Phase-specific intraoperative glycemic control in simultaneous pancreas-kidney transplantation

Abstract

In this review summarizes studies addressing a critical and long-overlooked vulnerability in simultaneous pancreas-kidney transplantation (SPKT): Perioperative metabolic instability during the transition from graft ischemia to endocrine recovery after reperfusion. Despite the central role of glycemia in pancreatic graft viability, intraoperative glucose management has remained largely empirical, reactive, and inconsistently standardized across transplant centres. The authors propose a structured, six-phase intraoperative glycemic control framework that aligns glucose targets with discrete operative stages, advancing a physiology-informed alternative to static, threshold-based insulin administration. In their single-centre experience, phase-adapted targets were associated with early insulin-independent euglycemia and the absence of severe hypoglycemia, ketoacidosis, early graft loss, or perioperative mortality. Notably, greater intraoperative glycemic variability clustered among recipients who developed early thrombotic and infectious complications, implicating glucose instability as a potential amplifier of endothelial injury and immunothrombotic risk at a moment of maximal graft vulnerability. Although limited by small sample size, lack of a control cohort, and short follow-up, this work demonstrates that intraoperative metabolic control in SPKT can be conceptualized and implemented using phase-specific objectives rather than uniform glycemic thresholds, laying the groundwork for future prospective validation incorporating time-in-range and variability metrics.

Key Words: Simultaneous pancreas-kidney transplantation; Intraoperative glycemic control; Glycemic variability; Immunothrombosis; Ischemia-reperfusion injury; Metabolic stewardship

Core Tip: Simultaneous pancreas-kidney transplantation (SPKT) represents a uniquely vulnerable metabolic state in which abrupt endocrine recovery occurs under conditions of ischemia-reperfusion injury and intense perioperative stress. In this review, we highlight the importance of treating intraoperative glycemia as a dynamic biological signal rather than a static safety parameter. A phase-specific approach to intraoperative glycemic control reframes anesthetic management as metabolic stewardship, emphasizing anticipation of predictable physiologic transitions, minimization of glycemic variability, and protection of the pancreatic microcirculation at reperfusion. Aligning glucose management with graft biology may reduce early immunothrombotic and infectious risk and represents an important, pragmatically implementable advance in SPKT care.

INTRODUCTION

Simultaneous pancreas-kidney transplantation (SPKT) represents one of the most profound physiologic interventions in modern transplantation medicine[1,2]. Unlike isolated kidney transplantation, which restores excretory function without fundamentally altering systemic metabolic regulation, SPKT initiates an abrupt endocrine and metabolic reconstitution[1,2]. Within hours of graft reperfusion, recipients transition from long-standing insulin dependence, advanced uremia, and maladaptive counter-regulation to endogenous insulin secretion, improving insulin sensitivity, and evolving renal clearance[3,4]. This transformation unfolds intraoperatively under conditions of inflammatory stress, ischemia-reperfusion injury, corticosteroid exposure, and dynamic hemodynamic shifts[5,6]. Few clinical interventions combine such dramatic metabolic reversal with such biological vulnerability[1,5].

Despite this unique physiology, intraoperative glycemic management in SPKT has remained poorly conceptualized and inconsistently standardized. In most centers, glucose control during pancreas transplantation is extrapolated from general perioperative diabetes or critical-care paradigms, where the dominant objective is avoidance of extreme hyperglycemia or hypoglycemia[7-15]. These paradigms implicitly assume metabolic continuity and physiologic stability, assumptions that are poorly suited to pancreas transplantation[1,3,4,16]. In SPKT, glycemia is not merely a monitored variable; it is a biologically active signal that may influence oxidative stress, endothelial function, inflammatory activation, and early graft adaptation[5,17-25].

