The effects of norepinephrine infusion combined with goal-directed fluid therapy on delayed graft function in patients undergoing kidney transplantations: study protocol for a multicenter randomized controlled trial

Abstract

Background

Chronic kidney disease presents a formidable challenge to global healthcare systems. With ongoing advancements in surgical techniques, kidney transplantation has emerged as a principal therapeutic modality for individuals afflicted with end-stage renal disease, markedly enhancing their long-term prognosis and overall quality of life postoperatively. Nevertheless, the occurrence of delayed graft function represents a prevalent early complication following kidney transplantations, mainly stemming from the ischemia-reperfusion injury incurred by the transplanted kidneys and the utilization of extended criteria donor organs. The manifestation of delayed graft function can precipitate primary allograft nonfunction, acute rejection episodes, and potentially fatal outcomes. Vigilant attention to perioperative fluid management emerges as a cornerstone in mitigating the risk of delayed graft function. Recent strides in Goal-directed fluid therapy have garnered substantial attention within critical care contexts, with empirical evidence underscoring its favorable impact on postoperative outcomes in critically ill cohorts. However, the efficacy of Goal-directed fluid therapy specifically in the context of kidney transplantation remains a subject of ongoing debate and scrutiny. Hence, the imperative arises to investigate potential strategies aimed at attenuating the incidence of delayed graft function in this patient demographic.

Methods

A multicenter, randomized, single-blind, two-arm parallel-group, controlled trial will be undertaken to assess the efficacy of norepinephrine in conjunction with Goal-directed fluid therapy on graft function recovery among individuals slated for kidney transplantations. Patients will be allocated randomly to either a control or intervention arm, wherein conventional fluid management or the administration of norepinephrine infusion combined with Goal-directed fluid therapy will be administered, respectively.

Discussion

The primary objective of this study is to investigate the potential efficacy of norepinephrine infusion in conjunction with goal-directed fluid therapy in mitigating the occurrence of delayed graft function among individuals undergoing kidney transplantations. The findings of this investigation have the potential to advance the field of perioperative care in kidney transplantations by providing insights into optimized management strategies.

Trial registration

ClinicalTrials.gov NCT06367205. Registered on April 16, 2024.

Administrative information

Note: the numbers in curly brackets in this protocol refer to SPIRIT checklist item numbers. The order of the items has been modified to group similar items (see http://www.equator-network.org/reporting-guidelines/spirit-2013-statement-defining-standard-protocol-items-for-clinical-trials/).

Title {1}	The Effects of Norepinephrine Infusion Combined with Goal-directed Fluid Therapy on Delayed Graft Function in Patients Undergoing Kidney Transplantations: Study Protocol for A Multicenter Randomized Controlled Trial
Trial registration {2a and 2b}.	ClinicalTrials.gov NCT06367205. Registered on April 16, 2024.
Protocol version {3}	The protocol version is 3.4, which was approved in September 30, 2024.
Funding {4}	Not applicable as the study is not funded.
Author details {5a}	Authors: Muyan Shi1,2, Yuhan Zhang1, Xibing Ding1, Xiangyang Cheng3, Jie Zhou1, Diansan Su3 1. Department of Anesthesiology, Renji Hospital, Shanghai Jiaotong University School of Medicine, 160 Pujian Road, Shanghai, 200127, China. 2. Department of Anesthesiology, Zhongshan Hospital, Fudan University, Shanghai, 200032, China; Shanghai Key Laboratory of Perioperative Stress and Protection, Shanghai, 200032, China. 3. Department of Anesthesiology, The First Affiliated Hospital, Zhejiang University School of Medicine, 79 Qingchun Road, Hangzhou, 310003, China. Email address Muyan Shi: jsqdsmy@163.com Yuhan Zhang: 1092619255@qq.com Xibing Ding: 442546909@qq.com Xiangyang Cheng: 1647384344@qq.com Jie Zhou: 13601693227@163.com Diansan Su: diansansu@yahoo.com Corresponding author: Diansan Su Department of Anesthesiology, The First Affiliated Hospital, Zhejiang University School of Medicine, 79 Qingchun Road, Hangzhou, 310003, China. Email address Diansan Su: +862168383702, Email: diansansu@yahoo.com Cocorresponding author: Jie Zhou Department of Anesthesiology, Renji Hospital, Shanghai Jiaotong University School of Medicine, 160 Pujian Road, Shanghai, 200127, China. Email address Jie Zhou: +862168383702, Email: 13601693227@163.com
Name and contact information for the trial sponsor {5b}	Not applicable as the study is not funded.
Role of sponsor {5c}	Not applicable as the study is not funded.

Introduction

Background and rationale {6a}

Chronic kidney disease (CKD) presents a substantial and widespread public health concern on a global scale, with an estimated prevalence reaching 9.1% worldwide and contributing to 2.6 million deaths directly or indirectly in 2017 [1]. Moreover, CKD stands as an established independent risk factor for cardiovascular morbidity and mortality [2]. In contemporary medical practice, kidney transplantation [3] has emerged as a pivotal therapeutic modality for end-stage renal disease (ESRD), offering notable advancements in mitigating CKD-related complications and enhancing both the postoperative quality of life and median survival of afflicted individuals [4]. Nonetheless, recipients of kidney transplants are susceptible to a spectrum of postoperative complications [5], among which delayed graft function (DGF) stands as the most prevalent. DGF, delineated by the necessity for dialytic intervention within the initial week post-transplantation, afflicts approximately 20–50% of recipients [6, 7] due to ischemia-reperfusion injury inflicted upon the transplanted organ [4]. This incidence may escalate with the utilization of extended criteria donor organs [8]. Concurrently, DGF imparts an elevated vulnerability to acute rejection episodes, jeopardizing long-term graft viability, while engendering prolonged hospitalization and augmented healthcare expenditures [9].

