Comparative efficacy of balanced crystalloids versus 0.9% saline on delayed graft function and perioperative outcomes in kidney transplantation: a meta-analysis of randomised controlled trials

Abstract

Background

Delayed graft function after kidney transplantation is linked to poor graft survival and increased chronic allograft injury. Recent guidelines suggest using balanced crystalloids over 0.9% saline owing to better metabolic profiles, but their impact on DGF remains unclear.

Methods

We searched PubMed, Embase, and Cochrane Central Registry of Clinical Trials from inception until February 29, 2024, and included RCTs that randomised adult participants to receive either intravenous balanced fluids or 0.9% saline intraoperatively. We pooled data using a random-effects model and present risk ratios (RRs) or mean differences, with 95% confidence intervals (CIs). We assessed individual study risk of bias using the modified Cochrane tool and certainty of evidence using GRADE. Outcomes analysed were delayed graft function incidence, vasopressor requirements, length of hospital stay, and postoperative metabolic profiles.

Results

Of 106 publications identified, we included 11 RCTs (n=1717). Pooled analysis showed that the use of balanced fluids was associated with a lower incidence of delayed graft function compared with 0.9% saline (RR 0.82, 95% CI: 0.69 to 0.98, P=0.01, moderate certainty). Balanced crystalloids were associated with higher postoperative serum pH, higher serum bicarbonate, and lower serum chloride concentration, but effects on vasopressor requirements, length of hospital stay, and serum creatinine were uncertain.

Conclusions

Balanced crystalloid intravenous fluid therapy reduced delayed graft function incidence and maintained more favourable serum chemistry profiles compared with 0.9% saline in patients undergoing kidney transplantation. However, crystalloid type did not significantly influence vasopressor requirements and length of hospital stay.

Editor's key points.

• •Delayed graft function after kidney transplantation is a significant issue for patients and healthcare services. Intraoperative fluid management might impact outcomes and new evidence from RCTs is available.
• •This review comprised 11 RCTs from inception until February 29, 2024 (including the recently completed BEST-Fluids trial) that included 1717 patients.
• •Balanced crystalloid i.v. fluids resulted in lower risk of delayed graft function but no significant differences in perioperative vasopressor requirement, length of hospital, serum creatinine, sodium, or potassium when compared with 0.9% saline. Compared with the balanced crystalloid group, blood pH and serum bicarbonate were lower and serum chloride was higher in the 0.9% saline group.
• •This systematic review omitted studies of unbalanced solutions, included assessment of vasopressor use and type of donor, and used statistical methods to account for the influence of a large RCT (the BEST-Fluids trial) and missing data.
• •On the basis of this review, balanced intravenous crystalloid fluids are preferred over 0.9% saline for kidney transplantation.

Delayed graft function (DGF), necessitating dialysis in the first week post-kidney transplantation,¹ is linked to adverse outcomes such as decreased graft survival, reduced renal function at 6 months post-transplant, increased chronic allograft injury, and worse patient survival.² The incidence of DGF is <5% in living-donor transplants,³ but can reach up to 40% in deceased-donor transplants.⁴ Because of living-organ shortages, increasing numbers of transplants are performed with deceased donors, including older donors with comorbidities or after circulatory death.⁴ Consequently, DGF remains a clinical burden with no recognised preventive or therapeutic measures.