It is during surgery that the pancreatic graft transitions from ischemia to reperfusion, β-cells encounter systemic glucose after implantation, and endogenous insulin secretion resumes in a highly unregulated manner[3,4]. In this context, the term “early” refers to the intraoperative and immediate reperfusion phase, rather than preoperative preparation or later postoperative recovery[4,9]. Hyperglycemia during this phase may amplify ischemia-reperfusion injury through oxidative and endothelial mechanisms[5,22-27]. Conversely, hypoglycemia may be clinically occult because counter-regulatory recovery is incomplete during the earliest post-reperfusion period[3,4,28-34]. Beyond absolute glucose values, rapid glycemic excursions may further destabilize the pancreatic microcirculation and contribute to early immunothrombotic risk[17,35-40].

In this issue, Montes et al[9] describe a single-center case series proposing a structured, six-phase intraoperative glycemic control framework for SPKT, explicitly aligning glucose targets with operative phases from induction through post-reperfusion endocrine recovery. By doing so, the authors move intraoperative glycemic management beyond reactive correction toward anticipatory, biology-aligned metabolic control[26].

The importance of this approach becomes evident when one considers the dynamics of endocrine recovery after pancreas transplantation. Restoration of β-cell mass does not equate to immediate restoration of coordinated glucose homeostasis[3,4,41]. Early after reperfusion, insulin secretion may be exaggerated, whereas counter-regulatory mechanisms remain blunted[3,4]. Treating glycemia as static across this transition ignores fundamental physiology and risks aggravating metabolic instability at precisely the moment when the graft is most vulnerable[3-5].

The six-phase framework addresses this vulnerability by explicitly anticipating metabolic transitions rather than reacting to them[26]. Before reperfusion, the emphasis is on avoiding hypoglycemia and abrupt insulin withdrawal in a stress-dominated state[7,12,14-16]. Around reperfusion, the strategy anticipates endogenous insulin release and seeks to prevent sudden glucose decline[3,4,26]. After reperfusion, tighter glycemic control becomes more appropriate as endocrine function stabilizes[26,42]. The objective is not rigid normoglycemia, but metabolic stability-minimizing abrupt excursions that may amplify endothelial injury and immune activation[22-26,29,43,44]. Stage-specific control therefore does not imply permissive hyperglycemia or abandonment of normoglycemia, but contextual prioritization of stability and hypoglycemia avoidance during phases of endocrine instability[7-15,26].

This conceptual shift is particularly timely, as contemporary SPKT increasingly involves marginal donors, prolonged ischemia times, and persistent vulnerability to early graft thrombosis-contexts in which metabolic instability may exert disproportionate harm[35-40,43,45-49].

PHASE-SPECIFIC INTRAOPERATIVE GLYCEMIC CONTROL

The principal advance offered by a phase-specific approach to intraoperative glycemic control lies not in the numerical glucose targets themselves, but in the conceptual repositioning of glycemia as a time-dependent biological signal rather than a static safety parameter. Conventional intraoperative glucose management has historically been reactive: Glucose is sampled intermittently, interpreted against generic thresholds, and corrected once deviations occur[7-15]. Implicit in this model is the assumption that a given glucose concentration carries the same biological meaning at all points during surgery. In SPKT, that assumption is biologically untenable[1,3,4].

SPKT is characterized by rapidly shifting metabolic states that alter how glucose should be interpreted and managed. During induction and early dissection, stress hormone surges dominate glucose homeostasis, favoring hyperglycemia driven largely by counter-regulatory physiology rather than graft function[7,12,14,16]. As the operation progresses toward vascular clamping, endothelial activation, inflammatory priming, and hemodynamic manipulation increasingly influence perfusion and substrate delivery[5,6,27,28]. The ischemic interval introduces a state of enforced metabolic quiescence, during which abrupt reductions in circulating glucose may deprive vulnerable tissues of critical substrate[5,27,28]. Reperfusion then represents an inflection point: Restoration of oxygen and glucose coincides with insulin release from a graft that has not yet re-established physiologic counter-regulation[3,4]. Finally, the post-reperfusion phase marks the beginning of endocrine adaptation, during which β-cell responsiveness, insulin clearance, and renal glucose handling remain in flux[3,4].

A phase-specific framework acknowledges these transitions explicitly[26]. Rather than pursuing a single “ideal” glucose value, it assigns distinct metabolic priorities to each operative phase, accepting that relative permissiveness may be safer in one context, whereas tighter control may be more appropriate in another[7-15,26]. This temporal alignment of metabolic intent with graft biology represents a decisive departure from traditional perioperative paradigms[26].