Individuals diagnosed with ESRD commonly manifest oliguria or anuria, requiring dialysis interventions and controlled dietary regimens to preserve homeostasis. Nonetheless, this patient cohort often shows marked variability in blood volume—a factor closely linked to dialysis efficacy. Intraoperative volume perturbations entail substantial risks: volume overload may lead to cardiac decompensation and acute pulmonary edema [10], while volume deficit may compromise graft perfusion and predispose to DGF. Therefore, establishing strategies to maintain optimal volume status during kidney transplantation is critically important in clinical practice.

Goal-directed fluid therapy (GDFT), denoting the application of minimally invasive cardiac output monitoring to guide fluid administration towards achieving predefined parameters such as stroke volume variation (SVV) and pulse pressure variation (PPV) [11], has garnered considerable attention in recent medical discourse. A systematic review has indicated that GDFT holds promise for enhancing postoperative outcomes among moderate- and high-risk surgical populations [12]. Moreover, a randomized controlled trial (RCT) has demonstrated the potential of intraoperative fluid optimization in facilitating the rehabilitation of hip-fracture patients [13]. However, the efficacy of GDFT in various clinical contexts remains equivocal, with disparate findings emerging from different trials [14–16]. This variability may be partially explained by differences across studies in the selected parameters, target hemodynamic states, and patient populations, which preclude direct comparisons between interventions. Notably, SVV has been regarded as a preferred parameter for volume management, given its perceived superiority over conventional central venous pressure (CVP) monitoring [17]. Nevertheless, the available evidence remains inconclusive regarding the overall benefit of GDFT in surgical patient populations.

Previously, the administration of intraoperative continuous norepinephrine infusion in conjunction with restrictive deferred hydration was established to notably diminish postoperative complications in patients [18]. A RCT conducted in 2021 further corroborated these findings, showing that a norepinephrine infusion rate of 0.06 μg/kg/min, when combined with Goal-directed fluid therapy, was associated with favorable intraoperative and postoperative outcomes in high-risk patient cohorts [19]. Given the particularly high vulnerability of ESRD patients, who often present with poor clinical status and elevated surgical risks, the use of intraoperative continuous norepinephrine infusion emerges as a viable strategy. Therefore, the present study was designed to improve prognostic outcomes following renal transplantation in ESRD patients.

Objectives {7}

Our aim is to investigate whether norepinephrine infusion combined with GDFT reduces the incidence of DGF following renal transplantation, thereby establishing a safe and effective fluid management strategy to improve patient outcomes. The primary objective is to assess the incidence of DGF. We hypothesize that the combination of norepinephrine infusion and GDFT will lower the incidence of DGF in kidney transplant recipients. This trial evaluates a standardized hemodynamic management care bundle (fixed low-dose norepinephrine infusion combined with SVV-guided GDFT) versus routine fluid therapy; it is not designed to isolate the independent contributions of vasopressor support and fluid optimization, which should be addressed in future factorial trials.

Trial design {8}

This study is a multicenter, prospective, randomized, single-blind design with two-arm parallel-group allocation. The objective is to assess the influence of norepinephrine infusion in conjunction with GDFT intervention on the incidence of DGF in individuals undergoing kidney transplantation. The trial was duly registered on ClinicalTrials.gov (No. NCT06367205) on April 16, 2024.

Methods: participants, interventions, and outcomes

Study setting {9}

This study aims to recruit 380 participants from Renji Hospital Shanghai Jiao Tong University School of Medicine, General Hospital of Northern Theater Command, The First Affiliated Hospital of Zhengzhou University, and The First Affiliated Hospital, Zhejiang University School of Medicine. Approval and support for this clinical trial (LY2023-135-A) were granted by the ethics committee of Renji Hospital Shanghai Jiao Tong University School of Medicine. We have added a summary of the standardized training and operational manual. To ensure multicenter reproducibility, all anesthesiologists completed a standardized online training course covering (i) connection, calibration, and interpretation of Vigileo/FloTrac SVV; (ii) the fluid responsiveness assessment algorithm; and (iii) norepinephrine infusion pump settings and adjustment rules. Each center submitted five simulation videos for quality review before enrolling patients. Quarterly on-site audits compare recorded SVV values with hospital information system data.

Eligibility criteria {10}

The clinical trial encompasses recruitment from four distinct centers. A concise overview of the inclusion and exclusion criteria is provided in Table 1.

Table 1.

Inclusion/exclusion criteria

Inclusion criteria

Exclusion criteria

Recipients aged 18 years or older* Scheduled to undergo kidney transplantations under general anesthesia Cadaveric kidney transplantations Sign the informed consent form

Donors aged under 18 years Donor kidneys classified as Maastricht category I or II Contraindications to radial artery catheterization Pregnancy Cardiac dysfunction (exercise tolerance less than 4 METS) Severe liver dysfunction (Child-Pugh C-grade) Respiratory diseases with tidal volume intolerance exceeding 8 ml/kg Severe arrhythmias#, including atrial fibrillation, frequent atrial or ventricular premature beats, moderate or severe aortic and mitral regurgitation Double-kidney transplantations Simultaneous organ or additional surgeries during kidney transplantations Repeat kidney transplantations Concurrent participation in other clinical trials Patients deemed ineligible by researchers

^*Age is determined by computing the integer value of [(the date of signing informed consent − the date of birth + 1) divided by 365.25]

^#Severe arrhythmias are defined as heart rhythm disturbances substantial enough to preclude reliable SVV assessment by FloTrac/Vigileo

Who will take informed consent? {26a}

Trained anesthesiologists will provide potential participants with a comprehensive explanation of the trial and will furnish them with the informed consent document. Participants will be given sufficient time to consider their decision regarding trial enrollment. Subsequently, participants or their legal representatives will sign the informed consent form, with the understanding that they retain the right to withdraw from the trial at any time. After the consent process, participants will be randomly assigned using a centralized randomization system, and baseline data will be systematically collected. Throughout the trial, participants will be encouraged to report any health-related concerns to the research team. All procedures related to participant recruitment and consent acquisition will strictly adhere to the principles of Good Clinical Practice (GCP). In the event of any adverse events (AEs) occurring during the trial—whether or not related to the study procedures—the researchers will promptly notify the overseeing clinical trial director at the research institution and seek guidance from Professor Jie Zhou. The consent process is initiated once the participants are admitted to the hospital, ensuring participants have adequate time—at least 24 h whenever logistically feasible—to discuss with their family members and weigh the benefits and risks to make their decisions before signing the informed consent form.

