In this study, we found that only severe AKI(RIFLE-F) was independently associated with increased in-hospital or 1-yr mortality, whereas mild AKI(RIFLE-R or I) was not associated with increased risk of mortality. We also detected a marked increase in risk of in-hospital and 1-yr mortality for patients needing post-LTx RRT, and this effect was more pronounced for in-hospital mortality. Sixty-three percent of patients experienced AKI(as a binary variable RIFLE-R, I, or F), whereas 13% of patients required postoperative RRT. Our observed AKI rate is similar to the 56% AKI rate observed by Rocha et al. in the pre-LAS era, although they only incorporated RIFLE-I.5
There are several potential mechanisms specific to LTx that in part explain such high rates of AKI.
First, several authors have postulated “lung biotrauma,” whereby lung injury influences distant effects on the kidney.12–14
Imai et al. observed renal epithelial apoptosis in a mouse model of lung injury, while Gurkan et al. detected elevations in the inflammatory marker interleukin-6 in mouse kidney tissue in a similar model.12,14
Second, patients with respiratory failure are noted to have renal hypoperfusion, and this relative hypoperfusion may aggravate the injury attributable to hemodynamic instability during the perioperative period.15,16
Third, calcineurin inhibitors are a routine part of immune-suppression regimens, and are known to decrease renal perfusion due to vasoconstriction.17,18
Finally, LTx recipients are often subjected to aggressive diuresis in the immediate postoperative period to reduce pulmonary edema and protect allograft function, and they are also exposed to nephrotoxic antibiotics.
We used the highest serum creatinine level within the first seven postoperative days to detect perturbations in renal function that were due to insults incurred during the intraoperative and immediate postoperative period. In addition, all RIFLE classes were incorporated into our definition of AKI in order to assess the presence of a graded association with mortality; however, we did not observe such an association. Instead, there appeared to be an abrupt breakpoint, as only RIFLE-F was associated with a significant increase in mortality rates. We speculate this finding may be due, in part, to the aggressive fluid management strategy that we employ in the postoperative period. LTx recipients are routinely administered an intravenous loop diuretic within twelve hours postoperatively, and maintained on an aggressive diuretic regimen to achieve negative fluid balance, likely leading to decreased renal perfusion. The use of nephrotoxic agents(antifungals, antibacterials, and calcineurin inhibitors) may work in synergy with this renal hypoperfusion to cause kidney injury. Although we do not have information regarding serum levels of calcineurin inhibitors, exposure to these agents was uniform across all patients in the study.
Large single and multi-institution series confirm the high mortality risk associated with PGD, particularly grade 3 at any of the reported time points.19–21
In 1000 consecutive LTx, Kreisel et al. report a 15% absolute decrease in 1-yr survival among patients who developed PGD.20
Currey et al. described a protocol for post-LTx management aimed at achieving negative fluid balance, and found that average PGD grades were lower at 48 and 72 hours in the negative fluid balance group, suggesting a protective effect on the allograft.22
It is difficult to assess the iatrogenic component to the development of AKI(diuretic use, nephrotoxic agents) in our study. Our findings suggest that mild AKI(RIFLE-R or I) is well-tolerated, and our aggressive diuresis regimen is likely justified given the serious consequences of PGD. However, a proper balance between aggressive diuresis and adequate organ perfusion must be achieved. It is critical to emphasize that when AKI progresses to RIFLE-F or RRT, patients suffer markedly higher mortality and thus clinicians should bear caution in overly aggressive diuresis in the postoperative period.
After adjusting for LAS values only, we detected an independent effect of AKI on mortality for only RIFLE-F and RRT. When incorporating additional postoperative variables in the multivariable analysis, only RRT had significantly elevated risk of in-hospital and 1-yr mortality, and RRT has previously been found to independently predict mortality in cardiac surgery.23
Baseline GFR did not predict increased mortality, but this likely reflects the well-preserved baseline renal function of patients in this series. Except in dire situations, we strive to select patients for LTx with normal renal function. When examining patients according to individual RIFLE class, we did not observe a statistically significant difference in survival curves, although our power to detect differences is likely hampered by small sample size in each group. Comparing our study findings to those of Rocha et al. also suggests that implementation of the LAS has not dramatically altered the incidence of AKI, although to confirm this claim larger sample size is necessary. Unfortunately, large national registries lack post-LTx creatinine data needed to conduct this type of analysis.
The development of AKI after LTx was associated with an absolute difference of approximately $25,000 in additional hospital charges. AKI did have a positive relationship with increasing charges, albeit the r-value indicated low predictive ability of the regression model. The positive relationship between RRT and charges on regression analysis was more pronounced, and the association between LAS values, RRT, and cost has been shown in previous studies.24,25
When grouping all RIFLE classes collectively as AKI (data not shown), patients with AKI had longer ICU and hospital LOS, thus explaining the increased hospital charges.
Data on RIFLE-E (endstage permanent dialysis) were not included because this information is not present in our database. In addition, it is unclear whether increasing severity of RIFLE score corresponds to a lower likelihood of recovery of renal function. It is unknown from these data whether those who only partially recover from their episode of AKI after LTx have worse long-term outcomes when compared to patients with complete recovery, and is a subject of future study. The urine output criteria, which also can be used to calculate the RIFLE class(), pose another difficulty with employing the RIFLE system during retrospective analysis as these data are not readily available. Future prospective studies that employ the RIFLE system will be able to identify patients that meet the urine output criteria for improved RIFLE classification, as well as identify patients with temporary(L-loss) or Permanent (E-endstage) requirements for RRT.
An added limitation of this study is the use of hospital charges as a surrogate index for cost. However, the unique system for medical reimbursement in the State of Maryland offsets this issue. To contain costs, the Maryland Health Services Cost Review Commission(HSCRC) defines payment rates for both private and public insurers, including Medicare and Medicaid, within Maryland hospitals. Therefore, “cost shifting” by overcharging privately insured patients is absent. The authors’ institution HSCRC rate for charge payment has been cost + 1–3% over the study period. Our study is further limited by the retrospective design and relatively small sample size.
In summary, incorporating the RIFLE criteria as a consensus definition for AKI in LTx recipients, we found that mild degrees of AKI(RIFLE-R or I) were not associated with increased mortality risk, whereas severe AKI(RIFLE-F) was associated with worse 1-year mortality.