This analysis represents the largest study to date to examine the incidence, impact, and risk factors for requiring RRT in the perioperative period after LTx. In our study of 12,108 LTx, we found a 5.51% incidence of RRT. The need for RRT after LTx was associated with decreased survival at 30 days, 1 year, and 5 years on both univariate and multivariable analysis. Although much of the difference in mortality occurs early, the need for RRT is still associated with increased 5-year mortality among patients who survive to 1 year. Additionally, implementation of the LAS has not changed the incidence of RRT, although there is a trend toward a higher associated mortality in the post-LAS era. Finally, a detailed analysis of risk factors for RRT demonstrated that, among other risk factors, poor preoperative renal function, a diagnosis of IPF or PPH, the need for ventilatory or ECMO support preoperatively, and bilateral lung transplantation were strongly predictive of RRT. Increasing center volume and a diagnosis of COPD were protective of the need for RRT.
Acute kidney injury has been previously associated with poor outcomes in critically ill patients [9
], patients undergoing cardiac surgery [7
], and solid organ transplant recipients [13
]. All patients with AKI, and particularly those requiring RRT, are at increased risk of mortality [7
]. Previous studies suggest that patients undergoing LTx are at particularly high risk of renal dysfunction, with AKI developing in 25% to 62% of recipients [1
] and 5% to 16% requiring RRT [2
]. Chronic renal failure in this population is also problematic as more than 90% of LTx recipients will have renal dysfunction, and an increasing number of patients will require RRT as time passes [6
Numerous explanations have been offered to explain why LTx recipients are at high risk of renal dysfunction. First, several authors have suggested that lung injury damages the kidneys through “lung biotrauma.” In this paradigm, lung injury results in the release of inflammatory mediators that mediate renal epithelial apoptosis, resulting in AKI [5
]. Second, lung injury and the resulting fluid retention and hypoxemia may be associated with renal hypoperfusion [17
]. Such injury may be exacerbated by perioperative hemodynamic instability [18
]. Third, the postoperative administration of nephrotoxic agents including calcineurin inhibitors and nephrotoxic antibiotics [1
]. Finally, in an effort to protect the allograft and avoid primary graft dysfunction, LTx recipients undergo aggressive diuresis in an effort to maintain a negative fluid balance [5
]. Although this practice can improve graft function, it may result in iatrogenic AKI.
The incidence of AKI after LTx reported in the literature varies widely and is dependent on the definition utilized. Therefore, we examined the need for RRT because it is a concrete marker of severe AKI. In our study, we found an overall incidence of RRT of 5.51%. As in other studies, the need for RRT was independently associated with dramatically decreased survival at 30 days, 1 year, and 5 years [4
]. The exact reason for this increased mortality is unclear. The need for RRT is likely a surrogate for critical illness [7
]. Additionally, AKI places patients at risk of chronic renal failure, which may increase their long-term mortality [6
Patients who needed RRT in the post-LAS period tended to have worse survival than patients in the pre-LAS era. While several explanations are possible, a comparison of their baseline characteristics suggests that patients in the post-LAS era tend to be older, have more comorbidities, and are of higher acuity at the time of transplant.
In analyzing predictors of RRT, worse preoperative renal function is associated with an increased incidence of post-LTx RRT. Although seemingly intuitive, the literature is divided on this question. Most previous studies have found GFR not to be associated with AKI but predictive of chronic renal dysfunction [1
]. This highlights the power of the UNOS database. Poor renal function is a relative contraindication to LTx. Therefore, most centers transplant only a small number of patients with poor baseline renal function. However, in the national experience as a whole, many patients with poor renal function have undergone LTx, which provides the statistical power to detect the impact of this risk factor.
As in previous studies, a diagnosis of COPD was protective whereas a diagnosis either IPF or PPH was predictive of RRT [4
]. In contrast to previous reports, these findings were independent both of the type of transplant performed and the age of the recipient. Previous reports have also suggested that cystic fibrosis is predictive of AKI [23
]. Further analysis is necessary to understand the reasons for the differential risk of RRT.
