Delayed graft function (DGF), typically defined as the need for dialysis during the first week after kidney transplantation, has long been considered a harbinger of poor transplant outcomes. Numerous studies have linked DGF to inferior long-term graft survival, worse renal function, and a higher incidence of acute rejection.1 Slow graft function (SGF), characterized by delayed creatinine reduction without dialysis, has also been associated with impaired graft performance and lower estimated glomerular filtration rate at 1 y, although its prognostic significance appears more variable across donor types.1,2 The relationship between DGF/SGF and rejection is dose-dependent: longer DGF duration increases the risk of acute rejection and subsequent graft loss, but acute rejection mediates only a minority of the impact of DGF on long-term transplant outcomes, suggesting other pathways contribute to this process.3 Together, these observations have established early graft function as an appealing clinical signal of future graft health. The biological plausibility supporting this association is compelling. Both DGF and SGF largely reflect ischemia/reperfusion injury, a process that initiates a cascade of inflammatory and maladaptive repair pathways. Complement activation, endothelial injury, tubular stress responses, epigenetic modifications, Klotho downregulation, and transforming growth factor-β–driven fibrogenesis have all been implicated in the progression from early injury to chronic graft dysfunction.4,5 At the same time, innate immune activation triggered by necrotic and inflammatory signals enhances alloimmune recognition and may amplify both acute and chronic rejection. In this context, it is reasonable to postulate that grafts suffering early injury might follow a less favorable trajectory.5 Despite its widespread use, DGF remains an imperfect proxy for true biological injury. Its definition, based on the need for dialysis, makes it highly susceptible to clinical decision-making. Dialysis thresholds vary widely across centers and clinicians, introducing substantial measurement noise. If dialysis is initiated liberally, DGF may capture episodes of transient dysfunction unrelated to meaningful graft injury, leading to nondifferential misclassification and attenuated associations with long-term outcomes. Conversely, if clinicians preferentially dialyze patients perceived as high-risk older recipients or those with perioperative complications, DGF may partly reflect recipient vulnerability rather than intrinsic graft injury, inflating its apparent prognostic impact. SGF is similarly vulnerable to measurement error. Early creatinine trajectories are influenced by factors unrelated to graft injury, including residual native kidney function, dialysis timing before transplantation, perioperative fluid shifts, and interindividual variation in creatinine production. These sources of variability further weaken the reliability of early creatinine-based metrics as markers of graft injury. In this issue of Transplantation, Gately et al6 revisit this question using a paired donor kidney design. Leveraging registry data from Australia and New Zealand (2000–2023, with up to 24 y of follow-up), they examined 3256 recipients from 1628 deceased donors in whom the 2 kidneys experienced discordant initial DGF, SGF, and immediate graft function (IGF): 832 pairs DGF versus IGF, 378 pairs DGF versus SGF, and 418 pairs SGF versus IGF. By comparing recipients of kidneys from the same donor, the authors inherently control donor-level confounders. Importantly, they used piecewise-constant proportional-hazards Cox regression models, allowing them to distinguish the relation between DGF and SGF by early versus late risk of graft loss (12 mo). Their findings are both reassuring and provocative. DGF was associated with above 3-fold increased rate of death-censored graft loss and 2-fold increased rate of all-cause graft loss within the first 6 mo posttransplant. However, this excess risk barely persists beyond that early period (no effect during the period 6–12 mo posttransplant, and ≥35% increased rate thereafter, limited to all-cause graft loss). SGF, in contrast, was not associated with either short- or long-term graft loss, although the Authors acknowledged the limited sample size in SGF comparisons. In this study, all donor-related confounding was eliminated by design. Recipient-level confounders, including age, sex, ethnicity, comorbidities, dialysis vintage, HLA mismatches, and cold ischemia time, were adjusted for through multivariable modeling, whereas posttransplant events, such as acute rejection was handled as time-varying covariates. However, some sources of residual confounding may remain unaddressed, including immunosuppressive protocols, machine perfusion use, center-level effects, and the moderating effect of the transplantation era. Despite these limitations, the paired donor kidney approach represents a methodologically rigorous strategy for isolating the independent effect of DGF on transplant outcomes. For the transplant community, the implications extend well beyond pathophysiology. Regulatory approval pathways for new therapies rely heavily on robust and clinically meaningful endpoints. Yet in kidney transplantation, such endpoints remain frustratingly limited. Acute rejection, once the cornerstone of transplant trials, has become too infrequent to serve as a practical primary endpoint. Meanwhile, the US Food and Drug Administration has not formally endorsed DGF as a validated surrogate endpoint for long-term graft outcomes, despite its frequent use in research and registry studies.7,8 Ironically, the clinical landscape in which DGF occurs is rapidly evolving. The increasing use of higher-risk organs, including donation after circulatory death and higher Kidney Donor Profile Index kidneys, has led to a growing incidence of early graft dysfunction. At the same time, advances in organ preservation technologies, such as hypothermic oxygenated perfusion and normothermic machine perfusion, offer promising strategies to mitigate ischemic injury. In this setting, reliable surrogate endpoints would be invaluable for evaluating the expanding range of interventions aimed at improving early graft recovery. The analysis by Gately et al6 therefore should not be viewed as discouraging. Rather, it highlights a fundamental challenge for the field: identifying biomarkers that capture the biological pathways linking early graft injury to long-term outcomes, whereas remaining robust to clinical variability and peritransplant management differences. Encouragingly, emerging laboratory biomarkers may help fill this gap. Molecular injury signatures, serial measurements of donor-derived cell-free DNA,9 and other mechanistically informed markers may offer a more direct window into early graft injury than creatinine kinetics alone. If validated, such approaches could provide the transplant field with the surrogate endpoints it has long sought. Until such tools are validated, DGF will remain an important clinical signal, but an imperfect compass for guiding therapeutic innovation.
Maggiore et al. (Wed,) studied this question.