Additional consent provisions for collection and use of participant data and biological specimens {26b}

Not applicable as no participant data and biological specimens were collected and used for ancillary investigations.

Interventions

Explanation for the choice of comparators {6b}

The selection of comparators will entail the utilization of a central randomization system across each study site. Upon randomization, participants will be allocated to receive either regular fluid therapy (arm 2) or norepinephrine infusion combined with GDFT (arm 1). In this trial, regular fluid therapy (arm 2) serves as the comparator.

Intervention description {11a}

The interventions administered to participants in this trial consist of two arms: regular fluid therapy arm (arm 2) and Goal-directed fluid therapy arm (arm 1). The regular fluid therapy arm entails the conventional fluid infusion, while the GDFT arm involves the application of norepinephrine infusion combined with Goal-directed fluid therapy.

Upon arrival at the operating room, patients are placed in the supine position and connected to standard monitoring, including electrocardiography, heart rate measurement, noninvasive blood pressure monitoring, and pulse oximetry (SpO₂). Subsequently, venous access is established, and patency is maintained with a minimal infusion of lactated Ringer’s solution (RL). Radial artery cannulation is then performed, followed by preoperative blood gas analysis to determine baseline parameters of internal homeostasis. If any disturbance in the internal environment is detected, appropriate interventions are promptly implemented. After a 5-minute rest period, mean arterial pressure (MAP) is recorded three times at 1-minute intervals, and the average of these measurements is taken as the baseline MAP.

The induction protocol is structured as follows: etomidate at a dosage range of 0.2–0.3 mg/kg, propofol at 1–2 mg/kg, midazolam at 0.03 mg/kg, sufentanil at 0.4 µg/kg, and cisatracurium at 0.2 mg/kg. Mechanical ventilation will be performed after endotracheal intubation with basic parameters set to tidal volume 8 ml/kg, respiratory rate 10–14 times/min, oxygen flow rate of 50%, fresh gas flow rate of 2 L/min, maintaining end-expiratory carbon dioxide of 35–40 mmHg, heart rate 60–100 times/min, and cardiac index > 2.5 L/(min * m²) as much as possible. Anesthesia maintenance will be maintained with 0.5–1.5% sevoflurane, combined with intravenous infusion of 100–200 μg/(kg * min) propofol and 0.05–0.2 μg/(kg * min) remifentanil, with intermittent addition of cisatracurium to keep a bispectral index (BIS) value of 40–60 and  reduce the risk of intraoperative awareness. Notably, the utilization of drugs such as  ciprofol, dexmedetomidine, dexamethasone, and butorphanol during the surgical procedure is to be avoided.

Arm 1: After anesthesia induction, patients will be connected to the FloTrac/Vigileo system to monitor SVV, stroke volume, and cardiac output. Norepinephrine will then be infused intravenously at 0.06 µg/kg/min, followed by SVV-guided fluid therapy to achieve the target. If SVV ≤ 13% (indicating adequate effective circulating volume), the RL infusion rate will be set to 1–3 mL/kg/h. If SVV > 13% (indicating inadequate volume), a rapid crystalloid bolus of 1 mL/kg will be given over 2 min, and fluid responsiveness will be evaluated after another 2 min. This sequence will be repeated until SVV ≤ 13% is reached. After achieving the target SVV (≤13%), MAP will be maintained at ≥80 mmHg whenever possible. If SVV again exceeds 13% intraoperatively, the fluid challenge will be repeated. Should MAP drop below 80 mmHg, intravenous epinephrine or ephedrine may be used. Norepinephrine infusion will be continued for 5 min postoperatively. The SVV threshold of ≤13% is supported by evidence that SVV > 13% reliably predicts fluid responsiveness in mechanically ventilated patients [17] and that SVV-guided GDFT targeting ≤13% improves postoperative renal function in kidney transplantation [11]. The MAP target of ≥80 mmHg was selected because denervated transplanted kidneys lack autoregulatory capacity, rendering renal blood flow pressure-dependent. Increasing MAP from 60 to 75 mmHg with norepinephrine significantly improves renal blood flow (+18%) and GFR (+31%) [20]; a target of ≥80 mmHg provides a safety margin. Norepinephrine-mediated MAP elevation has been shown to reduce renal resistive index and improve renal oxygen delivery [21, 22].

Arm 2: Patients will not undergo monitoring with the FloTrac/Vigileo system throughout the whole procedure. Patient will be administered RL at an initial rate of 1–3 ml/kg/h, aiming to maintain MAP ≥ 80 mmHg. If MAP < 80 mmHg, give phenylephrine, ephedrine, or increase the rate of fluid infusion until MAP ≥ 80 mmHg. If the above measures remain inadequate, administer small doses of norepinephrine, epinephrine, or dopamine via an infusion pump as supplemental support. Anesthesiologists will rely on their clinical expertise or intraoperative CVP trends to regulate fluid infusion rates and administer medications to sustain a MAP of ≥80 mmHg as much as possible during the surgical procedure. The cumulative intraoperative dose of all vasopressors administered—norepinephrine (μg), phenylephrine (μg), ephedrine (mg), epinephrine (μg), and dopamine (μg)—will be documented in the Case Report Form (CRF) for both treatment arms to enable assessment of between-group vasopressor exposure.

During the surgical procedure, the administration of all additional medications will align with the established management protocols for kidney transplantations at each respective center, guided by the professional expertise of the anesthesiologists. In the event of any exigent circumstances necessitating immediate action to ensure patient well-being, trial interventions will be discontinued, and patients will be promptly rescued and managed in accordance with established clinical routines, with paramount consideration given to patient safety.

Postoperative management {11b}

Postoperative fluid management, blood pressure targets, immunosuppressive induction therapy, and dialysis initiation criteria follow center-specific protocols that have been harmonized across participating sites through the pre-enrollment standardized training program and will be recorded in CRF.

