The Devil Is in the Details: The Effect of Contrast Medium Administered Before Organ Procurement on Kidney Transplant Outcomes

In 1898, the first studies using contrast were conducted with bismuth salts in cats. Since then, various radiographic contrast media (CM) types have been used in medical imaging, displaying different chemical and physical properties. Additionally, the number of computed tomography (CT) examinations worldwide is increasing by 4% annually, totaling around 300 million CT scans per year, with 40% of them employing contrast.1 Similarly, >1 000 000 cardiac catheterization procedures are performed annually in the United States.2 With the projected rise in the use of CM in the coming years, safety is a significant concern. Ideally, a “perfect” contrast agent would not cause any adverse effects. Although severe dose-dependent immediate idiosyncratic anaphylactic reactions are rare (0.02%–0.04% of intravenous procedures),3 nonidiosyncratic reactions, primarily acute kidney injury (AKI), whether chemotoxic or osmotoxic, are more frequent and associated with the osmolality, viscosity, and ionic/nonionic properties of the CM. The first report of contrast-induced AKI (CIAKI) occurred in 1954 when Bartels et al4 reported a patient who developed anuria after intravenous pyelography. Currently, the incidence of CIAKI is a subject of debate, but clinically relevant CIAKI is less frequent than previously assumed, with estimates ranging from 0.8% to 1.7%.5 The definition of CIAKI also varies considerably. According to the European Society of Urogenital Radiology, CIAKI is defined as an increase in serum creatinine by >25% or 44 μmol/L (0.5 mg/dL) within 3 d of the intravascular administration of CM, with no alternative cause. However, serum creatinine, a surrogate marker for glomerular filtration rate, is notoriously insensitive in detecting renal injury.6 In this issue of Transplantation, Chotkan et al7 described the clinical outcomes of kidney recipients from deceased donors who received intra-arterial (IA) and/or intravenous CM before organ procurement. The novelty of this analysis lies in its large sample size, inclusion of older donors, and both donation after brain death (DBD) and donation after circulatory death (DCD) donors. This retrospective analysis included 2177 deceased donors (891 DBD and 1286 DCD donors) and 3638 corresponding recipients (1434 DBD and 2204 DCD recipients) in the Netherlands between 2011 and 2021. CM was used in 24% of the donors, corresponding to 23% of recipients. Overall, 316 donors (16%) underwent an enhanced CT scan with intravenous CM, 171 (8%) underwent coronary angiography with IA CM, and 33 (1.5%) received both. The indication for coronary angiography in the study cohort was solely to determine the heart’s suitability for donation. There were no differences in the incidence (DBD: 23% versus 20%; DCD: 47% versus 42%) and median duration (DBD: 7 versus 8 d; DCD: 8 versus 9 d) of delayed graft function (DGF) and primary nonfunction (DBD: 2% versus 3%; DCD: 3% versus 3%) between recipients of kidneys without and with CM exposure, respectively. There were also no differences in death-censored graft survival and the trajectories of kidney function from 1 to 6 y after transplantation. The key message of this analysis is that CM administration in DBD and DCD donors has no negative effect on early and long-term kidney graft function. This is reassuring as the number of kidneys recovered from older donors with comorbidities and from DCD donors is increasing worldwide. These donors are perhaps more likely to be exposed to CM for diagnosis, assessment, or organ suitability. However, this analysis has several limitations and opportunities for future research. First, like in the general population, the analysis cannot rule out selection bias. The analysis excluded 716 kidneys that were transplanted abroad or discarded. Comparing outcomes based on exposure to CM is susceptible to indication bias, which may require propensity score matching for a more precise comparison. A recent review highlighted that patients might be at high risk of developing AKI, regardless of exposure to CM. Additionally, the indication for contrast-enhanced imaging differs from nonenhanced imaging, reflecting differences in demographic characteristics.6 In this report, donors undergoing coronary angiography were older, had a higher body mas index, a higher percentage of history of smoking, and a higher incidence of cerebrovascular accidents as the cause of death. Second, key data relevant to CIAKI cannot be captured during the procurement period. There is no record of the timing, type, and volume of CM used in these donors, all of which are known factors associated with CIAKI. Large doses of CM, multiple administrations, excessive osmolality, or viscosity are common risk factors for CIAKI. There were no differences between the administration routes, whether IA or intravenous, which is also a subject of debate in the general population.6,8 Importantly, because of the nature of registry donor data, there is only 1 measurement of kidney function during the procurement process, and its association with the timing of CM administration is uncertain. Therefore, it is not possible to determine the various possible scenarios of donors with or without AKI before CM exposure. This would be important because, in patients with preexisting compromised renal perfusion such as dehydration, hemodynamic instability, and endothelial dysfunction, including hypertension and diabetes, all prevalent among deceased donors, CM exposure aggravates renal hypoperfusion and hypoxia.6 Ultimately, identifying donors with prior AKI who are then exposed to CM would be highly relevant. Another confounding factor is that a higher proportion of the kidneys exposed to CM were preserved with machine perfusion (58% versus 44%), with no differences in median cold ischemia time (12 versus 13 h), respectively. Based on the pathophysiological mechanisms of CIAKI, it is possible that machine perfusion may influence the recovery phase. Regarding transplant outcomes, considering the low incidence of CIAKI and the numerous risk factors associated with kidney function recovery after transplantation, the lack of detectable differences using imprecise definitions of kidney function such as DGF, duration of DGF, and primary nonfunction is not entirely surprising. The use of more sensitive biomarkers, such as neutrophil gelatinase-associated lipocalin and kidney injury molecule 1,6 and donor-derived cell-free DNA,9 to assess the rate of kidney function recovery may provide useful information to guide treatment and management. In summary, the data reported by Chotkan et al suggested that we should continue to use kidneys procured from donors exposed to CM. Simultaneously, we should continue to investigate kidneys prone to poor outcomes, possibly through more intensive monitoring of the donors using newer and more sensitive biomarkers. Additionally, several alternative treatments may prove effective during the period of machine perfusion. Ultimately, the goal is to reduce the discard rate as the demand for suitable organs continues to increase disproportionately.