The need for both ventilatory and ECMO support were highly predictive of post-LTx RRT. In both cases, these variables are markers of high recipient acuity. These patients often have or will have infections and multiorgan dysfunction, causing or predisposing them to kidney injury. They are thus less likely to tolerate perioperative hemodynamic instability, nephrotoxic medications, or aggressive diuresis without having AKI requiring RRT.
Finally, increasing annual center volume was protective of RRT when considered both as a continuous variable and when stratified by quartiles. This finding is consistent with previous reports that increasing annual center volume is associated with increased survival after LTx [24
]. Concerns about allograft function lead to aggressive efforts to maintain a negative fluid balance but may exacerbate kidney injury. It is likely that with their accumulated experience, high volume centers are better able to maintain the delicate balance between healthy lungs and prerenal azotemia.
Although some data suggest that mild AKI is not associated with higher mortality in LTx, the need for post-LTx RRT is unequivocally associated with worse outcomes [4
]. Although several risk factors such as low preoperative GFR and ECMO support are strongly predictive of post-LTx AKI, and thereby increased mortality, we are not suggesting any of these factors should be viewed as absolute contraindications to LTx. Rather, potential LTx recipients should be evaluated for their overall risk of mortality. Their risk of post-LTx RRT is one important component of this evaluation. For high-risk patients, referral to high volume centers should be considered. For recent LTx recipients who are high risk, after optimizing hemodynamics and carefully avoiding nephrotoxic drugs, particular attention should be paid to their fluid status. Although preservation of the allograft is of penultimate concern, it must be carefully weighed against the dramatically increased mortality associated with the need for RRT. Finally, given the mortality associated with AKI requiring RRT after LTx, strategies including combined lung-kidney transplants or early renal transplantation after LTx merit additional consideration.
Although we have chosen RRT as a concrete marker of severe AKI, this outcome lacks the sensitivity to encompass the broader range of renal dysfunction as defined by recent consensus criteria such as RIFLE (an acronym for risk, injury, failure, loss, end stage) [25
]. Therefore, our findings of the incidence, impact, and risk factors for severe AKI should be seen as focused on AKI requiring RRT.
One reason for avoiding RIFLE and other definitions for renal dysfunction in this study is the absence of longitudinal renal function measurements in the UNOS database. Given the uncertain impact of less severe AKI on survival, future inclusion of these data in the database should be considered.
Additionally, the data concerning RRT in the UNOS database are limited. We do not know whether peritoneal, intermittent, or continuous RRT were utilized. Moreover, although previous studies suggest that recovery of renal function may not completely mitigate the impact on mortality, duration of RRT is also not available.
Finally, our study is a retrospective cohort study, and thus it is not possible to control for all confounders. Other important variables, including the dosing of nephrotoxic medications and perioperative hypotension, are not included. In particular, there are no data on the need for cardiopulmonary bypass during implantation. Cardiopulmonary bypass may be associated with AKI, and previous work suggests that the use of cardiopulmonary bypass may protect against rejection. Furthermore, the database does not include the dates of various postoperative complications; therefore, it is impossible to determine whether implementation of RRT is temporally related to a particular complication. For example, although drug-treated rejection was associated with the need for RRT on univariate analysis (odds ratio 1.82 [0.996 to 3.33], p = 0.052), we do not know if rejection occurred before AKI. Therefore, we have excluded these covariates, although they may be risk factors for RRT.
In conclusion, in the largest study to evaluate AKI requiring RRT after LTx, the incidence of RRT is 5.51%. The need for post-LTx RRT is independently associated with both short-term and long-term mortality. Several variables, including preoperative renal function, are predictors of post-LTx RRT and could be used to identify transplant candidates at risk for RRT.