Criteria for discontinuing or modifying allocated interventions {11c}

If patients are unwilling or unable to participate in this trial (including withdrawal of informed consent), or the kidney transplantation is canceled, the allocated intervention for the respective trial participant will be promptly discontinued.

Strategies to improve adherence to interventions {11d}

Adherence to interventions primarily pertains to the adherence of patients to self-manage their treatment protocols.

Relevant concomitant care permitted or prohibited during the trial {11e}

No concurrent care or interventions will be allowed throughout the trial.

Provisions for post-trial care {30}

Should a participant experience any adverse effects attributable to this trial, they will be eligible for appropriate financial compensation. The determination of the compensation amount will be made collaboratively through consultation with pertinent departments and the affected participant.

Outcomes {12}

Primary outcome

The principal outcome of this study pertains to the incidence of DGF in the two study arms. DGF is defined as the requirement for at least one dialysis session within the first 7 days after kidney transplantation [23–25].

Secondary outcome

The secondary outcomes comprise the following:

1. Area under the curve (AUC) of serum creatinine levels from postoperative day 1 to 7.

2. Duration of DGF which is defined as the interval from surgery completion to the last dialysis up to 84 days post-surgery. This indicator applies only to patients who develop DGF. If the first postoperative dialysis session takes place after postoperative day 7, the patient no longer meets the definition of DGF, and thus the indicator is not applicable. For patients who do develop DGF and require dialysis for more than 84 days, the duration of DGF-related dialysis for that case should be recorded as 84 days.

3. Number of dialysis sessions during postoperative hospitalization.

4. Total urine output on the second postoperative day.

5. Duration of intensive care unit (ICU) stay.

6. Length of hospitalization.

7. The incidence of readmission within 30 days post-discharge. This refers to the first unplanned hospital readmission occurring within 30 calendar days of the initial post-transplant discharge date.

Exploratory outcome

1. The incidence of acute rejection during hospitalization.

2. The survival rates of transplanted kidneys at the 1-year postoperative mark. One-year graft survival indicates that the transplanted kidney is functioning adequately, obviating the need for dialysis at the 12-month follow-up.

3. The survival rates of patients at the 1-year postoperative mark. One-year patient survival indicates that the patient remains alive at the 12-month follow-up after kidney transplantation.

Safety outcome

The safety outcome of this trial is the occurrence of AEs using the common terminology criteria for adverse events (CTCAE) 5.0, providing comprehensive details.

Participant timeline {13}

Figure 1 illustrates the schedule for the participant enrollment, interventions, assessments, and visits throughout the study duration.

Fig. 1.

Timeline of the trial

The informed consent process is initiated while the patient is admitted. Trained anesthesiologists provide a comprehensive verbal explanation of the trial together with the written informed consent document. Participants are given adequate time—at least 24 h whenever logistically feasible, given the time-sensitive nature of deceased-donor kidney transplantation—to consider their decision and to discuss participation with family members. On the day of surgery, eligibility is reconfirmed upon arrival in the operating room, and participants are given the opportunity to ask any remaining questions before randomization is performed. Consent may be withdrawn at any point without affecting the participant’s clinical care. Following completion of the informed consent process, allocation to either arm 1 or arm 2 will be executed via the central randomization system, and a 1-year follow-up will be conducted (Fig. 2).

Fig. 2.

Flow chart of the trial

Sample size {14}

The medical history revealed an observed incidence of DGF among patients undergoing kidney transplantation at approximately 34%. However, our pre-experiments illustrated that the incidence can potentially be reduced to 20% through the implementation of our proposed intervention. A comparative analysis of outcomes between the goal-directed fluid therapy group and regular fluid therapy group will be conducted to discern any discernible differences in proportions. We utilize PASS 15.0 with a randomization ratio of 1:1, a statistical power of 0.80, and a two-sided α level of 0.05, accounting for a projected dropout rate of 10%. Consequently, our calculations indicate that a sample size of 380 patients will be necessary for the study. To address concerns about potential underpowering, we will perform post-hoc sensitivity power analyses using more conservative effect sizes.

Recruitment {15}

Figure 1 presents the schedule of major events for each study visit. The study enrolls patients with ESRD who are scheduled to undergo kidney transplantation. Investigators will conduct initial screening of eligible patients and provide recruitment materials to patients and their families for preliminary assessment. In addition, recruitment posters highlighting the potential benefits of trial participation will be prominently displayed in both the kidney transplantation ward and the operating room. All pharmaceuticals and medical supplies used in this trial are standard clinical items that are readily available and impose no additional financial burden on participants. Given the anticipated large pool of eligible patients corresponding to hospital admission volumes, we expect the recruitment process to proceed smoothly.

The entire process of participant recruitment and consent acquisition conducted by the research team will adhere rigorously to the principles outlined in GCP.

Assignment of interventions: allocation

Sequence generation {16a}

In this trial, we employed a stratified block randomization method to design the central randomization system. The risk factors contributing to DGF after kidney transplantation encompass patient-related, anesthesia-related, surgery-related, and donor-kidney factors. Patient-related factors include baseline physiological status and advanced age. Notably, the incidence of DGF varies among patients with different underlying medical conditions. However, our trial focused primarily on patients with uremia, the majority of whom maintain a stable physiological state through either hemodialysis or peritoneal dialysis. Age restrictions were not imposed due to the overall similar physical condition observed across all age groups following prolonged conditioning. Nevertheless, emerging literature [26, 27] suggests that machine perfusion of donor kidneys prior to transplantation can reduce the incidence of DGF, while there is also literature [28] indicating no significant advantages. Therefore, we stratified patients based on the center of treatment and whether they received machine perfusion therapy. Comprehensive baseline data, including demographic details such as name, gender, and date of birth, were collected from each patient. Subsequent to eligibility assessment, informed consent was obtained from eligible participants. Participants were randomized in a 1:1 ratio using stratified permuted block randomization with randomly varying block sizes (4 and 6) to prevent prediction of the allocation sequence.

