Risk factors for acute kidney injury following orthotopic liver transplantation: the impact of changes in renal function while patients await transplantation

Acute kidney injury (AKI) occurs commonly in the setting of orthotopic liver transplantation (OLT). The incidence varies widely, from 12% to 80%, depending on the definition of AKI[1–4]. While awaiting OLT, patients often develop varying degrees of renal impairment, ranging from prerenal azotemia to hepatorenal syndrome and acute tubular necrosis. Although a majority of studies has identified a pre-operative elevation of serum creatinine (SCr) as a risk factor for the development of AKI post-OLT, the timing and definition of AKI have been imprecise and inconsistent[1, 4–6].

Transient changes of SCr in patients awaiting OLT most often occurs as a result of changes in renal perfusion. These changes, which are attributable to events and/or interventions such as large-volume paracentesis, diuretic therapy, sepsis, or gastrointestinal bleeding, tend to reduce the predictive power of pre-OLT SCr[7, 8]. To date, the correlation between the development of AKI post-OLT and pre-operative changes in renal function, as assessed by SCr, blood urea nitrogen (BUN), or estimated glomerular filtration rate (eGFR), has not been rigorously examined.

To determine the impact of pre-OLT changes in SCr, BUN, and eGFR on development of AKI post-OLT, as well as to identify additional potential risk factors for AKI, we performed an analysis of the prospectively maintained National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) Liver Transplantation Database (LTD)[9]. Given the previous lack of consistency among studies in terms of criteria and timing of AKI, we used the Acute Kidney Injury Network (AKIN) definition of AKI[10].

We performed a retrospective analysis of patients enrolled in the NIDDK-LTD to identify risk factors for the development of AKI immediately following OLT (≤ 48 hours). We examined a variety of demographic, clinical, and laboratory variables obtained at registration, pre-OLT, intra-operatively, and after OLT in 688 patients undergoing OLT between April, 1990, and June, 1994. Our most important finding is that those patients whose renal function declined while awaiting OLT, as assessed by an increased SCr or a decreased eGFR, were at decreased risk for AKI post-OLT. This seemingly paradoxical result is in contrast to previous studies, in which pre-OLT renal dysfunction was identified as a strong predictor of AKI post-OLT. In our analysis, the absolute level of renal function, as assessed by ¹²⁵I-iodothalamate clearance, eGFR, SCr, or BUN, obtained at registration or immediately pre-OLT, did not differ between patients with and without AKI. Rather, the change in renal function in the interval from registration to OLT was the critical determinant whether OLT recipients developed AKI.

Several considerations bear on the discrepancy between our results and those of previous studies. The most important is a previous lack of consensus with respect to the definition and timing of AKI. Earlier studies varied widely in the definition and timeframe in which AKI was studied[12, 13]. To circumvent these issues, we used the AKIN definition of AKI, and limited our analysis to within 48 hours following OLT.

The issue of timing is subtle but potentially critical. While AKI can occur anytime following OLT, its etiology likely varies with time from surgery. AKI occurring immediately following OLT and AKI occurring later during the post-OLT course are probably distinct entities with distinct predisposing factors and epidemiology. Moreover, as compared to the general surgical population, patients undergoing OLT have both shared and specific risk factors for AKI [13]. Our interest was in risk factors specific to OLT. We reasoned that the shorter the interval between OLT and AKI, the more likely that AKI would reflect factors particular to OLT.

In addition to issues of timing, most previous studies, identifying pre-operative renal dysfunction as a risk factor for AKI, have focused on more severe degrees of renal dysfunction. For example, renal dysfunction pre-OLT has been defined categorically as a SCr > 1.5 mg/dL, while AKI post-OLT has been defined as a requirement for RRT or a doubling of SCr[14–17]. Contreras et al showed that an elevated pre-OLT SCr was the strongest predictor of AKI requiring RRT within the first 7 days post-OLT[12]. Similarly, Sanchez et al found that a SCr > 1.9 mg/dL or a BUN > 27 mg/dL were strong predictors of AKI requiring RRT, although these authors did not indicate clearly the timeframe post-OLT that they studied[13].

