In our study, we focused on the development of AKI within 1 month, a longer follow-up duration than those in previous studies, which primarily focused on AKI at post-operative 72 hrs or 1 week. 3–9, 18 Reflecting the natural course of kidney injury after LT, AKI more often appears to be an epiphenomenon of the pre-, intra-, and post-operative clinical course after LT. A longer duration of follow up would be necessary to analyze post-operative factors, such as using nephrotoxic agents, sepsis, and other post-operative complications that affect AKI.
The incidence of AKI within 1 month after LT defined by AKIN classification was 39% in our cohort, lower than that reported in other studies. This could be explained by the older age and different proportions of primary lung disease compared to other studies. Serum creatinine is usually underestimated in older adult patients due to reduced muscle mass 19, and thus, changes in sCr levels could have been underestimated in our cohort. In the ISHLT registry report chronic obstructive pulmonary disease (COPD) was the most common indication in the last decade, while idiopathic interstitial pneumonia was the second. 20 However, in our cohort the proportions of IPF and connective-tissue disease related interstitial lung disease were over 60%, while that of COPD was lower than 10%. These differences may explain the lower incidence of AKI development, compared to other studies.
Prior studies have reported on the risk factors of AKI after LT. Ishikawa et al. reported that perioperative risk factors of AKI within 72 hrs included intraoperative hypoxemia (SpO2 < 90%) in patients that underwent double-lung transplantation, compared to those that underwent single-lung transplantation. 7 Balci et al. reported on perioperative risk factors of LT within 1 month as intraoperative hypotension and systemic infection in the post-operative period.8 Amphotericin B use and high tacrolimus level were reported as risk factors of AKI in some studies.9,21
The main finding of our study is that pre-operative anemia, number of RBC units transfused during surgery, and usage of colistin intravenous for multi drug resistant (MDR) pathogens independently are correlated with AKI development. Ho et al reported that in cases of cardiac surgery with cardiopulmonary bypass, nearly all patients are at the ‘initiation phase’ of ischemia-reperfusion kidney injury with proximal tubular dysfunction. They suggested that the ‘extension phase’ of kidney injury is related with the severity of inflammatory response, renal hypoxia, and oxidative stress.22,23 As CPB, and ECMO are used during LT, similar principals would likely apply. Accordingly, one could be reason that those described risk factors would be variables preventing recovery from initial kidney injury, therby leading to, progressing to AKI.
Underlying anemia has been shown to be associated with prolonged hypoxemia and could result in AKI in the post LT period. 24 Recipients of LT already face respiratory failure due to primary lung disease, which could be further aggravated by anemia, inducing a prolonged hypoxemic status. This reduced oxygen-carrying capacity elicits sympathetic nerve system increases in vascular resistance, causing vasoconstriction and leading to renal hypo-perfusion. 25Thus, anemia prior to surgery risk for developing AKI in LT recipients.
An increased amount of packed RBC transfusion units can induce transfusion-related adverse effects. Intraoperative RBC requirements are most likely necessary due to intraoperative requirements for hemodynamics, although in our analysis, observed hemodynamic instability during surgery was not statically related to AKI development, despite RBC requirements being statistically higher in the AKI group. Garg et al. reported in a randomized controlled trial, that restrictive transfusion of RBC was not inferior as an outcome of post-operative AKI in cardiac surgery with CPB.23,26 A unit of RBC is known to be stored up to 42 days and can undergo erythrocyte membrane change, becoming more fragile and leading to progressive hemolysis. Accumulation of pro-inflammatory molecules, free hemoglobin, and iron can lead to the development of AKI.27
Among nephrotoxic antibiotics, Intravenous colistin which was used to treat MDR pathogens, was an independent risk factor for developing AKI. Colistin has high intrinsic renal toxicity and accumulates within the proximal cortical tissue. Combined with anemia, age, liver disease, and baseline GFR, colistin has been reported as a risk factor for AKI.28 Thus, these findings support that LT recipients who already have anemia are prone to AKI after colistin use. In Southeast Asia, an increased incidence of MDR infections among ICU patients has been reported. 29 A similar situation was observed in our study. A total of 54% (n = 80) of the recipients experienced infections with MDR pathogens. The proportions of Acinetobacter, Pseudomonas, and Klebsiella were 30.4% (n = 45), 15.1% (n = 22), and 18.9% (n = 28), respectively.
In patients who developed AKI, post-operative complications of post-operative bleeding, grade 3 PGD, and sepsis occurrence were more common, compared to those without AKI. The cause and effect of AKI, as well as the complications, were unclear because patients with these complications could develop AKI both early and later after LT. However, in our study, it was clear that sepsis and grade 3 PGD were strongly associated with severe AKI, the majority of cases of which occurred within 7 post-operative days, resulting in increased mortality.
In this study, poor respiratory outcomes (prolonged ventilator days and longer ICU stay) were more common in the AKI group. The renal tubular epithelium is a major site of cell injury and death in AKI, where cytokines, oxidative stress, and leukocytes initiate local and systemic inflammation. The lungs, with thier large capillary networks, are capable of sequestering a large number of inflammatory/immune cells. 30 Moreover, AKI-induced derangement of nitric oxide synthase and heme oxygenase (key oxidative stress enzymes) may influence lung function. 31 This could lead to post-LT respiratory failure, leading to difficulty in weaning a patient off the ventilator.
Post-operative treatment of transplanted sick patients can be difficult and challenging. In our study, recipients who develop of AKI experience poor post-operative outcomes and mortality. Post-operative AKI could be a marker indicating that LT recipients are not going to do well. Pre-operative anemia, number of RBC transfused units during surgery, and usage of intravenous colistin were independent predictors of the development of AKI (Fig. 3).
Managing the difficult course involving AKI could be important in post-operative care of transplanted sick patients. Technical bleeding control and not having an excessive packed RBC transfusion would be considered in individuals susceptible to AKI. Also, in instances where an infection with MDR pathogens is documented within 7 days, waiting to determine whether it is a true infection or contamination may be advisable, and using colistin inhalation rather than colistin infusion could be another option for post op management. Also, if the candidates were in vulnerable for developing many complications such as AKI selection of recipients for lung transplantation would be a better management strategy, considering organ scarcity and predicted survival outcome.
Our study had several limitations. It was single-center, retrospective cohort study, thus generalizability of our findings may be limited. Second, dosage and duration of administered nephrotoxic agents were not fully evaluated due to inadequate information.