What this framework truly adds, therefore, is anticipation. Glycemic management is no longer only an after-the-fact correction of deviations, but a forward-looking strategy that prepares for predictable physiologic events[26]. Nowhere is this more relevant than at reperfusion. Treating reperfusion with the same insulin strategy used during induction ignores the potential for early insulin hypersecretion and risks precipitating clinically silent hypoglycemia at a moment of maximal endothelial vulnerability[3-5,26]. By modulating insulin and dextrose exposure before reperfusion, the framework seeks to smooth metabolic transitions rather than merely react to their consequences[26,42].

Equally important is the framework’s reinterpretation of early postoperative insulin use. In many settings, insulin independence within hours of transplantation is implicitly regarded as a marker of graft success. A phase-specific perspective challenges that notion[26]. Early insulin supplementation may instead represent a deliberate strategy to reduce β-cell workload during a period of ischemia-reperfusion-induced oxidative stress and inflammatory signaling, thereby supporting endocrine recovery[4,5,22,41]. By decoupling immediate insulin independence from simplistic success metrics, this framework prioritizes physiologic stability over symbolic milestones[26].

Crucially, this approach is conceptual rather than prescriptive. It does not establish universal superiority of specific glucose targets, nor does it invalidate all existing practices. Its value lies in demonstrating that intraoperative glycemia can be managed coherently, with explicit attention to timing, biology, and transition[26]. In doing so, it elevates metabolic control to the same level of deliberation traditionally afforded to hemodynamics, anticoagulation, and ischemia time-domains already recognized as major determinants of graft survival[6,35-40,48,49].

GLYCEMIC VARIABILITY, IMMUNOTHROMBOSIS, AND EARLY PANCREAS GRAFT RISK

Beyond absolute glucose values, glycemic variability (GV) has emerged as a biologically important driver of early graft injury[29-34]. Mean glucose provides a convenient summary of metabolic exposure, but it obscures the amplitude and frequency of excursions that may exert disproportionate harm[29-34].

Clinical transplant literature increasingly supports the relevance of GV-derived metrics, with continuous glucose monitoring (CGM)-based analyses and contemporary syntheses in kidney transplant recipients linking greater glycemic instability with adverse allograft-related outcomes, although confounding and heterogeneity remain important limitations[29,43,44,50,51]. In SPKT recipients with functioning grafts, CGM studies demonstrate that durable success tracks more closely with high time-in-range and low GV than with mean glucose alone[29,45,51]. This reinforces the concept that variability is a clinically meaningful exposure rather than a cosmetic statistic[29-34].

In pancreas transplantation, where microvascular integrity is central to graft viability, such excursions assume particular importance[43,35-40]. The principal biological pathways linking intraoperative GV to early pancreas graft complications are summarized in Table 1.

Table 1 Biological pathways linking intraoperative glycemic variability to early pancreas graft complications[5,22-25,27-40].

Domain	Pathophysiologic effect	Clinical consequence
Endothelium	Oxidative stress, nitric oxide disruption	Microvascular injury
Coagulation	Platelet activation, procoagulant signaling	Graft thrombosis
Innate immunity	Impaired neutrophil function	Infection
β-cell adaptation	Insulin hypersecretion followed by instability	Hypoglycemia

Rapid fluctuations in glucose amplify oxidative stress, impair nitric oxide signaling, and promote endothelial dysfunction[22-25]. These effects are especially concerning during ischemia-reperfusion, when reactive oxygen species generation is already heightened and endothelial defenses are compromised[5,27,28]. At the same time, glucose variability enhances platelet activation and coagulation cascade signaling, fostering a prothrombotic milieu. These processes converge on immunothrombosis, a biologic construct describing thrombosis driven by inflammatory and immune mechanisms rather than mechanical factors alone[22-25,35-40]. At a mechanistic level, acute glycemic fluctuations promote immunothrombosis through oxidative stress-mediated endothelial injury characterized by excess reactive oxygen species generation and nitric oxide depletion, while simultaneously enhancing platelet activation via dysregulation of intracellular cyclic adenosine monophosphate-dependent signaling pathways[5,22-25,27-28,35-40].