Concealment mechanism {16b}

After providing signed informed consent, participants will be randomly assigned to either the goal-directed fluid therapy group or the conventional fluid therapy group using the central randomization system. The randomization outcomes, associated random numbers, and group assignments will remain strictly confidential throughout the trial to ensure that participants remain blinded. All patients in both groups will undergo standard monitoring, including electrocardiography, heart rate monitoring, noninvasive blood pressure measurement, and SpO₂. After anesthesia induction, patients in the Goal-directed fluid therapy group will be connected to a FloTrac/Vigileo monitoring system for continuous assessment of SVV, stroke volume, and cardiac output. In contrast, those in the regular fluid therapy group will not receive FloTrac/Vigileo monitoring. Importantly, participants will remain unaware of their group allocation throughout the entire trial, including before, during, and following their kidney transplantation, thereby ensuring the integrity of the blinding process.

Implementation {16c}

Qualified medical professionals will be responsible for generating the allocation sequence, enrolling participants, and assigning them to their respective interventions.

Assignment of interventions: blinding

Who will be blinded {17a}

Following the assignment of interventions, the trial patient participants, endpoint evaluators, and statisticians will undergo blinding procedures. The results generated by the central randomization system will be maintained confidential throughout the entirety of the trial. Both groups of patients will undergo standard monitoring procedures, encompassing electrocardiography, heart rate monitoring, noninvasive blood pressure measurement, and SpO₂ assessment. Subsequent to anesthesia induction, patients allocated to the goal-directed fluid therapy group will be connected to the FloTrac/Vigileo monitoring system to monitor specific parameters such as SVV-guided, stroke volume, and cardiac output. Conversely, patients assigned to the regular fluid therapy group will not undergo monitoring with the FloTrac/Vigileo system. The researcher will take measures to ensure that participants remain unaware of their own or others’ group assignments throughout the trial period. The anesthesiologists will not be blinded. Both the control and experimental groups follow standardized protocols. The primary outcome, DGF, is highly objective. Moreover, the clinicians involved in surgical anesthesia will not participate in postoperative data collection, outcome assessment, or data analysis.

Procedure for unblinding if needed {17b}

Patients will be informed of their group assignment only after the overall trial results have been analyzed and the primary manuscript has been accepted for publication. Individual-level unblinding on a per-patient basis will not be performed at any stage.

Data collection and management

Plans for assessment and collection of outcomes {18a}

This study constitutes an internal multicenter clinical trial. All data collection physicians will undergo specialized training conducted by assessors. Regular online meetings will be conducted to facilitate trial progress updates and facilitate discussions surrounding encountered challenges. Additionally, field visits to subcenters will be organized to ensure quality control measures are upheld. Regular organization of trial data will be performed to identify any instances of missing data. Furthermore, to enhance data quality, additional methods will be employed, including participant outreach through telephone calls.

Plans to promote participant retention and complete follow-up {18b}

Since all interventions are completed during surgery and no special treatment is required after surgery, the study center can retain patients through long-term regular telephone care until the final follow-up.

Participants can withdraw from the study at any time voluntarily or at the request of the attending physician.

Subjects who withdraw will not be replaced. Participants who withdraw from the study due to a study-related adverse event will be followed until the adverse event is resolved.

Participants who withdraw from the study will continue to receive their usual treatment, with assurances that this decision will not change their subsequent treatment.

Data management {19}

All patient data collected during this clinical trial will be meticulously entered and recorded in the CRF. Each CRF will include the study number, filtered number, subject information, and details pertaining to informed consent. The source data will be archived in accordance with GCP guidelines. The data manager will oversee data processing and conduct routine monitoring, adhering to the investigator’s standard operating procedures to ensure data adequacy, accuracy, and completeness. The process of source data lock will only commence following the completion of thorough quality assurance procedures.

Confidentiality {27}

Participant information will be handled in strict accordance with the Data Protection Act, NHS Caldecott Principles, The Research Governance Framework for Health and Social Care, and the conditions stipulated in the Research Ethics Committee approval. The confidentiality of all data collected throughout the research will be rigorously upheld, with access restricted solely to authorized members of the trial team. All documents containing patient information will be stored in locked cabinets within the anesthesia department. Access to or removal of these documents will require explicit authorization from the principal investigator. Each participant will be assigned a unique trial identification number, and their identifying information will be kept in a secure, dedicated database managed by qualified researchers. Only the principal investigator will have access to this database. To maintain confidentiality, anonymized trial data will not be disclosed to external researchers.

Plans for collection, laboratory evaluation, and storage of biological specimens for genetic or molecular analysis in this trial/future use {33}

Not applicable as no biological specimens were collected in this trial.

Statistical methods

Statistical methods for primary and secondary outcomes {20a}

Data selection for statistical analysis

1. Intention-to-treat (ITT) analysis: This analytical approach involves the inclusion of all participants randomized into the study, irrespective of subsequent adherence to the assigned treatment regimen.

2. Full analysis set (FAS): Following the principle of ITT analysis, the FAS encompasses all subjects randomized into the study who receive the designated treatment.

3. Per-protocol set (PPS): The PPS comprises all patients from the FAS without significant protocol deviations that might impact the assessment of primary outcomes. Efficacy analyses will be conducted on both the FAS and PPS populations. Major protocol deviations (leading to exclusion from the PPS) are pre-specified as (a) withdrawal of informed consent; (b) failure to receive the allocated intervention (e.g., surgery canceled after randomization); (c) receipt of the alternative arm’s intervention in full (crossover); (d) intraoperative administration of a prohibited medication (cyprinone, dexmedetomidine, dexamethasone, butorphanol) at a clinically significant dose; and (e) loss to follow-up before the primary outcome can be assessed. Protocol deviation classification will be performed independently by two clinicians blinded to treatment allocation, who will review each case before database lock. Disagreements will be resolved by a third adjudicator. All decisions will be documented in the trial master file. The PPS population will be finalized before unblinding and before any outcome analysis is conducted, thereby preventing biased post hoc exclusions.

