#NephJC Chat
Tuesday July, 25th, 2023 at 9 pm Eastern (AEST = July 25th, 11am)
Wednesday July 26th, 2023, at 9 pm Indian Standard Time and 3:30 pm GMT (AEST = July 26th, 2am)
Lancet. 2023 Jul 8;402(10396):105-117. doi: 10.1016/S0140-6736(23)00642-6.
Balanced crystalloid solution versus saline in deceased donor kidney transplantation (BEST-Fluids): a pragmatic, double-blind, randomized, controlled trial
Michael G Collins, Magid A Fahim, Elaine M Pascoe, Carmel M Hawley, David W Johnson, Julie Varghese, Laura E Hickey, Philip A Clayton, Kathryn B Dansie, Rachael C McConnochie, Liza A Vergara, Charani Kiriwandeniya, Donna Reidlinger, Peter F Mount, Laurence Weinberg, Colin J McArthur, P Toby Coates, Zoltan H Endre, David Goodman, Kirsten Howard, Martin Howell, Jagadish S Jamboti, John Kanellis, Jerome M Laurence, Wai H Lim, Steven J McTaggart, Philip J O’Connell, Helen L Pilmore, Germaine Wong, Steven J Chadban†, on behalf of the BEST-Fluids Investigators‡ and the Australasian Kidney Trials Network
PMID: 37343576 Full Text Link
Introduction
Around 20-30% patients receiving deceased donor kidney transplant (DDKT) suffer from delayed graft function (DGF), defined as requirement of dialysis within 7 days of transplant (Lin MA, et al, CJASN 2008; Yarlagadda et al, NDT 2008). This, in turn, leads to acute rejection, worse 5-year graft survival and ultimately graft loss (Budhiraja P et al, BMC Nephrol 2022). BEST-Fluids is a trial aimed to minimize this burden by choosing the right fluid around the time of transplant.
Meticulous fluid therapy is crucial in preventing delayed graft function and it varies from center to center and is largely driven by unit protocols. 0.9% saline is the most commonly prescribed fluid (O’Malley CM et al, Transplant Proc 2002) and has been implicated in AKI among critically ill (Yunos NM et al, JAMA 2008) and peri-operative patients (Weinberg L et al, Anaesth. Intensive Care 2018). Stakes are probably higher with DDKT due to the higher risk of DGF secondary to ischemia reperfusion injury. Notably, the incidence of DGF is significantly higher in donation after circulatory death (DCD) (45-55%) than in donation after brain death (DBD) (20-30%) (Mannon RB, Nephron 2018). Hyperchloremic metabolic acidosis and reduced cortical perfusion due to renal vasoconstriction are attributed for the poorer outcomes with 0.9% saline, but remains to be proven at large (Chowdhury AH et al, Ann Surg 2012).
Adapted from Collins MG et al, Trials, 2020
Hence, balanced crystalloid solutions such as Lactated Ringer’s, Plasmalyte and Hartmann's solution (which are not all the same, see above) have been studied as an alternative to NS. Only 1 of the 5 large trials, on the choice of fluid in critically ill patients, showed slight advantage of balanced crystalloid solutions over normal saline in terms of major adverse kidney events at 30 days (a composite outcome of death, new RRT and persistent kidney dysfunction) and the rest showed no difference. We have discussed these on NephJC previously (see summary on BASICS for more).
A common theme through all these is that the amount of IV fluids used in sepsis and resuscitation these years has decreased substantially, with the use of ionotropic support early being preferred over the ‘fill them up’ approach previously done (See NephJC summary and podcast on the CLASSIC trial). However - in the post transplant setting, we still do high volume crystalloid resuscitation to ensure good prefusion of the graft. Along with the high rate of DGF, could this be the prefect setting to test the balanced approach? In transplant nephrology, a systematic review (Wan S et al Cochrane Database Syst Rev 2016) and a meta-analyses (Jahangir et al Kidney Res Clin Pract. 2021) pertaining to the choice of fluid have demonstrated lower incidence of metabolic acidosis & consequently hyperkalemia with the use of balanced crystalloids, however, there is uncertainty with regards to their impact on DGF.
Due to unconvincing evidence, transplant physicians are left to their own vices, based on individual or institutional experiences. While we await a miraculous advancement that tackles DGF once and for all, the investigators of BEST-fluids revisit the contention that balanced crystalloids are superior to NS in prevention of DGF.
The Study
Methods
Best Fluids was a large, pragmatic, registry embedded, multicenter, double blind RCT comprising 808 participants from 12 centers in Australia and 4 in New Zealand, to determine the best perioperative fluid during DDKT. A registry embedded trial is one where either the patients are recruited from a registry or their trial-related data is incorporated and entered in the registry, thus reducing the cost and resource-intensiveness, in comparison to a traditional RCT. Read the NephJC summary by Manasi Bapat on efficiency in clinical trials where she discusses the pros and cons of a registry based trial design.