Intravenous fluid infusion is vital for maintaining perioperative organ perfusion,⁵ and the choice of fluids may impact DGF in kidney transplantation.⁶ Crystalloid solutions, including 0.9% saline and balanced crystalloids, are the most frequently used. Traditionally, 0.9% saline was preferred owing to the absence of potassium,⁷ but recent guidelines recommend balanced crystalloids for their superior metabolic profiles, such as lower incidence of acidosis.⁸ Previous meta-analyses up to 2021 showed uncertain effects of balanced crystalloids on DGF compared with 0.9% saline.^9,10 However, several RCTs conducted after 2021, including the largest trial to date ‘Better Evidence for Selecting Transplant Fluids’ (BEST-Fluids) trial, indicated that balanced crystalloids reduce the incidence of DGF compared with 0.9% saline.¹¹ Therefore, an updated review of literature is required to refine clinical recommendations. The choice between balanced crystalloids and 0.9% saline might also impact other outcomes, such as vasopressor requirements and length of hospital stay. Balanced crystalloids have been associated with reduced vasopressor needs in major abdominal surgery,¹² and perioperative vasopressor exposure has been linked to worse postoperative outcomes in kidney transplantation.^13,14 Regarding length of hospital stay, balanced crystalloids have shown mixed results in critically ill patients¹⁵ and no effect in the general surgical population.¹⁶ However, these effects have not been systematically reviewed in kidney transplantation trials. Our objective was to summarise evidence from RCTs to determine whether balanced crystalloids, compared with 0.9% saline, impact DGF, vasopressor requirements, length of hospital stay, and metabolic profiles in kidney transplantation.

Methods

Search strategy and study selection

Systematic review and meta-analysis were conducted based on the Cochrane Collaboration methodology and Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) statement.¹⁷ We registered the protocol for this review on PROSPERO (CRD42024498028) on February 9, 2024. We searched PubMed, Embase, and Cochrane Central Registry of Clinical Trials, with the following terms used for searching: ([balanced crystalloid] OR [lactated ringer] OR [ringers lactate] OR [plasma-lyte] OR [plasmalyte]) AND (normal saline) AND ([renal transplant] OR [kidney transplantation]) published from inception until February 29, 2024. No filter was applied during the searching process. We initially screened the titles and abstracts, and studies that met the following criteria were included: (1) RCT; (2) patients with end-stage renal disease undergoing kidney transplantation; (3) studies comparing perioperative use of 0.9% saline against balanced crystalloid; and (4) full text available in English. Two reviewers (TC and TTW) independently performed the screening process. If an agreement could not be reached, the opinion of a third reviewer (MCS) was considered at the conclusion of the screening process.

Data extraction

We extracted data into one file modified from the data extraction template of the Cochrane Consumers and Communication Review Group. The following data were extracted from original articles: name of the first author and publication year, country and setting, grouping strategy, enrolment period, sample size, donor type, type and duration of study fluid used, inclusion criteria, and exclusion criteria. We also extracted outcome parameters including the incidence of DGF, defined as the need for at least one dialysis treatment within the first week after kidney transplantation,¹ perioperative vasopressor requirements, and the length of hospital stay. Given the potential association between perioperative vasopressor exposure and adverse outcomes after kidney transplantation, as observed in earlier studies,^13,14 and considering the variation in vasopressor usage across the literature, comparing vasopressor dosages is not applicable. Therefore, we conducted an analysis on the proportion of patients requiring both intraoperative and postoperative vasopressors. There were four trials reporting data on length of hospital stay with either median (interquartile range)^{11 18 19} or median (range).²⁰ To facilitate comparability, we converted the data into the mean (standard deviation [sd]) by using methods described by Wan and colleagues.²¹ To further elucidate the study designs and potentially obtain data that were not reported, we contacted the authors of eligible studies to inquire about the timing of postoperative dialysis,²⁰ information on the length of hospital stay, and the proportion of patients receiving vasopressors.²² However, we did not receive any responses.

We collected mean (sd) of postoperative blood chemistry studies, including creatinine, pH, bicarbonate, sodium, chloride, and potassium, and the length of hospital stay in each individual trials. The time point for serum creatinine measurement was postoperative days 2–3, whereas the time point for the other serum biochemical variables was at the end of surgery. In eight of the included 11 trials, we directly obtained the mean (sd) within the papers. For the remaining three trials, numerical data were extracted from the graphical figures. In the study by Kim and colleagues,²³ mean (sd) of chloride, sodium, bicarbonate, and pH were obtained by using a straightedge to project each data point to the y-axis and recording the corresponding value from the scale. The same method was applied to extract mean (sd) of chloride, potassium, and pH from the study by Potura and colleagues.²⁴ For the study by Collins and colleagues,¹¹ mean and 95% confidence interval (CI) of pH, sodium, chloride, bicarbonate, creatinine, and potassium were obtained using manual measurement, with the gridlines serving as a reference. The CIs were then transformed into sd through mathematical calculation.