Infectious risk follows a parallel pathway. Acute hyperglycemic spikes impair neutrophil chemotaxis, phagocytosis, and intracellular killing, while fluctuating glucose levels exacerbate stress hormone release and cytokine dysregulation. When such instability occurs intraoperatively, it may “prime” immune dysfunction that manifests clinically days later, even if postoperative glucose values appear acceptable[12,13,52].

A particularly important observation is the disconnect between intraoperative instability and early postoperative appearance. Insulin-independent euglycemia in the immediate postoperative period may coexist with extreme GV during surgery. Such apparent metabolic success can obscure the biologic stress imposed at reperfusion, highlighting the inadequacy of postoperative snapshots as proxies for intraoperative metabolic health[17,26,29,50].

The implication is not that GV alone determines outcome, but that it may function as a modifiable amplifier of risk[29-34,43]. A phase-specific framework inherently targets variability by minimizing abrupt transitions, even without formal computation of variability indices[26]. This provides a biologically plausible rationale for integrating stability-not merely target attainment-into intraoperative glycemic strategy[26,29-34].

POSITIONING THIS FRAMEWORK WITHIN GLOBAL SPKT AND PERIOPERATIVE LITERATURE

Progress in SPKT outcomes has traditionally been driven by refinements in surgical technique, donor selection, immunosuppression, and thromboprophylaxis[35-48]. Metabolic management, although universally acknowledged as important, has evolved more slowly and often in relative isolation from graft-specific biology[1,46,47]. Most perioperative glycemic protocols are extrapolated from non-transplant surgery, intensive care, or isolated organ transplantation, contexts in which endocrine dynamics differ fundamentally from those encountered in pancreas implantation[7-15].

In kidney transplantation, long-term metabolic control is associated with improved graft and patient survival, yet intraoperative glucose management remains relatively nonspecific[53]. In liver transplantation, perioperative glycemic control reduces infectious complications, but endocrine recovery is not a primary determinant of outcome[52]. Pancreas transplantation, by contrast, uniquely combines microvascular fragility with immediate endocrine activity, rendering direct extrapolation from other transplant models inadequate[1,2,35-40].

Continuous glucose monitoring studies in stable SPKT recipients have demonstrated that durable graft success is characterized by high time-in-range and low variability rather than simply normal mean glucose[29,43-45,50,51]. Related insights also arise from islet transplantation and from the broader CGM/GV literature[53-55]. However, these observations begin well after surgery, leaving the intraoperative period, arguably the most vulnerable phase of graft life, largely unexamined[19,20,55]. Emerging closed-loop insulin delivery systems show promise in major surgery, but sensor lag, calibration challenges, and limited validation during rapid physiologic transitions currently restrict their applicability in SPKT[19,20,53-55].

Interpretation of the findings by Montes et al[9] must be tempered by important methodological constraints. The single-center design and small sample size limit external validity and increase susceptibility to center-specific practices and unmeasured confounding. Absence of a control cohort precludes causal inference, as observed associations between intraoperative GV and early complications may reflect illness severity, operative complexity, or co-interventions rather than the phase-specific strategy itself. Accordingly, these data should be viewed as hypothesis-generating and require prospective, comparator-based validation[26].

Within this landscape, a phase-specific intraoperative framework occupies a distinct and previously underdeveloped niche. It does not compete with postoperative metabolic strategies, nor does it replace emerging technologies. Instead, it addresses a temporal blind spot, offering a biologically coherent approach to the earliest hours of graft adaptation[7-15,19,20,26]. Its pragmatic nature enhances generalizability across diverse healthcare settings, including centers without access to advanced glucose monitoring infrastructure[19,20,55]. Key differences between perioperative glycemic management paradigms across transplant settings are outlined in Table 2.

Table 2 Comparison of perioperative glycemic management paradigms across transplant settings[7-16,42,43,45,50-52].