Patients planned to undergo DDKT were randomized in a 1:1 ratio to receive either Plasma-Lyte 148 (balanced crystalloid) or NS perioperatively and up to 48 hours post op. Special care was taken to mask the type of fluid by providing them in similarly packaged 1L bags. The quantity and rate of fluid administration was left to the clinician’s judgment.
Figure depicting fluid masking from Collins MG et al, Trials, 2020
Randomization was done via adaptive minimization algorithm, whereby minimization factors were transplant center, deceased donor type (DBD or DCD), use of hypothermic machine perfusion, and Kidney Donor Risk Index (KDRI) tertile, using the Australian KDRI.
Patients of all age groups were included, unless weighing <20 kg. DCD (donation after circulatory death) as well as DBD (donation after brain death) donors were included in the study. However, multi-organ recipients were excluded.
Statistical Analysis
It was estimated that a sample size of 722 would be required to provide 80% power at a 5% two-sided α level to show an absolute difference of 10% (41% vs 31%) between the groups for the incidence of DGF, corresponding to a relative risk for balanced crystalloid versus saline of 0·76. This was adjusted to a sample size of 800 accounting for expected attrition (1% loss to follow-up and 4% non-adherence) (Pascoe EM et al, Trials 2022).
The safety analysis was done in all randomized participants whose surgery began, regardless of whether they received the kidney transplant. For the primary outcome, the authors used a log-bimodal regression model, incorporating minimization variables (decreased donor, KDRI tertiles). Clustering was done using a generalized estimated equation approach with exchangeable correlation structure and robust standard errors, as generalized mixed models encountered convergence issues.
To address missing data, prespecified sensitivity analyses were conducted using best-worst and worst-best imputation approaches for primary outcome. Prespecified analyses were performed to assess the impact of donor type, machine perfusion, KDRI tertiles, and ischemic time.
Figure 3: Outline of the components of the ranked composite outcome early kidney transplant function (secondary outcome 1) from Pascoe EM et al, Trials, 2022
For secondary analyses the authors used various statistical models depending on the nature of the outcome. For single occasion measurements, the fixed effects and clustering approach were consistent with the primary outcome model. The ordinal composite ranked outcome was analyzed using a proportional odds regression model.
Specific secondary outcomes, dialysis- related were analyzed only for patients who received dialysis, representing a non-intention-to-treat analysis. However, post-hoc analyses were also conducted on an intention-to-treat basis, including all participants.
Multiplicity wasn’t adjusted for in the analyses, making all secondary analyses hypothesis-generating.
Outcomes
Primary outcome was DGF, defined as receiving dialysis within 7 days after transplantation. In addition, those who died or had early graft failure (< 7 days of transplant) were also classified as DGF. Secondary outcomes included a ranked composite of DGF duration and creatinine reduction ratio on day 2 (the original primary outcome), number of dialysis treatments (to day 28) and duration of dialysis in days (to week 12), creatinine reduction ratio on day 2 and creatinine reduction of 10% or more in the first 3 days etc. Quality-of-life measures were collected, though not yet reported.
Data Collection – the pragmatic aspects of a registry embedded trial
A registry embedded trial meant that demographic and routine data, such as acute rejection, graft and patient survival, were collected and recorded into the ANZDATA Registry web platform. Whereas trial specific data was collected using a bespoke module added for this purpose, data on donor characteristics was retrieved from the Australia and New Zealand Organ Donation Registry.
Funding
Fluids were provided by Baxter Healthcare: 36 270$ the market value of Plasmalyte solution was granted to principal investigator. The rest of the trial funding was provided by Australasian Kidney Trials Network (AKTN; University of Queensland, QLD, Australia). The funders had no role in study design, data collection, data analysis, data interpretation, or writing of the report.
Results
From Jan 2018 to Aug 2020, 808 patients enrolled in the study, out of which 404 were randomized to the balanced crystalloid group and 404 to the normal saline group. 1 patient in the saline group withdrew consent before day 7, leaving a total of 807 patients in the primary intention to treat analysis.
Figure 1: Trial Profile from Collins MG et al, Lancet, 2023
The demographic profile of 2 groups was similar and largely representative of the population from Australia and NZ undergoing transplant. Most common cause of kidney failure was GN and only ~20% had diabetic nephropathy. The mean ischemia time was about 10 hours. Basiliximab (IL2R blocker) was the predominant induction agent in approx 90% patients in both groups. Most patients were on triple immunosuppression. Donor profile was 75% being donation after brain death (DBD) and 25% donation after cardiac death (DCD). In addition, 28% were expanded criteria donors and the overall modified Australian KDRI score was 1.24 (1.0-1.61).