Risk of bias and certainty assessment

The quality of eligible trials was assessed and graphically summarised using the tool of risk of bias summary according to revised Cochrane risk-of-bias tool for randomised trials (RoB 2).²⁵ The following domains were assessed: randomisation process, deviations from the intended interventions, missing outcome data, measurement of the outcome, and selection of the reported result. Two investigators (TC and TTW) independently performed extraction and risk of bias assessment. Our evaluation of the certainty of evidence for each outcome was conducted through the application of the Grading of Recommendations Assessment, Development, and Evaluation (GRADE) framework.²⁶ Using an online tool (GRADEpro GDT) for guideline development, we crafted a comprehensive GRADE evidence profile.

Data synthesis and analysis

Study design, population size, donor type, type of balanced crystalloid used, and intervention duration were summarised. We conducted meta-analyses of DGF, perioperative usage of vasopressor, length of hospital stay, and postoperative serum creatinine, potassium, pH, sodium, chloride, and bicarbonate concentrations. Random-effects meta-analyses were carried out with risk ratio (RR) and mean difference (MD) as effect measure for binary and continuous outcomes, respectively. For continuous outcomes, additional sensitivity analyses were performed using Hedges' g²⁷ and Glass's delta²⁸ as effect measures. Robust CIs were constructed using the truncated Hartung–Knapp–Sidik–Jonkman (HKSJ) method owing to the potential for high heterogeneity among studies and the disproportionately larger sample size of the BEST-Fluids trial.²⁹ It is noteworthy that the initial analysis plan registered with PROSPERO specified the use of odds ratios for binary outcomes. However, after consultation with a statistical expert, RRs were recommended as the more appropriate effect measure given the prospective nature of the included trials. In accordance with the PRISMA 2020 guidelines,¹⁷ to investigate potential sources of heterogeneity across study findings, we conducted post hoc subgroup analysis for our primary outcome, namely DGF, stratified by donor type (living donor vs deceased donor) to explore whether the type of donor influences the incidence of DGF. To assess subgroup interaction, we used meta-regression with the truncated HKSJ method. Additionally, we performed a meta-regression analysis to investigate whether the type of deceased donor (circulatory death vs brain death) influenced the effect of balanced crystalloids vs saline on DGF.^11,19,30

To assess the possible influence of missing data on the results of meta-analyses, we conducted sensitivity analyses under different scenarios of informative missingness using metamiss2 package in STATA (StataCorp LP, College Station, TX, USA).³¹ Adopting the informative missingness difference of means approach, we considered two scenarios: in the first scenario, missing participants receiving balanced crystalloid have higher outcome levels (on average 1.5 times sd higher than non-missing), and missing participants receiving saline have lower outcome levels (on average 1.5 times sd lower than non-missing); in the second scenario, the higher/lower direction was switched between two groups. The sd of the difference of means were set as the treatment-specific sd. We then compared the resulting CIs of these scenarios with the complete-case analysis results.

Statistical heterogeneity was assessed using Cochran's Q through the χ² test and was quantified using the I² statistic proposed by Higgins and colleagues.³² Publication bias was assessed by visual inspection of a funnel plot and by using Egger test. All statistical analyses were performed using STATA 17 (Stata Corp LP). A result was considered statistically significant when its two-sided P-value was less than 0.05.

Results

Search results and trial characteristics

A total of 106 publications were identified using our search strategy, and 11 papers were included for the meta-analysis.^11,18, 19, 20^,22, 23, 24^,30,33, 34, 35 Figure 1 shows the study flowchart. Among the included papers, two papers were registered under the same registration number while reporting different outcomes within the same trial.^24,30 Table 1 summarises the characteristics of the included individual studies. Intraoperative haemodynamic monitoring, fluid protocol, and intraoperative volume of study fluid for the included individual studies were summarised in Supplementary Table S1.