4. Safety analysis set (SAS): The SAS encompasses all individuals who undergo the study treatment. Safety data analyses within the study will be based on the safety population.

Statistical analysis plan

We will follow the general principles of statistical analysis. Numeric variables will be presented as mean (standard deviation) or median (minimum, maximum, or interquartile range) based on whether it is normal. Categorical variables will be presented as number of cases (percentage). Two-tailed tests will be used in all statistical analysis, and P values of less than 0.05 will be considered to be of statistical significance (unless otherwise indicated).

Description of baseline characteristics: In this study, the description for baseline characteristics will be performed on the FAS population and compared between two randomized groups. All demographics and baseline characteristics will be described in appropriate summary statistics. Comparison between groups will be performed with t-test or Mann-Whitney test for numeric variables and χ² test or Fisher’s exact test for categorical variables. Meanwhile, cumulative intraoperative vasopressor exposure (norepinephrine (μg), phenylephrine (μg), ephedrine (mg), epinephrine (μg), and dopamine (μg), and other agents) will be summarized and compared using the Mann-Whitney U test.

Evaluation of primary outcome: The incidence of DGF after surgery will be calculated. The primary analysis for the primary objectives will be based on FAS population. Comparison between groups will be performed with χ² test for two proportions comparison. The primary analysis has been performed among the FAS population without missing outcome data. We do not anticipate any missing data due to sufficient recovery time in hospital for primary outcome. The incidence of DGF will be analyzed using a mixed-effects logistic regression model with study center as a random effect. The model includes the treatment group and the stratification variable machine perfusion (yes/no) as a fixed effect. The random effect for center accounts for inter-center heterogeneity. In addition, we will perform a pre‑specified sensitivity analysis adjusting for recipient age and history of diabetes. All adjustments are pre-specified in the statistical analysis plan to avoid data-driven variable selection.

Evaluation of secondary outcomes: These analyses will be performed on FAS and PPS populations. The t-test or Mann-Whitney test will be used to make comparison of area under the curve of serum creatinine levels from postoperative day 1 to 7, duration of DGF, number of dialysis sessions during postoperative hospitalization, total urine output on the second postoperative day, duration of intensive care unit (ICU) stays, and length of hospitalization between two groups. The comparison of the incidence of readmission within 30 days post-discharge between groups will be done with χ² test. The area under the curve of serum creatinine from postoperative day 1 to 7 is designated as the key secondary endpoint. All secondary and exploratory outcome analyses are designated as hypothesis-generating rather than confirmatory. No formal multiplicity adjustment will be applied to secondary endpoints; instead, nominal (unadjusted) P values with 95% confidence intervals will be reported, and secondary findings will be interpreted with emphasis on biological plausibility and internal consistency across related endpoints rather than reliance on individual P value thresholds. For the repeated serum creatinine measurements (days 1–7), the Benjamini-Hochberg procedure will be applied as a supportive analysis to control the false discovery rate. Serum creatinine is measured once daily (morning blood draw) on postoperative days 1 through 7 per standard ward protocol at all centers. If a patient is discharged before day 7, the available data will be used to calculate the AUC using the trapezoidal method; a complete-case sensitivity analysis (restricted to patients with all 7 measurements) will also be performed. Patients who die before day 7 will be excluded from the creatinine AUC analysis, with the number of such exclusions reported. In addition, in our institutional experience, this event is exceedingly rare in donor kidney transplantation. If >5% of creatinine measurements are missing, multiple imputation using chained equations will be performed as a sensitivity analysis.

Evaluation of exploratory outcomes: 1-year graft survival and patient survival will be analyzed as time-to-event endpoints using the Kaplan-Meier method, with between-group comparisons by the log-rank test. Kaplan-Meier curves with numbers at risk will be presented for both endpoints. Patients alive with a functioning graft at 1 year will be administratively censored at the 1-year anniversary of transplantation; patients lost to follow-up before 1 year will be censored at the date of last known contact. Cox proportional hazards models will estimate hazard ratios (95% CI), adjusting for the stratification factor (machine perfusion, yes/no) and, in sensitivity analyses, for recipient age and diabetes history. The proportional hazards assumption will be tested using Schoenfeld residuals. For graft survival, a competing-risk sensitivity analysis using the Aalen-Johansen estimator will treat death with a functioning graft as a competing event. Patients lost to follow-up before 1 year will be censored at the date of last contact. The incidence of acute rejection during hospitalization will be compared using the chi-squared test. The chi-squared test is retained only for the incidence of acute rejection during hospitalization, which is a binary, non-time-dependent endpoint.

Safety analysis: General safety evaluations will entail a comprehensive evaluation of AEs, encompassing their incidence and classification. Safety variables will be systematically tabulated and presented for all patients within the designated safety sets. AEs will be categorized using the CTCAE 5.0.

Moreover, to account for potential center effects in the multicenter study, we utilized a robust mixed-effects model, which provides unbiased estimates of the overall treatment effect by controlling for inter-center variability. An exploratory contamination analysis will be conducted according to actual norepinephrine exposure. Because excluding control-group patients who received rescue norepinephrine will break randomization and may introduce confounding by indication, any exposure-based analysis will be clearly identified as exploratory and will not replace the primary intention-to-treat analysis.

Sensitivity analysis

We will perform the analysis according to per protocol analysis set. Also, to ensure the reliability of our analyses, multiple imputation will be used in this study for sensitivity analysis. For subjects with missing primary endpoints, multiple imputation will be performed based on baseline information. In addition, we will incorporate an intraclass correlation coefficient for center effects.

Interim analyses {21b}

Not applicable as interim analyses are not contemplated in this study.

Methods for additional analyses (e.g., subgroup analyses) {20b}

The relationship between baseline characteristics, interventions, and the likelihood of DGF incidence was assessed utilizing both univariable and multivariable-adjusted logistic regression models. The outcomes were reported as odds ratios along with their corresponding 95% confidence intervals. We will perform a post hoc descriptive assessment of between-center consistency after the primary analysis is complete.