Table 1: Baseline characteristics of participants from Collins MG et al, Lancet, 2023
The mean volume of fluid received was higher in the balanced crystalloid arm (8143 ml) as compared to the saline arm (7180 ml [SD 4077]). Non-trial fluids, which mostly constituted open-label saline for medicine administration, were given to 63% in both groups.
Figure S1: Volumes of Trial Fluids and other Non-trial Fluids administered from Collins MG et al, Lancet, 2023
Expectedly, the saline group had higher mean serum sodium and chloride and a lower bicarbonate and pH.
Figure 2: Chloride, bicarbonate, sodium and pH trend post DDKT, from Collins MG et al, Lancet, 2023
Notably, potassium concentration was similar in both groups, as was serum creatinine. At day 2 also, there was no difference between groups when it came to urea, hemoglobin and body weight.
Figure 2: Serum potassium and creatinine trend post DDKT, from Collins MG et al, Lancet, 2023
Plasmalyte arm demonstrated slightly higher urine output during the first 4 hours of transplantation.
Figure 2: Urine output for 4 hours post DDKT, from Collins MG et al, Lancet, 2023
The most common indications of dialysis were fluid overload, uremia and hyperkalemia. DGF, which was primary outcome of the study, was seen among 121 (30%) of 404 patients in the balanced crystalloid and 160 (40%) of 403 patients in the saline group (adjusted RR 0.74, 95% CI 0.66–0.84; p<0.0001), representing an adjusted risk difference of 10.1% (95% CI 3.5–16.6).
Table S6: Multivariable model of DGF, from Collins MG et al, Lancet, 2023
The benefit of Plasmalyte extended to mostly all subgroups, except in DBD where the point estimate of benefit was smaller and the 95% CI do cross 1.00 with a significant interaction (though not adjusted for multiple testing).
Figure 3: Subgroup analysis of DGF, from Collins MG et al, Lancet, 2023
The post hoc analysis displayed lower number of dialysis sessions [IRR 0.75 (0.59 to 0.95)] and duration of dialysis [HR 1.10 (1.03 to 1.16)] in the balanced crystalloid group, though the primary analysis was inconclusive in this respect.
Table 2: Trial Outcomes, from Collins MG et al, Lancet, 2023
Creatinine reduction ratio on day 2, duration of DGF and their composite outcome, all were similar in both groups, as were mortality, graft survival to 52 weeks, graft function (based on eGFR at 12, 26 and 52 weeks) and the duration of initial hospitalization (though these numbers are small and the trial was not powered for these outcomes).
Adverse events were similar in both groups, however ICU admissions requiring ventilation were higher in the saline group (p 0.0015).
Table 3: Adverse events, from Collins MG et al, Lancet, 2023
Discussion
In this RCT, Plasma-Lyte 148 was found to be significantly more effective in preventing DGF than NS among DDKT recipients. This finding remained robust even after adjustment with deceased donor type, KDRI, and ischemia time. Moreover, recipients using Plasmalyte were observed to have lower serum chloride, higher bicarbonate and pH and a better postop urine output (even if we consider only the first 4 hours) than the saline group.
Patients receiving saline experienced more DGF and hence, were treated with additional 190 dialysis sessions compared with the Plasmalyte group. However, among those who did develop DGF, the duration and number of dialysis treatments was similar between the two. Despite a positive impact on DGF, this benefit was not translated to a significant benefit in the secondary outcomes such as hyperkalemia, length of hospital stay, kidney function recovery, long term graft function, graft failure, mortality, possibly from the lower number of these events. Adverse events were infrequent and quite similar in both groups but admissions to ICU requiring ventilatory support were more in the saline arm.
the primary outcome was consistent with previous two observational studies, (Adwaney et al, Clin Kidney Journal 2017, and Kolodzie et al, Anesthesiology 2021) which showed perioperative use of balanced crystalloids had better graft function and reduced DGF. However, these studies were a retrospective cohort and involved both deceased and live related kidney donors. As it is, the rate of DGF is very low (3.6%) in living donor kidney transplants (Redfield RR, Transpl Int. 2016). In contrast, another two RCTs and one meta-analysis (Wan et al, Cochrane Database Syst Rev, 2016, Weinberg et al, BJ of Anaesthesia, 2017 and Jahangir et al, Kidney Res and Clin Pract) had previously reported no difference in the incidence of DGF based on fluid, though more hyperchloremic metabolic acidosis was observed in the NS group.