Fig 1.

Flowchart of study selection.

Table 1.

Characteristics of the included individual studies. ∗Potura (2015) and Pfortmueller (2017) report different outcomes from the same clinical trial; therefore, study characteristics are consolidated into one entry.

	Country	Study design	Donor type	No. of patients	Balanced fluid used	Duration of intervention fluid
O'Malley (2005)	USA	RCT	94.12% Living	51	Ringer's lactate	Intraoperative
Hadimioglu (2008)	Turkey	RCT	Living	90	Plasmalyte and Ringer's lactate	Intraoperative
Khajavi (2008)	Iran	RCT	Living	52	Ringer's lactate	Intraoperative
Kim (2013)	South Korea	RCT	Living	60	Plasmalyte	Intraoperative
Potura (2015)	Austria	RCT	Deceased	148	Elomel Isoton	During and after surgery until discharged
Pfortmueller (2017)∗
Kanithi (2017)	India	RCT	Living	30	Plasmalyte	Intraoperative
Weinberg (2017)	Australia	RCT	Deceased	49	Plasmalyte	During and after surgery until 48 h after transplantation
Saini (2021)	India	RCT	Living	180	Plasmalyte and Ringer's lactate	Intraoperative
do Nascimento Junior (2022)	Brazil	RCT	Deceased	101	Plasmalyte	Intraoperative
Collins (2023)	Australia, New Zealand	RCT	Deceased	808	Plasmalyte	During and after surgery until 48 h after Transplantation or cessation of i.v. fluids

Figure 2 shows the quality assessment of the included individual studies. The risk of bias assessment across the five domains revealed a low risk for the randomisation process, missing outcome data, and outcome measurement domains, whereas some concerns were raised regarding potential deviations from the intended interventions and the selection of reported results. Instances of missing serum biochemical data were documented in only two of the included studies, those by Collins and colleagues¹¹ and do Nascimento Junior and colleagues.¹⁸ In the study by do Nascimento Junior and colleagues,¹⁸ 16 of 101 participants were excluded from postoperative blood examination as a result of sample clotting or inappropriate blood collection procedures. In the study by Collins and colleagues,¹¹ however, reasons underlying missingness for postoperative blood test data were not reported. For most evaluated outcomes, the proportion of missing data was projected to be markedly subthreshold relative to the 5% general guideline occasionally referenced to warrant complete-case analytic approaches.³⁶ This expectation is predicated upon the relatively short follow-up durations. In the present meta-analysis, the mechanism underlying missingness was unlikely to be related to the true outcome status, thus the risk of bias stemming from missing outcome data was deemed to be low. Furthermore, sensitivity analyses showed that under informative missingness of either direction, the effect estimates only slightly differ, and the conclusions of the significance tests mostly held (with the only exception of scenario 2 for sodium, Supplementary Table S2).

Fig 2.

Quality assessment of included trials.

Results of meta-analysis

Table 2 provides a summary of findings and the certainty of evidence for each outcome. Supplementary Figures S1–S9 illustrate the funnel plots associated with each specific outcome.

Table 2.