Methods in analysis to handle protocol non-adherence and any statistical methods to handle missing data {20c}

Statistical analysis was conducted following the ITT principle. Irrespective of adherence to the protocol, outcome analyses were randomly conducted. The occurrence and nature of missing data for all variables were examined, and if the missingness > 5% for any variable, sensitivity analysis was performed to address missing data through appropriate imputation methods.

Plans to give access to the full protocol, participant-level data, and statistical code {31c}

Due to Chinese data protection regulations (Personal Information Protection Law of the People’s Republic of China) and the conditions stipulated in the ethics committee approval, individual participant-level data cannot be deposited in public repositories. However, the de-identified dataset supporting the conclusions of this article, together with the statistical analysis code (R scripts), will be made available from the corresponding author upon reasonable request, subject to institutional data transfer agreement approval. The full protocol and statistical analysis plan will be published as online supplementary material alongside the final manuscript.

Oversight and monitoring

Composition of the coordinating center Trial Management Group {5d}

Diansan Su, Yugang Diao, and Jianjun Yang serve as members of the Trial Management Group. This trial does not have an independent Trial Steering Committee. Diansan Su is tasked with the preparation and revision of the protocol, as well as the dissemination of any modifications. Jie Zhou assumes responsibility for supervising the study design and protocol and interpreting the study findings. Muyan Shi and Yuhan Zhang are responsible for coordinating data collection and analysis, as well as drafting the scientific manuscript. Xibing Ding and Xiangyang Cheng are tasked with overseeing all statistical analyses and ensuring adherence to the protocol during study implementation.

Composition of the data monitoring committee, its role and reporting structure {21a}

A standing data monitoring committee (DMC) operates within the Clinical Research Center of Renji Hospital, affiliated with Shanghai Jiao Tong University School of Medicine, and is responsible for the review and monitoring of various interventional trials undertaken at this hospital. DMC at our institution is composed of independent clinical experts, biostatisticians, and epidemiologists, none of whom has any conflicts of interest with the study. The committee is responsible for the ongoing, independent review of accumulating study data to ensure participant safety, data integrity, and the continued validity of the trial. The DMC regularly evaluates adverse event profiles, protocol adherence, and key efficacy endpoints. Formal reports are generated at predefined intervals and submitted directly to the principal investigator and the institutional review board. In the event of significant safety concerns or clear evidence of efficacy or futility, the committee has the authority to recommend protocol modifications or early trial termination. All DMC proceedings and reports are strictly confidential and maintained in a secure, access-restricted repository.

Adverse event reporting and harms {22}

The administration of norepinephrine infusion alongside GDFT aims to address potential volume discrepancies often overlooked in routine anesthesia practices. Potential risks of norepinephrine combined with GDFT in renal transplantation patients include (i) excessive vasoconstriction, (ii) dose-dependent renal medullary hypoxia, (iii) arrhythmias, and (iv) compromised graft microcirculation. Throughout the clinical trial, any AEs will be meticulously recorded, irrespective of their perceived association with the intervention. Furthermore, all anticipated and unanticipated trial-related AEs will be duly documented and reported in the trial publications. Meanwhile, stopping criterion will be introduced: (1) Intraoperative MAP > 120 mmHg for 5 min, (2)  New-onset arrhythmia, and (3) a Clinical Research Center reviews serious adverse events.

Frequency and plans for auditing trial conduct {23}

The investigators will uphold stringent adherence to GCP standards in managing all study data. Original study data and pertinent information will be preserved for a minimum of 5 years post-trial completion. Moreover, data security measures will be implemented, and monitoring reports will be submitted to the ethical committee on a quarterly basis.

Plans for communicating important protocol amendments to relevant parties (e.g., trial participants, ethical committees) {25}

The clinical trial will be executed in strict accordance with the approval granted by the ethical committee. Any issues or modifications to the protocol arising during the trial will be promptly communicated to the ethical committees, trial participants, trial registries, journals, and regulators. Approval from the ethical committee will be sought before implementing any changes to the protocol.

Dissemination plans {31a}

The findings of this trial will be disseminated to participants, healthcare practitioners, the general populace, and other relevant constituencies, via scholarly articles.

Discussion

This study is the first randomized controlled trial designed to investigate the potential benefits of norepinephrine infusion combined with GDFT in patients undergoing kidney transplantation. Given the steadily increasing number of kidney transplant procedures performed worldwide each year, establishing an optimal fluid management strategy has become a clinical priority. DGF stands as the most prevalent complication following kidney transplantations, primarily attributed to ischemia-reperfusion injury of the transplanted kidney [4]. Concurrently, the utilization of extended criteria donor organs may further elevate the incidence of DGF [8].

Intraoperative fluid management during kidney transplantation has traditionally been guided by CVP, despite its limited reliability in assessing intravascular volume [29, 30]. However, this approach may increase the risk of pulmonary edema, volume overload with tissue edema, impaired tissue perfusion, infection, reduced renal perfusion, prolonged hospital stay, and even death [31]. Recent investigations have demonstrated enhanced predictive accuracy compared to CVP in estimating right ventricular preload and intravascular volume status in major surgical procedures, employing dynamic parameters such as SVV and PPV [32]. However, consensus remains elusive regarding whether GDFT efficaciously reduces the incidence of DGF after kidney transplantations [11, 33, 34]. The literature on this topic remains limited, and few recent studies have focused on patients undergoing kidney transplantation. Our study design addresses key limitations of previous investigations and more closely reflects real-world clinical practice. We anticipate that this trial will provide higher-level evidence, thereby improving prognostic assessment for kidney transplantation in patients with ESRD. In our study, norepinephrine is selected for its α-adrenergic agonist properties and partial β-adrenergic activity to increase systemic pressure [35]. This may enhance renal blood flow both directly and indirectly—by reducing vascular resistance through flow-induced dilation and changes in the number of perfused renal vessels. However, at higher doses, norepinephrine can also exert a vasoconstrictive effect on renal vessels, leading to increased vascular resistance and reduced renal blood flow [21]. Findings [21, 22] have shown that increasing MAP with norepinephrine from 65 to 75 mmHg significantly decreases the renal resistive index measured by Doppler ultrasonography, increasing renal blood flow. At low doses (≤0.1 µg/kg/min) [36], norepinephrine increases systemic arterial pressure predominantly via α1-receptor activation, thereby improving renal perfusion pressure. This is particularly important for transplanted kidneys, which often cannot respond adequately to physiological and pharmacological stresses due to denervation. Norepinephrine’s ability to improve systemic hemodynamics and ensure adequate renal blood flow makes it a potentially superior choice for optimizing renal function during the intraoperative and early postoperative periods [35]. Therefore, our fixed low dose (0.06 µg/kg/min), combined with GDFT to maintain SVV ≤ 13%, is designed to mitigate potential renal vasoconstriction by ensuring adequate circulating volume.