Setting	Primary focus	Timing emphasized	Limitation for SPKT
General surgery	Threshold avoidance	Intra-/postoperative	Ignores endocrine recovery
ICU protocols	Tight control	Postoperative	Assumes metabolic stability
Kidney transplantation	Long-term control	Postoperative	Limited intraoperative detail
Liver transplantation	Infection reduction	Peri-/postoperative	Endocrine effects indirect
Phase-specific SPKT approach	Metabolic stability	Intraoperative	Requires validation

ICU: Intensive care unit; SPKT: Simultaneous pancreas-kidney transplantation.

CLINICAL IMPLICATIONS: ANESTHESIOLOGY AS METABOLIC STEWARDSHIP

A phase-specific approach reframes the role of anesthesiology in SPKT from perioperative support to metabolic stewardship. In this model, anesthesiologists actively shape the biochemical environment in which the graft adapts, much as they already do for hemodynamics, temperature, and coagulation. Glycemic control becomes a core component of graft protection rather than an ancillary task[6,26].

Importantly, this approach does not increase anesthetic workload or mandate novel technology; rather, it restructures existing insulin and dextrose decisions around predictable physiologic transitions. Anticipating endogenous insulin release, modulating dextrose exposure, and avoiding abrupt insulin withdrawal demand close coordination among anesthesiologists, surgeons, and transplant physicians. Importantly, this approach fosters shared ownership of metabolic outcomes, integrating glycemia into multidisciplinary decision-making rather than relegating it to postoperative care alone[6,19,20,26].

Establishing robust real-time communication within the intraoperative multidisciplinary team, through structured briefings around key operative transitions and shared situational awareness rather than rigid protocols, may further enhance the operability and reproducibility of phase-specific metabolic stewardship across transplant centers.

FUTURE DIRECTIONS

The next phase of progress should focus on prospective validation. Multicenter studies incorporating time-in-range, GV metrics, and phase-resolved glucose dynamics are needed to determine whether intraoperative metabolic stability translates into improved graft-related outcomes[29,45,50,51,43,44]. Integration of CGM into SPKT research may enhance real-time metabolic assessment, although intraoperative use still requires confirmation against conventional sampling because of accuracy and lag limitations[19,20,55].

Equally important is the development of SPKT-specific perioperative glycemic guidance that recognizes temporal vulnerability rather than relying on static thresholds extrapolated from general perioperative diabetes care[7-15]. Such guidance should emphasize anticipation, stability, and multidisciplinary coordination over rigid numeric targets[26]. It should also be integrated with established evidence on graft thrombosis risk, donor quality, and ischemia-reperfusion vulnerability, because these factors materially shape the consequences of metabolic instability during the peri-reperfusion period[35-48].

In parallel, future research should extend beyond immediate perioperative endpoints to examine whether intraoperative metabolic strategies influence the long-term survival and cardiometabolic benefits that define successful SPKT. Emerging data indicate that SPKT outcomes are increasingly being evaluated across broader recipient phenotypes, including selected patients with type 2 diabetes, necessitating refinement of perioperative metabolic frameworks across heterogeneous populations[56]. Importantly, sustained pancreas graft function has been consistently associated with improved long-term survival after transplantation[57]. Comparative analyses further suggest that the benefit of SPKT should be interpreted not only in terms of perioperative risk but also in relation to durable metabolic and survival advantages over kidney transplantation alone[58]. These benefits extend to cardiovascular outcomes, with evidence demonstrating improvement in cardiovascular risk profiles following successful SPKT, reinforcing the central role of early graft preservation strategies in determining long-term patient trajectories[59,60].

CONCLUSION

A phase-specific approach to intraoperative glycemic control represents a meaningful conceptual advance in SPKT care. By aligning metabolic management with graft biology, it challenges long-standing assumptions and elevates intraoperative glycemia from a background parameter to a modifiable determinant of early graft health. While definitive outcome data are awaited, this framework offers a biologically grounded, pragmatically implementable strategy that merits serious consideration. In pancreas transplantation, where the margin between success and failure is narrow, metabolic stewardship during surgery may prove as consequential as any technical refinement.