The perioperative care of a patient undergoing kidney transplantation is organized around one relatively straightforward conceptual goal: protect the kidney. Although fluid therapy remains the first therapeutic approach to maintaining or restoring circulatory function in every patient undergoing kidney transplantation, a coherent evidence–based perioperative strategy for fluid management in this setting has been elusive with a dearth of—and a desperate need for—large-scale, well-designed fluid interventional and hemodynamic trials. Examining the acute effects of intraoperative fluid management on outcomes after kidney transplantation is challenging because fluid therapy and hemodynamics are inseparably linked and are critical to renal circulation.
The consensus statement of the Committee on Transplant Anesthesia of the American Society of Anesthesiologists (ASA) guidelines1 published in Transplantation underscores the importance of perioperative fluid intervention—with respect to achieving favorable patient outcomes—in the context of kidney transplantation. Such recommendations are commendable and serve as a tool to overtly inquire, through a microscopic lens, into the traditionally clandestine aspects of fluid therapy for transplant recipients. Although such recommendations may deeply challenge our habits, attitudes, and beliefs about perioperative fluid therapy for the transplant recipient, they also contribute to our overall pursuit of the Holy Grail in this setting—appropriate fluid management. Is it too simplistic a view to consider, on their own as independent predictors of outcome, both “volume” and “type” of fluid administered and the use of goal-directed therapy to monitor volume status? Or should we pursue and consider, as a comprehensive fluid management strategy, a broader understanding of the combined effects of interrelated factors?
While we eagerly await larger trials in the transplant setting to control each of the above elements concurrently, the ASA consensus statement should not be seen as a pivotal and authoritative position statement for fluid intervention. Rather, it should be viewed as shaping and fostering a collaborative approach that bestows upon the fluid landscape in kidney transplantation a prerogative to interject, question, consider, and—maybe at times—even assert. In doing so, the guidelines extend into kidney transplant medicine, generally, and the often-blurred fluid management boundaries between nephrologist, anesthesiologist, physician, intensivist, and transplant surgeon. We should welcome these recommendations as a soundtrack to important conversations. Whether we choose to yell, sing, or chant about these guidelines, they voice to the kidney transplant community that collaborative, interdisciplinary, well-funded, multicenter, and well-designed randomized controlled trials are urgently needed for this patient population.
What does the consensus statement by Wagener et al1 state? How should we translate the current body of evidence for our practice? Based on the Grading of Recommendations, Assessment, Development, and Evaluations system to assess evidence,2 the Committee on Transplant Anesthesia of the ASA makes the following 4 strong recommendations for fluid management in kidney transplantation:
- Do not routinely use albumin over crystalloids.
- Avoid the use of starch.
- Do not use central venous pressure (CVP) as an endpoint for fluid administration.
- Balanced crystalloid solutions are at least equal, if not better, than 0.9% saline.
Finally, the ASA committee makes 1 weak recommendation against the use of large volume fluid administration or “high CVP.” The committee recommends that similar principles to the approach to fluid management be followed for both deceased-donor and living-donor kidney transplantation.
Although these recommendations are a maritime map that chart important islands in the otherwise amorphous and disorienting sea, we must be clear that recommendations are not evidence. The strength of each recommendation in favor of or against an intervention reflects the extent to which the ASA committee is confident that the desirable effects of an intervention outweigh its undesirable effects, or vice versa, respectively, across the range of kidney transplant patients for whom the recommendation is intended.3 A strong recommendation is not necessarily a high-priority recommendation, nor should it be confused with strong evidence. Likewise, some may interpret the term “weak recommendation” as the kidney transplant patient experiencing an unintended negative effect or may confuse it with weak evidence; however, these terms are often conditional, and practices should always be contextualized before being applied. For example, the ASA committee strongly cautions against the use of starch (grade 4 strength of recommendation). However, in a transplant patient with critical and ongoing bleeding that is refractory to crystalloid resuscitation, the use of a starch (if albumin was not available) as part of the resuscitation armamentarium may be justified; moreover, it may be beneficial for that individual patient.
The notion of “large volume fluid administration” or “high CVP” being “not recommended” should be interpreted cautiously. Acknowledging the limitations of extrapolating results of trials of patients undergoing “nontransplant surgery” to those undergoing “kidney transplantation,” the Restrictive versus Liberal Fluid Therapy for Major Abdominal Surgery trial4 investigated the outcomes of 3000 high-risk patients undergoing major abdominal surgery and randomized patients to either a restrictive or liberal volume of fluid. Importantly, patients recruited into Restrictive versus Liberal Fluid Therapy for Major Abdominal Surgery trial had similar characteristics to many patients undergoing kidney transplantation. The study reported an increase in perioperative complications in patients who received a more restrictive volume of intravenous fluid (median 3.7 L during and within 24 h of surgery, according to a weight-based protocol) compared with the liberal volume group (median 6.1 L within 24 h of surgical start). Moreover, a significant increase in the risk of acute kidney injury and surgical site infection was observed in the restrictive administration group. Translating these findings to kidney transplant patients is not perverse given the similarities of the patients enrolled in the study; nonetheless, this underlines the urgency and importance of undertaking high-quality, large, randomized, multicenter clinical trials in kidney transplantation to confirm or refute the findings of smaller studies.
The strong recommendation to avoid the use of hydroxyethyl starch in kidney transplant recipients, given the levels of evidence demonstrating nephrotoxicity in critical illness,5,6 is biologically and physiologically plausible. This recommendation is welcomed and further supported by robust evidence evaluating the effect of hydroxyethyl starch on postoperative kidney function in 44 176 patients undergoing noncardiac surgery.7 After controlling for confounding variables, the odds of developing a more serious level of acute kidney injury with starch was 21% (95% confidence interval, 6%-38%) greater than with crystalloid only.