Our study treats norepinephrine infusion and GDFT as a combined package, which may create limitations that it is unclear whether the benefit arises from vasopressor use or GDFT. Here, the reasons we apply the combined package are as follows: (i) patients undergoing kidney transplantation frequently present with unstable circulating blood volume and impaired cardiac function. The sole use of GDFT to stabilize circulating volume may lead to excessive fluid infusion and fluid overload, thereby increasing the risk of postoperative dialysis, confounding the primary outcome of this experiment—delayed graft function (DGF). Low-dose norepinephrine used as an adjunct to maintain blood pressure helps increase renal perfusion pressure and renal blood flow. Therefore, it is administered in combination with GDFT; (ii) our pilot data showed that a fixed low-dose norepinephrine infusion (0.06 µg/kg/min) stabilizes mean arterial pressure without significantly increasing renal vascular resistance, thereby providing a “vascular tone platform” for SVV-guided fluid therapy; (iii) a factorial design would require four groups, substantially increasing the sample size beyond feasibility for this multicenter trial. Accordingly, this trial should be interpreted as an evaluation of a perioperative hemodynamic care bundle, encompassing both vasopressor support and protocolized fluid optimization, rather than a mechanistic test designed to isolate the independent contribution of either component. We suggest that future studies adopt a factorial design to evaluate the independent contributions of each component.

Therefore, future investigations ought to address certain limitations inherent in this study. Firstly, the 14% reduction of DGF rate may overestimate the effect size, which needs a larger sample size. Secondly, our trial was confined to domestic settings, conducted solely within grade III class A general hospitals in China, while anesthesia protocols and practices for kidney transplantations can diverge significantly across institutions and nations. Fortunately, the selected intravenous anesthetics boast widespread clinical utilization, rendering the data garnered from our study applicable across various clinical contexts. Thirdly, although all centers received a standardized video training and case simulation before enrollment, there still exists heterogeneity in perioperative management of renal transplantation anesthesia among different centers. Fourthly, our trial included only adult donors and recipients and excluded pediatric donors—particularly infants—as well as pediatric recipients. We plan to conduct a future study specifically designed to address this population. Fifthly, our findings may not directly generalize to living donor kidney transplantation, in which substantially shorter cold ischemia times and lower baseline DGF rates (approximately 5–15%) may attenuate the hemodynamic benefit observed in deceased donor transplantation. The results similarly do not extend to pediatric recipients (or recipients of pediatric donor kidneys), for whom body surface area-based fluid calculations and distinct hemodynamic targets apply, or to recipients with severe cardiovascular dysfunction (exercise tolerance < 4 METS or severe valvular disease), who were excluded from enrollment. Sixthly, no formal interim analysis with pre-specified stopping boundaries was included in the original protocol. These limitations underscore the need for further investigation into optimal fluid management strategies in kidney transplantation.

Trial status

The trial is presently in the process of recruiting patients, with the initial participant enrolled on March 1, 2024. All designated participating centers are operational and actively enrolling patients. The anticipated completion date of the trial is November 30, 2026.

Abbreviations

CKD

Chronic kidney disease

ESRD

End-stage renal disease

DGF

Delayed graft function

GDFT

Goal-directed fluid therapy

SVV

Stroke volume variation

PPV

Pulse pressure variation

RCT

Randomized controlled trial

CVP

Central venous pressure

GCP

Good Clinical Practice

AEs

Adverse events

BIS

Bispectral index

CRF

Case Report Form

SpO₂

Peripheral capillary oxygen saturation

RL

Sodium lactate Ringer’s solution

MAP

Mean arterial pressure

AUC

Area under the curve

ICU

Intensive care unit

CTCAE

Common terminology criteria for adverse events

OR

Operating room

PACU

Postanesthesia care unit

ITT

Intention-to-treat

FAS

Full analysis set

PPS

Per-protocol set

SAS

Safety analysis set

DMC

Data monitoring committee

Authors’ contributions {31b}

Jie Zhou is the principal investigator of this clinical trial, coming up with the idea of the study. Diansan Su is the senior investigator of this clinical trial. They are both responsible for the conception and design of the study. Muyan Shi and Yuhan Zhang contributed equally to this work and they shared first authorship and contributed to the final manuscript. Muyan Shi, Yuhan Zhang, Xiangyang Cheng were in charge of literature search. Muyan Shi, Xibing Ding contributed to conducting experiment and data collection. Jie Zhou was responsible for organizing and reviewing the data. Diansan Su was mainly involved in revising the manuscript. All authors have approved the final manuscript and agreed to its submission, and no professional writers were used.

Funding {4}

Not applicable as the study is not funded.

Data availability {29}

Due to Chinese data protection rules and regulations, the participant-level data set cannot be made publicly accessible. However, the statistical code is available if necessary.

Declarations

Ethics approval and consent to participate {24}

The Ethics Commission of Renji Hospital Shanghai Jiao Tong University School of Medicine approved and supported this clinical trial (LY2023-135-A).

Consent for publication {32}

We do not intend to disclose any personal information of participating patients. The informed consent materials can be obtained upon request from the corresponding author.

Competing interests {28}

The authors declare that they have no competing interests.