There is a hypothesis that hyperchloremia can lead to vasoconstriction, reduced kidney perfusion, renal ischemia and reduced urine output (Wilcox et al, J Clin Invest, 1983). Therefore prevention of hyperchloremia could prevent kidney injury. In various studies, it is clear that participants using physiological saline have lower hyperchloremic metabolic acidosis, hyperkalemia and better urine output but inconsistent with prevention of DGF. In this study, Plasma-Lyte 148 was selected among various balanced crystalloids because it is isotonic and it does not contain lactate or calcium, and is easily available in study areas. Therefore the mechanism of significantly reduced DGF in this study might be due to specific use of Plasma-Lyte 148 and avoidance of hyperchloremia. Although there was more acidosis and hyperchloremia in the NS group, acidosis did not represent the main reason for clinicians to require non-trial fluids to administer the non- fluid trials aiming to correct it. Also, only 2 patients in every group required dialysis for acidosis. (table S9 from Collins MG et al, Lancet, 2023).
Table S5: Reasons for Non-trial Fluids use by treatment group from Collins MG et al, Lancet, 2023
DGF is generally associated with increased risk of acute rejection, graft failure, and mortality at 1 year (Li et al, Transplantation Direct, 2023) but in this trial, graft function from week 12 to 52, graft failure rate and mortality were found not different between two study groups likely because it was underpowered to see long term effect.
In the non-transplant population, only SALT-ED and SMART trials have had less major adverse kidney events but other trials (PLUS, BaSICS and SPLIT) have showed no significant benefit of balanced crystalloid over saline. The effects of physiological saline were heterogeneous in the non-transplant population compared to this trial. The possible mechanisms of reducing the potential harm for normal saline in the general population were substantial use of lower volume than transplant population, patients were less likely to have ischemic kidney injury than transplant, and that the fluids were open-label before enrollment in the non-transplant trials - which can affect any benefit from balanced crystalloid.
Strengths
BEST-Fluids trial was an investigator-initiated, double-blind RCT with a robust and high quality study design. Selection bias was minimal because of the registry-embedded design which was used to enroll a representative population. Randomisation was done before transplantation to avoid contamination due to open-label fluid usage. Blinding was well done with fluids appearing identical as shown above. Adherence was good with negligible missing data for primary outcome. Trial results were quite generalizable because BEST fluid trial involved 808 of 2373 (37%) deceased donor kidney transplants which were performed in Australia and New Zealand during the trial period and baseline characteristics were similar between participants and non-participants. Data accuracy and completeness was guaranteed because hospital research staff and audition were involved in data collection and entry.
Limitations
Because it was a pragmatic trial, data collection had some limitations for ICU admissions and a few adverse events which might be trial fluid related. Apart from serum creatinine, the trial did not collect other important parameters which may affect DGF like pretransplant lab tests, BP, residual urine output, anastomosis ischemia times, immunosuppressive drug dosing and their therapeutic level. Machine perfusion of kidneys is an effective strategy to prevent DGF in DDKT but in this trial, its use was infrequent (2%). Looking from a global perspective, there are issues with generalizabillity (for the geographical area characteristics): the BMI is not be representative for Asian and US population, the KDRI used had only tertiles, the third one including percentile 67-100%, and also induction treatment used in almost 90% cases was basiliximab and not a T-cell depleting agents (even if more than 30% of included population had 5-6 HLA mismatch).
Few questions remain unanswered. First, even with a good representative population for Australia and New Zealand, is this replicable in an even diverse population, with a higher BMI or with a higher immunologic risk? Secondly, would the DGF lowering effect still persist in living donor recipients, where DFG is quite low already, at about 3.6%? (Redfield RR, et al, Transpl Int. 2016). Thirdly, will these results be relevant at places where DBD is the predominant source of deceased donor kidneys?
Conclusion
DGF has emerged as an escalating quandary in kidney transplant, owning to the acceptance of marginal key donor. Although short term benefits might not lead to significant long term gains, tenacious nephrologists cling to hope for better outcomes on the horizon. Nevertheless, pragmatism sneaks in, and amidst the lingering doubts on worldwide generalizability, the allure of a positive result remains almost irresistible. Not mentioning the delightful perk of saving costs- Plasma-Lyte prancing at a regal 4.5$ per liter, while humble NS stands at a mere 2$. But keep in mind the costs of dialysis while weighing the balance of cost-benefit for Plasma-Lyte 148 use (Kwong YD, Am J Kidney disease, 2018).
Summary by Saumya Vishnoi
Clinical Associate
Institute of Renal Sciences, Global Hospital
Mumbai, India
And
Nyi Min Han
Consultant Nephrologist
No (2) DSGH, Nay Pyi Taw, Myanmar
NSMC interns, class of 2023 #TeamTRIPOD