Summary of review outcomes and certainty assessment for each outcome. CI, confidence interval; MD, mean difference; RR, risk ratio. ^aThe uneven allocation of weights to each study led to a downgrade in our assessment results. ^bVisual inconsistency. Statistical analysis also showing high heterogeneity. ^cIncluded studies: ^11,18, 19, 20^,23,30,35. ^dIncluded studies: ^11,18,30,34. ^eIncluded studies: ^11,18, 19, 20. ^fIncluded studies: ^11,20,22, 23, 24^,34,35. Data were collected on postoperative day 2 in trials by Kim and colleagues,²³ Saini and colleagues,²² and Collins and colleagues¹¹; data were collected on postoperative day 3 in trials by O'Malley and colleagues,²⁰ Hadimioglu and colleagues,³⁵ Khajavi and colleagues,³⁴ and Potura and colleagues.^24gIncluded studies: ^11,18, 19, 20^,22,24,33, 34, 35. ^hIncluded studies: ^11,18, 19, 20^,22, 23, 24^,33, 34, 35. ⁱIncluded studies: ^{11,18,19,23,34}. ^jIncluded studies: ^11,18, 19, 20^,22, 23, 24^,35. ^kIncluded studies: ^{11,18,20,22,23,33,35}. ^lThree trials reported intraoperative vasopressor usage^18,30,34 and one trial reported both intraoperative and postoperative vasopressor usage.^11mIn the trial by Potura and colleagues,²⁴ data were collected 240 min after the start of surgery, with a mean operation time of 175.24 min.

Certainty assessment							No. of patients		Effect		Certainty
No. of studies	Study design	Risk of bias	Inconsistency	Indirectness	Imprecision	Other considerations	Balanced crystalloid	Normal saline	Relative	Absolute
									(95% CI)	(95% CI)
Delayed graft function
7c	Randomised trials	Seriousa	Not serious	Not serious	Not serious	None	194/591 (32.8%)	243/548 (44.3%)	RR 0.82	80 fewer per 1000	⨁⨁⨁◯
									(0.69–0.98)	(from 133 fewer to 9 fewer)	Moderate
Perioperative vasopressor requirement				Time point of measurement: intraoperative and postoperativel
4d	Randomised trials	Seriousa	Not serious	Not serious	Not serious	None	278/552 (50.4%)	304/556 (54.7%)	RR 0.93	38 fewer per 1000	⨁⨁⨁◯
									(0.78–1.10)	(from 120 fewer to 55 more)	Moderate
Hospital length of stay
4e	Randomised trials	Not serious	Seriousb	Not serious	Not serious	None	503	505	–	MD 1.69 days lower	⨁⨁⨁◯
										(5.11 lower to 1.72 higher)	Moderate
Postoperative serum creatinine concentration				Time point of measurement: postoperative day 2–3f
7f	Randomised trials	Seriousa	Not serious	Not serious	Not serious	None	736	740	–	MD 0.04 higher	⨁⨁⨁◯
										(0.2 lower to 0.27 higher)	Moderate
Postoperative serum potassium concentration				Time point of measurement: at the end of surgerym
9g	Randomised trials	Not serious	Seriousb	Not serious	Not serious	None	785	791	–	MD 0.15 lower	⨁⨁⨁◯
										(0.46 lower to 0.16 higher)	Moderate
Postoperative serum pH concentration				Time point of measurement: at the end of surgerym
10h	Randomised trials	Not serious	Not serious	Not serious	Not serious	None	733	733	–	MD 0.05 higher	⨁⨁⨁⨁
										(0.04 higher to 0.06 higher)	High
Postoperative serum sodium concentration				Time point of measurement: at the end of surgery
5i	Randomised trials	Seriousa	Not serious	Not serious	Not serious	None	523	525	–	MD 1.43 lower	⨁⨁⨁◯
										(3 lower to 0.13 higher)	Moderate
Postoperative serum chloride concentration				Time point of measurement: at the end of surgerym
8j	Randomised trials	Not serious	Seriousb	Not serious	Not serious	None	765	775	–	MD 7.25 lower	⨁⨁⨁◯
										(12.73 lower to 1.77 lower)	Moderate
Post-operative serum bicarbonate concentration				Time point of measurement: at the end of surgery
7k	Randomised trials	Seriousa	Not serious	Not serious	Not serious	None	685	693	–	MD 2.25 higher	⨁⨁⨁◯
										(1.25 higher to 3.25 higher)	Moderate

Figure 3 illustrates the meta-analysis for DGF. Balanced crystalloid likely reduces the incidence of DGF compared with 0.9% saline, yielding an RR of 0.82 for overall DGF (95% CI: 0.69 to 0.98, P=0.01, moderate certainty). Among the included trials for the analysis of DGF, O'Malley and colleagues²⁰ did not specify the exact time point at which the dialysis was performed. The DGF definition was applicable to the other six included trials. Therefore, we conducted a sensitivity analysis by performing a meta-analysis excluding the study by O'Malley and colleagues,²⁰ as shown in Supplementary Figure S10 (RR 0.82, 95% CI: 0.68 to 0.99, P=0.01). The results were consistent regardless of whether the study by O'Malley and colleagues²⁰ was included, demonstrating that the use of balanced crystalloid solutions reduces the incidence of DGF in patients undergoing kidney transplantation.

