[14]. Additionally, dexmedetomidine has been shown to attenuate systemic inflammatory responses, reduce oxidative stress, and limit ischemia–reperfusion injury—pathophysiological processes that are central to renal injury during liver transplantation[15]. Studies have also suggested that dexmedetomidine may exert direct protective effects on renal tubular cells through modulation of apoptosis and inflammatory signaling pathways[16].

The relevance of these mechanisms is particularly pronounced in liver transplantation, where renal hypoperfusion frequently occurs during the anhepatic phase and reperfusion is associated with profound hemodynamic and inflammatory disturbances[17]. Furthermore, patients with end-stage liver disease often have baseline renal vulnerability due to cirrhosis-related hemodynamic alterations, hepatorenal physiology, and pre-existing renal impairment. In this context, preoperative/perioperative interventions that stabilize hemodynamics and modulate inflammatory responses may offer incremental renal protection.

Despite the statistically significant pooled effect, substantial heterogeneity was observed among the included studies. This variability likely reflects differences in study design, patient characteristics, timing and dosage of dexmedetomidine administration, anesthetic protocols, preoperative/perioperative fluid and vasopressor management, and timing of postoperative creatinine measurement. In addition, variations in baseline renal function and severity of liver disease may have influenced the observed effect sizes. These factors underscore the challenges of synthesizing evidence across heterogeneous preoperative/perioperative settings and highlight the need for standardized protocols in future research.

Importantly, while serum creatinine remains the most widely used marker of renal function, it has well-recognized limitations in patients with advanced liver disease. Reduced muscle mass, altered creatinine production, and dilutional effects may result in underestimation of renal dysfunction[18]. Moreover, changes in serum creatinine may lag behind actual renal injury. Consequently, the modest reduction in creatinine observed in this meta-analysis should be interpreted cautiously, as it may not fully capture clinically meaningful renal outcomes such as AKI incidence, severity, or need for renal replacement therapy. Only a limited number of included studies reported such secondary outcomes, precluding robust pooled analysis. Moreover, although the reduction in serum creatinine (MD: -0.06 mg/dL) reached statistical significance, its clinical relevance remains uncertain when viewed against established AKI thresholds such as the KDIGO criteria, which define AKI as an increase of ≥ 0.3 mg/dL within 48 hours or ≥ 1.5 × baseline. Given that the observed difference represents only a small fraction of these diagnostic cut-offs, it is unlikely to independently alter AKI classification in most patients. This emphasizes the need for future studies to evaluate whether dexmedetomidine meaningfully affects clinically defined AKI incidence rather than solely biochemical changes. Notably, despite the observed reduction in serum creatinine, there was no consistent evidence of improvement in clinically meaningful renal outcomes. Among studies reporting KDIGO-defined AKI, no statistically significant reduction was observed with dexmedetomidine. The largest randomized trial demonstrated numerically lower AKI incidence in the dexmedetomidine group, although this difference was not statistically significant. Furthermore, renal replacement therapy was not reported in any of the included studies. These findings underscore the distinction between modest biochemical changes in creatinine and clinically meaningful renal protection.

The assessment of publication bias did not reveal obvious asymmetry on funnel plot inspection; however, the small number of included studies limits the reliability of this evaluation. It is possible that smaller studies with neutral or negative findings remain unpublished, which could influence the overall effect estimate. Additionally, the inclusion of both randomized and observational studies introduces potential confounding and selection bias, despite formal risk-of-bias assessment. Similarly, sources of heterogeneity may also stem from clinically relevant preoperative/perioperative differences across studies. Variability in dexmedetomidine dosing strategies—including loading doses, infusion rates, and timing relative to graft reperfusion—could meaningfully influence renal perfusion and inflammatory responses. Likewise, differences in cold and warm ischemia times, donor quality, and intraoperative hemodynamic stability may alter the extent of ischemia–reperfusion injury and thereby impact postoperative creatinine trends. Furthermore, heterogeneity in immunosuppressive regimens, particularly the timing and dosage of calcineurin inhibitors, introduces additional variability given their known nephrotoxic potential.

Several limitations of this meta-analysis warrant consideration. First, the overall sample size remains relatively small, limiting statistical power and generalizability. Second, heterogeneity among studies reduces confidence in the pooled estimate. Third, variations in dexmedetomidine dosing regimens and timing of administration prevent identification of an optimal therapeutic strategy. Finally, reliance on serum creatinine as the primary endpoint limits conclusions regarding clinically relevant renal outcomes. As detailed in Supplementary Tables 1-4, there was substantial heterogeneity in renal outcome definitions, creatinine measurement timing, and analytical approaches across studies. Importantly, the pooled estimates were derived from unadjusted group-level creatinine values rather than adjusted effect measures. While randomized controlled trials inherently account for confounding, observational studies included in this analysis relied on unadjusted comparisons, and adjusted creatinine-specific estimates were not consistently available. Additionally, baseline renal function was not uniformly reported, further limiting the ability to fully account for pre-existing differences between groups.

Although preoperative/perioperative dexmedetomidine administration was associated with a statistically significant reduction in postoperative serum creatinine, the pooled effect size (MD: -0.06 mg/dL) represents a biochemically small change that falls well below clinically meaningful thresholds such as the KDIGO AKI criterion of a ≥ 0.3 mg/dL increase. Interpretation is further limited by substantial heterogeneity (I² = 75%), likely reflecting differences in dosing strategies, preoperative/perioperative practices, ischemic durations, and immunosuppressive regimens. Accordingly, these findings should not be taken as evidence of a definitive renoprotective effect, as the observed biochemical change does not necessarily translate into improvements in meaningful clinical outcomes such as AKI incidence or need for renal replacement therapy. Larger, methodologically standardized trials are needed to clarify whether dexmedetomidine offers true clinical benefit beyond modest changes in serum creatinine.

CONCLUSION

In conclusion, this study provides a focused synthesis of available evidence and suggests that preoperative/perioperative dexmedetomidine administration is associated with lower postoperative serum creatinine levels in liver transplant recipients. These findings support further investigation into dexmedetomidine as a potential renoprotective adjunct in this high-risk population. Future research should prioritize large, well-designed randomized controlled trials with standardized dexmedetomidine protocols and uniform definitions of AKI, such as KDIGO criteria. Incorporation of novel renal biomarkers and clinically meaningful endpoints, including AKI incidence, duration, and need for renal replacement therapy, will be essential to determine whether the observed biochemical benefits translate into improved patient outcomes.