In contrast, we used continuous measures of renal function pre-OLT as well as a standardized definition for post-OLT AKI. To our knowledge, no studies have evaluated post-OLT AKI by AKIN definitions, and only two studies have used the RIFLE criteria, on which the AKIN definitions are based[18]. Like AKIN, RIFLE uses three categories of graded renal dysfunction (denoted risk, injury, and failure). Earlier studies using RIFLE criteria offer some support to our conclusions. O'Reardon et al found that an increased SCr pre-OLT was a risk factor for the development of renal failure, the most severe RIFLE category[4]. Notably, an elevation of SCr pre-OLT was not a risk factor for renal injury, a less severe RIFLE category. As in our study, patients who developed renal injury had better pre-operative renal function, with lower SCr and higher eGFR. It should be noted, however, that these authors evaluated renal failure and injury at a later time, namely, two weeks post-OLT[4]. While Guitard et al, in a retrospective analysis of 100 OLT patients, also using RIFLE criteria, found that an elevated SCr pre-OLT was associated with renal failure by univariate analysis, elevated pre-OLT SCr dropped out as an independent predictor by multivariate analysis[18].

Several potential explanations may account for the apparent protective effect of pre-OLT renal functional impairment on the development of AKI post-OLT. First, AKI in these patients may have been masked by an improvement in renal perfusion, leading to increased eGFR and decreased SCr. Because OLT reverses many circulatory abnormalities associated with decreased renal perfusion [19], patients often recover renal function post-OLT. It is estimated that a majority of patients awaiting OLT have some form of reversible renal dysfunction due to diminished renal perfusion[20–23]. Thus, in our study, it is possible that pre-OLT declines in renal function were reflective of changes in renal perfusion rather than intrinsic injury or loss of renal mass. OLT, by improving renal perfusion and inducing a decline in SCr and rise in eGFR, could mask small deteriorations in renal function consistent with milder stages of AKI. In accord with this possibility is the fact that an improvement of renal function was a more powerful predictor for AKI-2/3 than for AKI-1 (Additional file 1 Tables S2, S3, and S4). Second, consideration should be given to the possibility that the pre-OLT decline in SCr among patients developing AKI is dilutional rather than indicative of improved renal function. While we cannot formally exclude this possibility, it is noteworthy that AKI patients sustained a loss, rather than gain, of weight (14.5 ± 32.0 kg) during the time from registration until OLT, making it unlikely that their decline of SCr can be attributed to dilutional effects. Third, the pre-OLT decline in SCr may reflect a loss of lean body mass, and it is the debilitation resulting from such a loss of lean body mass that predisposes to the development of AKI. Finally, pre-operative declines of renal dysfunction may truly protect patients from AKI, perhaps via ischemic preconditioning, as previously described for liver, kidney, and heart[24–26].

Other independent predictors of AKI post-OLT were increased BMI, decreased urine output during cross-clamp, increased post-OLT SV, non-Caucasian race, post-OLT use of tacrolimus, and Childs Pugh Turcott score. These factors likely reflect the severity of underlying liver disease (Childs-Pugh-Turcott score and increased post-OLT SV) and/or degree of renal ischemia (decreased urine output and post-OLT tacrolimus). Non-Caucasian race has been identified in other studies as a risk factor for AKI, for example, among patients undergoing cardiopulmonary bypass[27, 28]. Other studies have noted an association between tacrolimus and renal dysfunction[29–32].

An increased BMI was the strongest independent predictor of AKI post-OLT. A larger BMI may affect dosing and volume of distribution for drugs with a potential for nephrotoxicity[33]. Obese patients may have a greater post-operative inflammatory response with increased risk of multi-organ dysfunction[34]. In addition, patients with larger BMI may receive small-for-size hepatic grafts with resultant graft dysfunction and renal hypoperfusion[35]. Finally, the possibility exists that a larger BMI reflects volume overload and profound ascites, with the observed decline of SCr in AKI patients being a dilutional effect rather than an indication of improved renal function. As discussed above, this seems inlikely, since these patients lost, rather than gained, considerable weight while awaiting OLT. However, it is important to note that the determination of BMI in patients with ascites is fraught with error, and no formula for BMI in these patients has been validated.