Fig 3.

Forest plot of incidence of delayed graft function (DGF) of included eligible studies. CI, confidence interval.

Four trials investigating perioperative vasopressor usage were included^11,18,30,34; three trials reported intraoperative vasopressor usage^18,30,34 and one trial reported both intraoperative and postoperative vasopressor usage.¹¹ Figure 4 shows the meta-analysis for perioperative vasopressor requirement, which did not reveal any statistically significant differences between balanced crystalloid and 0.9% saline (RR 0.93, 95% CI: 0.78 to 1.10, moderate certainty). Supplementary Figure S11 demonstrates the meta-analysis for length of hospital stay, showing no statistically significant differences between balanced crystalloid and 0.9% saline (MD –1.69, 95% CI: –5.11 to 1.72, moderate certainty).

Fig 4.

Forest plot of vasopressor requirement of included eligible studies. CI, confidence interval.

There was no significant effect of type of i.v. fluid on serum creatinine concentration on postoperative days 2–3 (MD 0.04 higher for balanced crystalloids, 95% CI: –0.2 to 0.27, moderate certainty, Supplementary Fig. S12).

Regarding postoperative serum pH and electrolyte profiles, perioperative administration of balanced crystalloid led to a higher postoperative serum pH concentration compared with 0.9% saline (MD 0.05, 95% CI: 0.04 to 0.06, high certainty, Supplementary Fig. S13). Furthermore, a higher postoperative serum bicarbonate concentration (MD 2.25, 95% CI: 1.25 to 3.25, moderate certainty, Supplementary Fig. S14) and a lower serum chloride concentration (MD –7.25, 95% CI: –12.73 to –1.77, moderate certainty, Supplementary Fig. S15) are associated with perioperative balanced crystalloids administration. Conversely, perioperative administration of balanced crystalloids or 0.9% saline has no impact on both postoperative serum potassium concentration (MD –0.15, 95% CI: –0.46 to 0.16, moderate certainty, Supplementary Fig. S16) and serum sodium concentration (MD –1.43, 95% CI: –3 to 0.13, moderate certainty, Supplementary Fig. S17). All conclusions for continuous outcomes remain unchanged when Hedges' g or Glass's delta is used as alternative effect measures.

Subgroup analyses

The results of the subgroup analyses are presented in Supplementary Figure S18. Among the included trials, the study by O'Malley and colleagues²⁰ was excluded from the subgroup analysis, as the donor population comprised a mixed cohort including 48 living donors and three deceased donors, precluding meaningful stratification by donor type. Supplementary Figure S18 shows subgroup analysis of DGF stratified by donor type (deceased vs living). No significant between-group differences were observed in the studied population (P=0.81), indicating no statistically significant interaction between fluid choice and donor type for risk of DGF. Three trials reported the proportion of donation after circulatory death or brain death.^11,19,30 Meta-regression analysis revealed that the proportion of donation after circulatory death did not significantly modify the effect of balanced crystalloid on DGF (ratio of RR per 10% increase in proportion of circulatory death = 0.94, 95% CI: 0.695 to 1.273, P=0.691).