Similarly, we welcome the strong recommendation that static indexes such as CVP consistently fail to predict fluid responsiveness. A growing body of inquiry into goal-directed therapy incorporating dynamic assessment of fluid responsiveness is still emerging in the spheres of major surgery. Although these methods appear to accurately predict fluid responsiveness, the clinical impact of dynamic fluid responsiveness remains unclear in the domain of kidney transplantation. However, advanced hemodynamic monitoring, with avoidance of intraoperative hypotension, allows integration of most of the information needed for rational decision making about the timing and volume of fluid administration.
Although we agree with the statement that “balanced crystalloid solutions are associated with a better metabolic profile compared with 0.9% saline” in the context of kidney transplantation, all clinical trials to date in kidney transplantation comparing balanced solutions with 0.9% saline have been insufficiently powered and of insufficient quality to detect differences in clinically important transplant outcomes such as delayed graft function or other adverse events.8 However, evidence from the large SOLAR Fluid trial in 8717 patients undergoing nontransplant (elective orthopedic and colorectal) abdominal surgery who received either unblinded 0.9% saline or lactated Ringer’s solution)9 showed that there was no clinically meaningful difference in the risk of a composite of in-hospital mortality and major postoperative complications including acute kidney injury. Thus, from an adverse events perspective, data from large studies in surgical patients currently support the use of either solution intraoperatively by clinicians.
To definitively address the question of which fluid type to use, the Better Evidence for Selecting Transplant Fluids trial is a large multicenter, double-blind randomized controlled trial10 that will compare the effect of a balanced, low-chloride solution (Plasma-Lyte 148) versus 0.9% saline on the incidence of delayed graft function in deceased-donor kidney transplant recipients. Results from this study are expected in 2022 and will provide high-quality evidence to inform clinical decision making regarding the choice of crystalloid fluid in kidney transplant recipients. It is clear that there is still a significant need for high-quality trials to definitively address other questions regarding the perioperative fluid management of these patients, and we strongly advocate for these to be performed.
In summary, the consensus statement on fluid management during kidney transplantation from the Committee on Transplant Anesthesia of the ASA provides some guidance in the midst of uncertainty. The guidelines highlight not only the importance of fluid management in kidney transplantation but also the significant knowledge gaps in this setting, in particular the lack of high-quality clinical trials. The guidelines are a step closer to sailing calm on a stormy sea; in many situations, common sense is the guiding principle—after all, every patient has their own optimum fluid balance! Instead of “goal-directed therapy” or “protocolized fluid pathways,” we need to work together as a transplant community and further elucidate strategies for “individualized perioperative fluid and hemodynamic management” specific to kidney transplantation. Finally, as the possibility grows that we can monitor physiological parameters with direct relevance for kidney outcomes and the various complications associated with kidney transplantation, we may finally move away from static therapy recommendations and toward individualized, precision therapy. Wherever possible, eligible kidney transplant patients should be enrolled into appropriately powered, prospective clinical outcome trials designed to resolve some of these important questions.
1. Wagener G, Benzinover D, Wang C, et al. Fluid management during kidney transplantation: a consensus statement of the Committee on Transplant Anesthesia of the American Society of Anesthesiologists (ASA). Transplantation. [Epub ahead of print. December 14, 2020]. doi:10.1097/TP.0000000000003581
2. Guyatt GH, Oxman AD, Kunz R, et al.; GRADE Working Group. Going from evidence to recommendations. BMJ. 2008;336:1049–1051.
3. GRADE Handbook. Handbook for Grading the Quality of Evidence and the Strength of Recommendations Using the GRADE Approach. Schünemann H, Brożek J, Guyatt G, et al, eds. Available at https://gdt.gradepro.org/app/handbook/handbook.html#h.33qgws879zw
. Accessed October 11, 2020.
4. Myles PS, Bellomo R, Corcoran T, et al.; Australian and New Zealand College of Anaesthetists Clinical Trials Network and the Australian and New Zealand Intensive Care Society Clinical Trials Group. Restrictive versus liberal fluid therapy for major abdominal surgery. N Engl J Med. 2018;378:2263–2274.
5. Myburgh JA, Finfer S, Bellomo R, et al.; CHEST Investigators; Australian and New Zealand Intensive Care Society Clinical Trials Group. Hydroxyethyl starch or saline for fluid resuscitation in intensive care. N Engl J Med. 2012;367:1901–1911.
6. Perner A, Haase N, Guttormsen AB, et al.; 6S Trial Group; Scandinavian Critical Care Trials Group. Hydroxyethyl starch 130/0.42 versus Ringer’s acetate in severe sepsis. N Engl J Med. 2012;367:124–134.
7. Kashy BK, Podolyak A, Makarova N, et al. Effect of hydroxyethyl starch on postoperative kidney function in patients having noncardiac surgery. Anesthesiology. 2014;121:730–739.
8. Wan S, Roberts MA, Mount P. Normal saline versus lower-chloride solutions for 971 kidney transplantation. Cochrane Database Syst Rev. 2016;8:CD010741
9. Maheshwari K, Turan A, Makarova N, et al. Saline versus lactated Ringer’s solution: the Saline or Lactated Ringer’s (SOLAR) Trial. Anesthesiology. 2020;132:614–624.
10. Collins MG, Fahim MA, Pascoe EM, et al.; BEST-Fluids Investigators and the Australasian Kidney Trials Network. Study Protocol for Better Evidence for Selecting Transplant Fluids (BEST-Fluids): a pragmatic, registry-based, multi-center, double-blind, randomized controlled trial evaluating the effect of intravenous fluid therapy with Plasma-Lyte 148 versus 0.9% saline on delayed graft function in deceased donor kidney transplantation. Trials. 2020;21:428.