The Impact of Intraoperative Diuretic Use on Delayed Graft Function Following Deceased Donor Renal Transplantation

Overview

Delayed graft function, defined as the need for dialysis within seven days of kidney transplantation, is a common complication affecting deceased-donor kidney transplant recipients. It is associated with prolonged hospitalization, increased healthcare costs, higher rates of acute rejection, and poorer long-term graft survival. Intraoperative diuretics are routinely administered during kidney transplant surgery to promote early urine output and protect the kidney from injury during reperfusion. The two most commonly used agents are furosemide and mannitol. Despite decades of clinical use, no prospective randomized trial has directly compared these two medications, and practice remains highly variable across centres and individual surgeons. This single-centre, prospective, randomized, surgeon-blinded pilot trial will enroll 240 deceased-donor kidney transplant recipients at London Health Sciences Centre. Participants will be randomized in a 1:1 ratio, stratified by donor type, to receive either intraoperative furosemide or intraoperative mannitol. The primary feasibility outcomes include recruitment rate. The primary clinical outcome is the incidence of delayed graft function. Secondary outcomes include serum creatinine trajectory, urine output, dialysis requirements, perioperative complications, length of stay, and one-year graft and patient survival. This pilot trial will provide feasibility data and effect-size estimates necessary to inform the design of a future definitive multicentre randomized controlled trial.

Kidney transplantation has been the treatment of choice for end-stage renal disease for over six decades, yet delayed graft function (DGF) remains one of the most common and clinically significant complications of deceased-donor kidney transplantation. Defined as the requirement for at least one session of dialysis within the first seven days following transplantation, DGF affects 20-40% of deceased-donor kidney transplant recipients depending on the donor population and centre. DGF is associated with prolonged hospitalization, increased healthcare costs, a 1.4- to 2-fold increase in acute rejection risk, and inferior long-term graft survival. The pathophysiology centres on ischemia-reperfusion injury (IRI), which causes acute tubular necrosis, endothelial dysfunction, microvascular thrombosis, and upregulation of allograft immunogenicity through increased expression of MHC molecules and damage-associated molecular patterns. Donor type significantly influences DGF risk: donation after circulatory death (DCD) organs carry the highest historic rates due to sustained hypoperfusion and anaerobic metabolism during the agonal phase, while donation after neurological death (NDD) organs are affected by systemic inflammatory responses driven by loss of sympathetic regulation. Intraoperative diuretics, furosemide and mannitol, have been used for decades during reperfusion to enhance early urine output and mitigate IRI. Furosemide, a loop diuretic, inhibits the NKCC2 co-transporter in the thick ascending limb, reducing tubular metabolic oxygen demand, promoting tubular flushing, and stimulating renal prostaglandin-mediated vasodilation. Mannitol, an osmotic diuretic, maintains high tubular flow rates, reduces tubular cell swelling, acts as a hydroxyl radical scavenger, and promotes intrarenal vasodilation through prostaglandin and natriuretic peptide release. Despite these plausible mechanisms, the evidence supporting either agent remains weak. A comprehensive review by Sandal et al. (2018) found that the evidence supporting loop diuretics in preventing DGF was poor, with no data on patient survival identified. Schnuelle and van der Woude similarly concluded that loop diuretics had not been shown to affect DGF rates or improve outcomes. For mannitol, while van Valenberg et al. described its intraoperative use as "indispensable" based on early trial data, and a systematic review by van de Laar et al. (2021) suggested lower rates of DGF with mannitol use, that review emphasized significant limitations in evidence quality and heterogeneity. A randomized trial by Reiterer et al. evaluating mannitol versus placebo in 34 deceased-donor recipients found no significant effect on oxidation-reduction potential. A preclinical study by Bipat et al. demonstrated that mannitol preserved diuresis and creatinine clearance in a rabbit model of hypoxic kidneys, providing mechanistic support but not clinical confirmation. Current clinical practice is highly heterogeneous. A UK survey of 40 transplant surgeons from 18 centres revealed that 13 used no intraoperative diuretics, 10 used mannitol alone, 6 used furosemide alone, and 11 used a combination, underscoring the complete lack of consensus. A Canadian survey similarly demonstrated wide variation in practice patterns across transplant centres. Retrospective data from the investigators' centre suggest DGF rates of approximately 30% with furosemide and 22% with mannitol, but these non-randomized data preclude definitive conclusions. The existing literature is limited by small sample sizes, retrospective designs, inconsistent dosing protocols, heterogeneous patient populations, and the absence of standardized outcome definitions. No adequately powered, prospective, randomized trial has compared furosemide head-to-head against mannitol. Multiple reviews have concluded that well designed prospective randomized data are needed. This pilot trial addresses that evidence gap by providing the first direct, randomized, blinded comparison of these two agents with standardized dosing and timing, generating feasibility data, effect-size estimates, and operational infrastructure to support a future definitive multicentre trial.