Discussion

In this meta-analysis, we have demonstrated a reduced risk for postoperative delayed graft function in the balanced crystalloid group, indicating more favourable graft function with perioperative balanced crystalloid administration. However, no significant differences were observed in perioperative vasopressor requirement, hospital length of stay, serum creatinine, sodium, or potassium concentration when comparing perioperative administration of balanced crystalloid and 0.9% saline. Significant differences were noted in lower blood pH, higher serum chloride concentration, and lower serum bicarbonate in the 0.9% saline group, which were consistent with previous studies of kidney transplantation.^9,10

In 2021, Jahangir and colleagues⁹ conducted a meta-analysis to compare low-chloride fluid and 0.9% saline during kidney transplantation and revealed no significant differences in DGF. By comparison, the present study revealed the opposite findings. There were substantial differences between our study and the study by Jahangir and colleagues.⁹ Firstly, the uses of non-balanced low-chloride fluid, such as sodium bicarbonate and half-saline, were included to compare against 0.9% saline in the meta-analysis by Jahangir and colleagues,⁹ whereas only balanced crystalloid was included in the present study. Secondly, three recent RCTs were included in the present study,^11,18,22 which significantly increased the sample size of the analysis and potentially augmented the power of the meta-analyis.³⁷

In 2024, two updated systematic reviews were published, revealing findings similar to those of the present study regarding the effects of balanced crystalloids on DGF.^38,39 However, significant differences exist between these reviews and our study. Firstly, we excluded studies using solutions such as half-saline,^40,41 hypertonic saline,⁴² and sodium bicarbonate,⁴³ which are not currently classified as balanced crystalloids. Modern balanced crystalloids contain alternative anions, such as lactate, acetate, and gluconate,⁴⁴ rendering the previously prevalent bicarbonate-containing solutions less applicable in contemporary clinical practice. Secondly, we used the HKSJ method to obtain more robust CIs. This method is particularly appropriate in our meta-analysis, where the BEST-Fluids trial contributes a disproportionately large weight.¹¹ The HKSJ method has been shown to outperform the commonly used DerSimonian–Laird method, especially when the number of studies is small and there is substantial heterogeneity or unequal study sizes.²⁹ This approach provides more reliable and conservative estimates, reducing the risk of overstating the significance of our findings. Thirdly, although DGF is defined as the need for dialysis within 1 week post-transplantation,¹ the previous reviews included studies without a clear time frame for postoperative dialysis. For instance, O'Malley and colleagues²⁰ reported the number of patients requiring dialysis but did not specify the time point. We conducted a sensitivity analysis with and without this study to assess its impact on DGF conclusions. Fourthly, the impact of missing data was analysed in the present study using the Informative Missing Data On Missingness (IMDOM) approach, considering two opposing scenarios of missingness patterns between the balanced crystalloid and saline groups. This method investigates whether the pattern of missing data itself might be informative or potentially related to the study outcomes, further strengthening the robustness of our findings in the face of potential missing data bias. Fifthly, we comprehensively analysed relevant clinical outcomes, including the previously unaddressed perioperative requirement for vasopressors and a thorough examination of length of hospital stay, which were not uniformly covered in the previous reviews. Lastly, we performed a meta-regression to investigate the influence of the type of deceased donor (circulatory death vs brain death) on incidence of DGF among the included studies.

DGF represents acute kidney injury after kidney transplantation, which is more common in deceased donor than in living donors.⁴⁵ Previous literature showed that the use of balanced crystalloid was not associated with less acute kidney injury in both critically ill patients and non-critically ill patients.46, 47, 48 In contrast, we observed beneficial effects of the balanced crystalloid on DGF in kidney transplantation. The beneficial effects may be attributed to several mechanisms that are more prominent in kidney recipients. Firstly, 0.9% saline-related hyperchloraemic acidosis appears to induce inflammatory responses.⁴⁴ Conversely, balanced crystalloids were reported to attenuate inflammatory responses in the setting of acute pancreatitis^49,50 and in major abdominal surgery.⁵¹ During kidney transplantation, profound inflammatory responses associated with the activation of adaptive immune responses would be induced,⁴⁵ and the anti-inflammatory properties inherent in balanced crystalloid solutions may reduce the incidence of DGF. Secondly, hyperchloraemia induces vasoconstriction of the afferent arteriole and leads to a decrease in the glomerular filtration rate.⁵² Consequently, the perioperative use of 0.9% saline might reduce renal perfusion in patients undergoing kidney transplantation. Despite the observed differences in DGF between balanced crystalloid and 0.9% saline, we failed to observe differences in serum creatinine concentrations. This finding is consistent with the results of the BEST-Fluids trial,¹¹ and it may be attributed to the potential confounding effect of varying rates of dialysis on creatinine-based measures.