Our study has several strengths. The most important is our use of the NIDDK-LTD, which contains prospective data from three centers over a five-year period. Also, we evaluated risk factors for AKI over a prolonged timeframe, from registration up to and following OLT. Finally, we used a very rigorous definition of AKI, as well as continuous measures of renal function, and we limited our analysis to the initial 48 hours post-OLT.

Although data on urine output were not available for the pre- and post-OLT periods, AKI and NO AKI patients did not differ in relative weight change from immediately before OLT to either post-OLT day 1 (1.2 ± 37.0 kg vs. 1.2 ± 33.0 kg, p = 0.995) or post OLT day 3 (-0.2 ± 37.0 kg vs. -1.4 ± 35.0 kg, p = 0.70). These data lend support to the notion that the observed differences in renal outcome post-OLT in AKI vs. NO AKI patients cannot be attributed to differences in peri-operative volume status or extent of fluid administration. Moreover, as discussed above, AKI patients on average sustained a weight loss of ~14 kg while awaiting OLT. Indeed, it is noteworthy that SCr decreased despite a large decrease of weight, of which much was likely achieved through fluid removal. Taken together, the observed pre-OLT decrease of SCr among AKI patients would seem to be independent of dilutional factors.

We note the following limitations to our study. First, we were unable to determine the etiology of renal dysfunction in our patients. The distinction between prerenal and renal causes of renal dysfunction pre-OLT may impact on the interpretation and significance of improved renal function as a risk factor for AKI post-OLT.

Third, we used the MDRD formula to determine eGFR. Estimates of renal function in cirrhotic patients that are based on SCr are known to overestimate the true GFR. However, it is important to emphasize that our analysis was limited to the correlation between changes (not absolute levels) of eGFR and the development of AKI following OLT.

Finally, although we included MELD scores in our analysis, our patients came from the pre-MELD era, and risk factors for AKI may differ in the current era, in which patients undergo OLT with more severe renal function. In the last two decades, there have been medical and surgical advances in the management of patients undergoing OLT. These include caval sparing, split liver transplants, diminished usage of veno-veno bypass, shorter anhepatic times, improved anesthetic techniques, and strategies to minimize calcineurin exposure[36–38]. These improvements, while decreasing the risk for AKI during OLT, are counterbalanced by two factors, which simultaneously increase the risk for AKI: transplantation of patients with higher MELD scores, and expansion of the donor pool to include non-heart-beating and "expanded-criteria donors [39–41]." With those caveats in mind, we believe that the impact of pre-operative changes in renal function on the risk for peri-operative OLT AKI is a reflection of the cirrhotic hemodynamic milieu per se, rather than any specific level of hepatic dysfunction, as indicated by the MELD score. In addition, our results may have a more general relevance and extend to surgical procedures other than OLT in patients with end stageliver disease. Analysis of newer databases should help to resolve both of these points.

In summary, our study is the largest to date on the development of AKI post-OLT using AKIN definitions. Our most important finding is that the absolute level of renal function pre-OLT was not a risk factor for AKI post-OLT. Rather, patients whose renal function declined while awaiting OLT were protected from AKI. This finding may represent true protection, via perhaps ischemic pre-conditioning, or represent a masking of milder forms of AKI, via correction of the cirrhotic milieu and improved renal perfusion. Irrespective of mechanism, the seemingly paradoxical result that declining renal function identifies patients at lesser risk for AKI post-OLT underscores the complex interrelationship between liver and kidney disease. Given the scarcity of organs available for simultaneous liver-kidney transplant, there is a need for additional prospective studies, which might include an analysis of peri-OLT kidney biopsies as part of the study protocol, to dileneate the impact of pre-OLT renal dysfunction following OLT. Our study suggests that not only the etiology but also the course of of pre-OLT renal dysfunction may play a critical role.