Significant associations of higher vasopressor requirements with 0.9% saline, compared with balanced crystalloid, have been observed in RCTs involving major abdominal surgery, kidney transplantation, and critically ill patients.^12,24,30,53 Furthermore, the use of vasopressors during kidney transplantation has been reported to induce worse graft function in several retrospective studies.^13,14 Therefore, we considered this an important outcome to investigate when assessing the influence of crystalloid selection. Despite the present meta-analysis revealing a more favourable outcome regarding DGF in the balanced crystalloid group, we observed no significant differences in vasopressor usage between the two study groups. This lack of significance may be attributed to variations in fluid protocols across studies, with intraoperative fluid volumes ranging from 1500 ml to 6000 ml. Given that fluid protocols can substantially impact vasopressor requirements,⁵⁴ the influence of the type of crystalloid alone on vasopressor doses during kidney transplantation might be attenuated.

Consistent with prior literature, the present review observed more favourable profiles of serum chemistry, including pH, bicarbonate concentration, and chloride concentration, with balanced crystalloid vs 0.9% saline.^9,10 Conversely, serum potassium concentrations were less likely influenced by the choice between the two types of crystalloid solutions. In the past decades, the avoidance of balanced crystalloid solutions containing potassium during kidney transplantation was advocated owing to concerns that potassium ions within the solution might exacerbate hyperkalaemia in cases of impaired graft function.⁵⁵ However, hyperchloraemic metabolic acidosis can also lead to potassium shifting outside of the cell, potentially worsening hyperkalaemia.⁵⁶ Our study aligns with the acknowledgement that balanced crystalloids are noninferior in maintaining serum potassium concentrations for kidney transplantation patients.^8,9

The present study has several limitations. Firstly, it includes the BEST-Fluids trial, which had the largest sample size among the studies reviewed.¹¹ Although a study with large sample size can greatly increase the power of the study, it also carries a risk of introducing bias because of the large weight placed on a single trial. Secondly, studies conducted with living donors comprised smaller sample sizes. Hence, we considered that the benefits of balanced crystalloids might not have been sufficiently explored in this subpopulation yet. Thirdly, the impact of crystalloid selection on clinically important outcomes, such as the number of dialysis sessions after transplantation and long-term graft function, remains insufficiently explored in the current literature. Fourthly, because of the high variation in vasopressor usage (e.g. dopamine, norepinephrine) across studies, comparing vasopressor dosages is not feasible. As the count outcome (vasopressor dosage) is more sensitive than the binary outcome (vasopressor requirement), our findings regarding the influence of crystalloid selection on perioperative vasopressor use are limited.

In conclusion, balanced crystalloid emerges as the more favourable solution of choice for patients undergoing kidney transplantation, not only because of its impact on postoperative serum pH and electrolyte profile but, most importantly, because of its positive influence on early graft function. The notion of avoiding potassium-containing balanced fluid in patients with impaired renal function should be reconsidered.

Authors’ contributions

Performed abstract and full text article screening, data extraction, and assisted with the writing of the manuscript: TC, MCS, YLW, CYW

Provided expert commentary and edited the final manuscript: TC, MCS, CYW

Performed data synthesis and meta-analyses: TC, MCS

Supervised the project, assisted with protocol design, resolved screening disputes, and edited the final manuscript for submission: MCS, TTW, JTY

Declaration of interest

The authors declare that they have no conflicts of interest.

Handling Editor: Kate Leslie

Appendix A. Supplementary data

The following is the Supplementary data to this article: