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Acute Kidney Injury After Liver Transplantation

Durand, François MD1; Francoz, Claire MD1; Asrani, Sumeet K. MD2; Khemichian, Saro MD3; Pham, Thomas A. MD4; Sung, Randall S. MD5; Genyk, Yuri S. MD4; Nadim, Mitra K. MD6

doi: 10.1097/TP.0000000000002305
Reviews
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Since the implementation of the Model of End-stage Liver Disease score-based allocation system, the number of transplant candidates with impaired renal function has increased. The aims of this review are to present new insights in the definitions and predisposing factors that result in acute kidney injury (AKI), and to propose guidelines for the prevention and treatment of postliver transplantation (LT) AKI. This review is based on both systematic review of relevant literature and expert opinion. Pretransplant AKI is associated with posttransplant morbidity, including prolonged post-LT AKI which then predisposes to posttransplant chronic kidney disease. Prevention of posttransplant AKI is essential in the improvement of long-term outcomes. Accurate assessment of baseline kidney function at evaluation is necessary, taking into account that serum creatinine overestimates glomerular filtration rate. New diagnostic criteria for AKI have been integrated with traditional approaches in patients with cirrhosis to potentially identify AKI earlier and improve outcomes. Delayed introduction or complete elimination of calcineurin inhibitors during the first weeks post-LT in patients with early posttransplant AKI may improve glomerular filtration rate in high risk patients but with higher rates of rejection and more adverse events. Biomarkers may in the future provide diagnostic information such as etiology of AKI, and prognostic information on renal recovery post-LT, and potentially impact the decision for simultaneous liver-kidney transplantation. Overall, more attention should be paid to pretransplant and early posttransplant AKI to reduce the burden of late chronic kidney disease.

The authors provide a comprehensive review of the current understanding of acute kidney injury in liver transplant patients. Guidelines for prevention and treatment of acute kidney injury are provided based on a systematic literature review and expert opinion.

1 Hepatology and Liver Intensive Care, Hospital Beaujon, Clichy, France, University Paris Diderot, Paris, France.

2 Division of Hepatology, Baylor University Medical Center, Dallas, TX.

3 Division of Gastrointestinal and Liver Disease, Department of Medicine, Keck School of Medicine, University of Southern California, Los Angeles, CA.

4 Division of Hepatobiliary, Pancreas, and Abdominal Organ Transplant, Department of Surgery, Keck School of Medicine, University of Southern California, Los Angeles, CA.

5 Section of Transplantation, Department of Surgery, University of Michigan, Ann Arbor, MI.

6 Division of Nephrology and Hypertension, Department of Medicine, Keck School of Medicine, University of Southern California, Los Angeles, CA.

Received 11 January 2018. Revision received 26 April 2018.

Accepted 15 May 2018.

The authors declare no funding or conflicts of interest.

All authors participated in writing of the article.

Correspondence: Mitra K. Nadim, MD, Division of Nephrology and Hypertension, Department of Medicine, University of Southern California 1520 San Pablo St., Suite 4300 Los Angeles, CA 90033. (nadim@usc.edu).

Acute kidney injury (AKI) after liver transplantation (LT) is common with an incidence that exceeds 50% in some series.1,2 In other series, about 15% of patients required transient renal replacement therapy (RRT) immediately after LT.3,4 Importantly, pretransplant AKI is a predisposing factor for posttransplant chronic kidney disease (CKD), both which have been associated with higher morbidity and mortality especially in patients with acute tubular necrosis before LT as compared to patients with hepatorenal syndrome (HRS).5-7 A 50% increase in serum creatinine (sCr) from baseline to above 2.0 mg/dL within a week early after LT was associated with development of CKD within 1 year after LT.8 Posttransplant CKD is independently associated with late mortality and cardiovascular events.9,10 The overall incidence of stage ≥4 CKD 5 years after LT is 15% to 25% depending on the method of glomerular filtration rate (GFR) assessment.11-13 Additionally, stage 2 and 3 CKD develops in 50% to 60% of LT recipients.12 In patients with similar Model for End-stage Liver Disease (MELD) scores, posttransplant survival is significantly less in those with elevated sCr pretransplant.14 Early posttransplant AKI, even if transient, has been associated with a poor long-term survival, increased rates of acute rejection and infectious complications, longer intensive care unit (ICU) stays, greater hospital costs, and higher mortality rates independent of pretransplant renal function.3,6,15-18 Altogether, these findings demonstrate the detrimental effect of AKI after LT.

Serum creatinine is a significant component of the MELD scoring system. Since its implementation in 2002, the proportion of patients with impaired renal function who develop stage ≥4 CKD after LT has increased and will continue to increase, as the number of patients transplanted with MELD of 40 or greater is also increasing,19 at least in part because more patients will have renal dysfunction before transplantation.7,14,20,21 AKI is a major concern in the management of candidates for transplantation.22 However, there is increasing evidence that a substantial proportion of patients with end-stage liver disease and AKI have underlying CKD.23,24 In the United States, nonalcohol steatohepatitis is the second leading cause of liver disease in patients awaiting LT and is associated with a higher incidence of CKD in comparison to other causes of chronic liver diseases.25-29 Age at time of transplantation in combination with an increase in patients transplanted with MELD of 40 or greater may contribute to CKD after LT as many of these patients will have pretransplant AKI.19,30 Overall, it is anticipated that post-LT CKD will continue to increase in the future. However, prevention and early management of perioperative AKI is central in the prevention of CKD and the improvement of long-term outcomes.

The aim of this review is to present new insights in the definitions, and predisposing factors involved in the development of AKI post-LT and to propose guidelines for the prevention and treatment of post-LT AKI.

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DEFINITION OF AKI

AKI is difficult to define in patients with liver disease since renal dysfunction is reflective of a combination of functional change (eg, due to hemodynamic perturbations) and structural change (eg, intra renal inflammation and microvascular changes) in the setting of an underlying milieu predisposing to worse renal insults (eg, due to risk factors for underlying CKD).31 In the post-LT setting, AKI may not be a discrete event but rather lie on an AKI/CKD continuum and is often influenced by the aforementioned factors before LT. Furthermore, the relative contribution of patient characteristics (eg, chronic diseases and severity), unrecognized underlying renal disease, intraoperative factors and posttransplant factors are sometimes difficult to discern and quantify.23,32-35

The definition of AKI in cirrhosis has undergone several significant changes over the past several years (Table 1).37,38 In 2012, the Acute Dialysis Quality Initiative (ADQI) recommended adaptation of the Acute Kidney Injury Network (AKIN) criteria to define AKI in patients with cirrhosis instead of the traditional definition using a fixed sCr cutoff value greater than 1.5 mg/dL.38 These criteria were irrespective of the cause of AKI and as such, type 1 HRS was categorized as a specific type of AKI. These criteria have been validated in numerous studies of hospitalized patients with cirrhosis pre and post-LT.33,39-49

TABLE 1

TABLE 1

More recently, an International Consensus Conference and the International Ascites Club has defined AKI in cirrhosis based on the Kidney Disease Improving Global Outcomes (KDIGO) definition, which is an increase in sCr ≥ 0.3 mg/dL within 48 hours or a ≥ 50% increase in sCr from baseline that is known or presumed to have occurred within the prior 7 days.22,37 Once AKI is established, a staging system then defines its severity. This also allows for identification of patients at highest risk for short and long-term mortality and management decisions based on escalating stages within each criterion.

As a result of the changes in the definition of AKI in patients with cirrhosis, the definition of HRS has also been revised in recent years to be included in a more general entity which includes a departure from reliance on absolute sCr cutoffs of greater than 1.5 mg/dL and instead uses a relative change in sCr.37 This allows for earlier initiation of management therapies with a higher likelihood of pharmacological response.50,51 A major limitation of the HRS criteria, however, is that it does not allow for the coexistence of other forms of acute or CKD, such as underlying diabetic nephropathy or other glomerular diseases often associated with patients with liver disease (eg, IgA, membranous or membranoproliferative disease). However, patients with underlying kidney disease can still develop “hepatorenal physiology.” As a result, ADQI proposed that the term “hepatorenal disorders” be used to describe all patients with advanced cirrhosis and concurrent kidney dysfunction.38 Such a definition would allow patients with cirrhosis and renal dysfunction to be properly classified and treated while maintaining the term HRS.

UO has been found to be a sensitive and early marker for AKI in ICU patients and to be associated with adverse outcomes.52-54 Although UO has not been previously included in the definition for AKI in patients with cirrhosis, a recent study in critically ill patients with chronic liver disease has demonstrated a significant increase in mortality in patients who met UO criteria for AKI.55 In a large cohort of patients with chronic liver disease (n = 3458), Patients classified with AKI according to UO criteria had nearly a 3-fold increased rate of hospital mortality compared with patients without any AKI (14.6% vs 5%; P < 0.001) and more than a 50% increased mortality compared with stage 1 AKI based on sCr criteria only. (14.6% vs 9%; P < 0.001). Patients with transient oliguria had increased mortality rates compared with patients without oliguria (14.9% vs 6.9%; P < 0.001). Thus, we suggest incorporating UO into the diagnostic criteria for AKI.

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ASSESSMENT OF RENAL FUNCTION AFTER LT

Renal function is measured by the clearance of exogenous markers (eg, inulin, iohexol, and iothalamate), serum endogenous marker (eg, creatinine or cystatin C [CysC]) or quantified with radionuclide scans.56,57 Measured GFR remains the gold standard in assessment of renal function but is onerous to perform, costly and not easily repeatable.58 Glomerular filtration rate may be estimated based on sCr based equations (eg, Modification of Diet in Renal Disease and Chronic Kidney Disease Epidemiology Collaboration, CKD-EPI-Cr), CysC-based equations (CysC, CKD-EPI-CysC,) or both (CKD-EPI-Cr-CysC).59,60 The components of the equations are provided in Table 2. All current sCr-based estimating equations overestimate renal function in patients with low GFR and have not consistently been studied in patients with AKI.61 In a meta-analysis of sCr based equations that estimate GFR among solid organ transplant recipients (35% liver), CKD-EPI-Cr and the Modification of Diet in Renal Disease (MDRD)-4 study equation were the most accurate as compared to measured GFR and had the lowest mean absolute error. CKD-EPI-Cr was better at higher GFR and MDRD-4 was better at lower GFR.61 In a series of candidates for transplantation who all had measured GFR at evaluation, MDRD-6 equation was more accurate than other equation to identify patients with low GFR.13

TABLE 2

TABLE 2

Cystatin C is an alternative filtration marker for estimating GFR. It is produced by all nucleated cells, formed at a constant rate, freely filtered through the kidneys and is reabsorbed and metabolized by proximal renal tubules. CysC-based equations are superior to sCr-based equations with higher correct classification of measured GFR; performance for all equations however declines with declining GFR and its application in AKI may be unclear.62,63 In the pretransplant setting, it is unclear whether CKD-EPI-Cr-CysC is better than CKD-EPI-CysC.62,64 Post-LT, accurate estimation of GFR may be influenced by factors affecting CysC, namely, inflammation and immunosuppression. As compared to inulin clearance, CysC based equations had smaller bias and higher accuracy and precision as compared with sCr-based equations.65 As compared with measured GFR by iothalamate, equations with CysC had superior performance and were more accurate as compared to sCr based estimations, however, it underestimated measured GFR by approximately 12%.66 Higher discrepancy was seen in the lowest GFR group. Serum CysC itself or as part of the equation was the strongest independent predictor of mortality, an observation also noted in other populations.63,67

A novel equation termed “GFR Assessment In Liver disease (GRAIL)” has been developed recently in patients with liver disease.68 Among patients with low measured GFR, GRAIL was more accurate, had lower bias and lower rates of misclassification as compared to other sCr-based equations before and after LT. In internal and external validation, it predicted a higher percentage of patients that develop CKD after LT.

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BIOMARKERS

In the general population, conventional tools used to diagnose and determine the etiology of AKI include Scr, UO, fractional excretion of sodium or urea, and proteinuria. However, all of these tools have limitations, especially in patients with advanced cirrhosis. In addition, neither absolute values nor changes in Scr help differentiate functional impairment from structural changes. In candidates for LT, it has been shown that there is a poor correlation between conventional markers and biopsy findings.23,69

Despite its ubiquitous use, Scr is an imperfect marker for the early detection of AKI because rises in Scr are delayed after the kidney insult. In individuals with normal preoperative renal function, GFR may decrease significantly with only minimal effect on Scr. During LT, intravenous fluid administration and massive transfusions may lead to hemodilution of sCr in the perioperative period further delaying the recognition of AKI. These limitations of sCr have led to a call for the use of tubular damage and stress biomarkers for the recognition and diagnosis of AKI.70

In the last decade, several urinary and serum markers of AKI have been evaluated, though primarily in the pretransplant setting.24 Markers of acute tubular injury have been the most extensively studied since they typically reflect the earliest markers of ischemia-related events. Currently studied biomarkers are not always specific to renal injury, may be influenced by inflammation or infection and do not comprehensively discriminate dichotomous outcomes.71 Several proposed biomarkers have not been validated using renal biopsy as a gold standard. Markers of acute tubular injury (neutrophil gelatinase-associated lipocalin [NGAL], kidney injury molecule-1, and interleukin-18 [IL-18]) have been the most extensively studied since they typically reflect the earliest markers of ischemia-related events and may play a role in the differential diagnosis of AKI pretransplant.71-76 However, substantial overlap in these biomarkers have been observed between patients with a diagnosis of acute tubular necrosis as compared to patients with other causes of AKI. Urinary NGAL either immediately pretransplantation, during surgery or early after the procedure predicts postoperative AKI.77-79 Perioperative urinary NGAL may also identify patients at risk of CKD that would benefit from early sparing strategies.80

Post-LT, accurate biomarkers that specifically identify AKI along the spectrum of the AKI/CKD continuum are a challenge. In addition, markers of CKD may be different than those of AKI. However, urinary and plasma biomarkers measured pretransplant or immediately post-LT are inconsistent predictors of development of AKI post-LT.81-87 Variable performance may partly be driven by nonrenal determinants of biomarker elevation.88

Renal biomarkers predictive of recovery from AKI after LT could enhance decision algorithms regarding the need for simultaneous liver-kidney (SLK) transplant or renal sparing regimens.24,89 In a single-center study, levels of TIMP-1 (inhibits MMP which tend to degrade extra cellular matrix in kidney injury regeneration) and osteopontin (a nephroprotective protein induced in AKI and may contribute to regeneration of tubular epithelial cells) along with patient characteristics (age, diabetes) were able to differentiate between recipients that developed reversible versus irreversible AKI post-LT.89 However, these results need to be validated. Early biomarkers to identify patients at risk to develop calcineurin inhibitor (CNI) nephrotoxicity could also identify a population in which CNIs should be reduced or withdrawn.

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RISK FACTORS FOR AKI

Posttransplant AKI is typically due to a combination of factors which include those related to the recipient, to the donor, to surgical events and to early posttransplant immunosuppression (Figure 1). Any degree of renal dysfunction after LT portends poor long-term survival and is associated with increased rates of acute rejection and infection, longer ICU stays, greater hospital costs, and increased mortality. Strategies to optimize pretransplant renal function are paramount to ensure favorable postoperative outcomes for patients with HRS undergoing LT.

FIGURE 1

FIGURE 1

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Recipient and Donor Factors

Patients with a high MELD score at the time of transplantation are at higher risk of posttransplant morbidity including AKI.5,19,90 Indeed, several studies have shown an association between pre-LT MELD score and post-LT AKI.5,91 In 1 study, where the 3 components of the MELD score were analyzed individually, pre-LT INR but neither sCr nor bilirubin, was strongly associated with post-LT AKI,92 suggesting that the severity of liver disease is the key determinant of post-LT AKI. It is clearly established that patients with end-stage liver disease are at high risk to develop episodes of AKI and that recurrent AKI is associated with higher waiting list mortality.93 However, the impact of pre-LT AKI on the occurrence of post-LT AKI still needs to be clarified. Patients with decompensated cirrhosis are more susceptible to perioperative kidney ischemia and are prone to develop AKI in the perioperative period. This is likely due to renal vasoconstriction induced by the activation of endogenous vasoactive systems released during and after the transplant.31 The prevalence of underlying CKD in patients with cirrhosis who develop AKI is unknown. However, it can be reasonably assumed that patients with advanced cirrhosis frequently have chronic kidney changes due to comorbidities (eg, diabetes and hypertension) and/or specific causes of CKD (eg, IgA nephropathy and viral-induced glomerulopathy).23 As discussed above, nonalcohol steatohepatitis–related cirrhosis is a growing indication for LT in Western countries and is associated with an increased risk of posttransplant AKI.1

Donor factors associated with severe ischemia reperfusion injury include advanced age, steatosis, prolonged cold and warm ischemia time.94,95 Early allograft dysfunction, which is more commonly seen with extended criteria donors, is associated with posttransplant AKI requiring RRT within the first month and CKD.96 Patients who experience both early allograft dysfunction and AKI are at higher mortality risk compared to patients with either early allograft dysfunction or AKI.96

Donation after circulatory death has been shown to be associated with a higher incidence of post-LT AKI compared with deceased after brain death donors.97 In donation after circulatory death transplantation, the sum of warm ischemia time in the donor and recipient is associated with the risk of developing posttransplant AKI.98 Hypothermic or normothermic liver graft machine perfusion is an emerging technique to attenuate ischemia reperfusion injury. It has been shown that hypothermic machine perfusion of extended criteria graft was associated with a lower rate of early allograft dysfunction and a lower rate of postoperative AKI.99

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Surgical Factors

Any event resulting in kidney hypoperfusion during surgery may result in post-LT AKI.100 Reperfusion after unclamping of the portal vein is often followed by hemodynamic instability.101 Prolonged hypotension defines the postreperfusion syndrome, which is characterized by decreased systemic vascular resistance, increased pulmonary resistance and impaired cardiac output leading to ischemia.101 This ischemia reperfusion leads not only to the release of cold and acidotic components by the graft but also proinflammatory cytokines such as interleukin-6 or tumor necrosis factor alpha. Cytokines trigger inflammatory response and subsequent cellular damages, especially renal tubular injury, further increasing the risk of AKI.102,103

Vena cava-sparing technique (piggy back technique) avoids complete vena cava clamping for caval anastomosis.104 Preservation of caval flow during the entire procedure maintains venous return to the right chambers, reduces the risk of hemodynamic instability and prevents congestion of the kidneys.105 Creation of a temporary portocaval shunt during hepatectomy has been proposed to decrease portal pressure, and to prevent gut edema.106 If surgical portocaval shunt is not feasible, extracorporeal veno venous bypass can be used in patients with major portal hypertension to prevent hemodynamic instability.107 A recent meta-analysis has shown that this technique is associated with a lower amount of red blood cell transfusion as well as lower sCr in the early postoperative period as compared to no shunt.107 In experimental models, N-acetyl cysteine is protective against AKI after inferior vena cava clamping.108

In living donor LT (LDLT), remote ischemic postconditioning consisting in cycles of intermittent clamping performed in 1 upper limb after reperfusion of the graft may reduce the incidence of postoperative AKI.109

Severe portal hypertension with large/diffuse collateral vessels, portal vein thrombosis and previous abdominal surgery can lead to blood loss and renal hypoperfusion. In addition, transfusion of red blood cells also plays a role in AKI by inducing a proinflammatory state which contributes to impaired kidney oxygenation and increases concentrations of nephrotoxic free hemoglobin and iron in the circulation.110,111

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Postoperative Factors

Nephrotoxicity of CNIs which are the mainstay of immunosuppression regimens after LT is discussed below. It has been shown that hypoalbuminemia, a common finding in LT patients with severe cirrhosis, has been associated with the development of AKI.112 However, the administration of albumin failed to show any benefit on the outcome of AKI. Even though albumin infusion does not seem to have any beneficial effect, hypoalbuminemia is associated with increased free fraction of CNIs which is a possible source of nephrotoxicity.113 Postoperative sepsis, perioperative glucose variability, massive bleeding, reoperation, heart failure after LT, retransplantation and early allograft dysfunction have all been associated with the development of postoperative AKI.114-116

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PREOPERATIVE PREVENTION AND TREATMENT OF AKI

Preoperative Prevention

Candidates for LT with end stage cirrhosis and ascites are typically at high risk of developing AKI before and immediately after LT. Diuretics should be used with caution and be discontinued even in cases of mild increase in sCr (≥ 0.3 mg/dL or ≥ 1.5 times from baseline). Nephrotoxic agents (eg, nonsteroidal anti-inflammatory drugs, aminoglycosides, contrast agents) should be avoided.117 Albumin should be systematically administered in patients with large volume paracentesis and/or spontaneous bacterial peritonitis (SBP).118 However, there is no evidence that albumin in addition to antibiotics reduces the incidence of AKI in patients with bacterial infection other than SBP.119 Bacterial infections are a frequent trigger of AKI in cirrhosis. Early antibiotic administration is essential in patients with any bacterial infections.120 To prevent infections, patients with variceal bleeding should also receive antibiotics. It has been shown that prophylaxis of SBP with quinolones in patients with low protein ascitic concentration delays HRS and improves survival.119,121 N-acetylcysteine in association with steroids does not improve survival in severe alcoholic hepatitis as compared to steroids alone. However, death due to HRS is less frequent in patients receiving N-acetylcysteine.122 Studies on rifaximin in the prevention of SBP yielded conflicting results. Rifaximin however, is associated with a lower rate of SBP as compared to no antibiotics.123 Several studies have shown that nonselective β-blockers (NSBBs) in patients with refractory ascites were associated with an increased risk of AKI and significantly higher mortality.124-126 Nonselective β-blockers may worsen circulatory dysfunction after large volume paracentesis.127 By decreasing cardiac output, NSBBs may also compromise renal perfusion and precipitate HRS.128 However, other recent reports do not describe an increased risk with NSBB.129-133 Despite discordant results, discontinuation of NSBBs in patients with refractory ascites could help prevent episodes of AKI.

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Treatment of HRS

By definition, type-1 HRS, recently termed HRS-AKI, is unresponsive to fluid administration and treatment is based on vasopressor.22,37 Terlipressin, in combination with albumin, is the preferred vasopressor with an initial recommended dose of 1 mg/ 4 to 6 hours intravenously.134-142 If decrease in sCr is less than 25% of the initial value after 3 days, the dose of terlipressin can be increased up to 2 mg/4 h. Continuous infusion of terlipressin is preferred over bolus since efficacy is similar but with less adverse events.134 In the absence of response, terlipressin should be discontinued by day 14. Complete response to terlipressin and albumin can be achieved in about 50% of patients (Table 3). Lower rates of response are observed in series where the dose of terlipressin does not exceed 4 mg/d. However, it must be noted that even in responders, 3-month transplant-free survival may not exceed 50% and that recurrence of HRS-AKI is relatively common.135,142 Therefore, terlipressin should be considered a bridge to transplantation rather than a cure for HRS. The effect of terlipressin in improving renal function can reduce the MELD score without improving 3-month survival. Therefore, it has been suggested that the baseline MELD before treatment or treatment of HRS as dialysis in the calculation of the MELD score be considered in responders.143 In countries where terlipressin is not available, noradrenaline is an alternative with similar response rate compared to terlipressin.137,140,144 A combination of midodrine, octreotide and albumin is associated with lower response rates compared to terlipressin.141 Reversal of type-2 HRS can be achieved in more than 50% of patients with the use of terlipressin and albumin.145,146 However, relapse after discontinuation of therapy is common and even in responders, a significant proportion of patients develop posttransplant CKD.37,145

TABLE 3

TABLE 3

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Renal Replacement Therapy

The initiation of RRT should be made on clinical grounds, including electrolyte disturbances, oliguria with increasing volume overload, and diuretic resistance or intolerance and RRT per se is not a contraindication for LT.22 The optimal timing of RRT initiation remains a topic of much debate. Meta-analyses examining the timing of initiation of RRT,147-149 have suggested that earlier initiation of RRT in critically ill patients with AKI may have a beneficial impact on survival. The ideal timing for initiation of RRT has not been studied in patients with cirrhosis; however, 2 recent randomized control trials (ELAIN150 and AKIKI151) in critically ill patients suggest that early RRT initiation may have a beneficial impact on survival.150,151 Even though in the AKIKI trial patients randomized to ‘early’ treatment had a similar morality (approximately 50%) to patients randomized to ‘late’ treatment, those who were eventually started on RRT in the late arm had a higher mortality (62%) in comparison to patients in the ‘early’ RRT (48.5%). In addition, 40% of the patients were excluded on the basis of emergent indications, already receiving RRT or had indications for initiation of RRT more than 5 hours.151

Both studies excluded patients with cirrhosis and HRS however, the ELAIN trial150 included a small percentage of patients post-LT (8%), therefore, we cannot definitively identify which patients are likely to benefit most from early initiation of RRT post-LT and recommend that the decision to start RRT be individualized. RRT may be required to prevent fluid accumulation and should be considered when patients cannot maintain an even or negative daily fluid balance despite normal urine output. A positive fluid balance is associated with poorer outcomes and may lead to underestimation of the severity of AKI.22,152 Initiation of RRT before the onset of severe AKI could improve survival and promote earlier recovery of kidney function by mitigating injury from acidemia, uremia, fluid overload, and systemic inflammation. Continuous RRT is generally preferred to intermittent dialysis as it provides greater cardiovascular stability.

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PERIOPERATIVE AND POSTOPERATIVE PREVENTION AND TREATMENT OF AKI

Perioperative and Early Postoperative Management of AKI

Perioperative RRT may help control fluid shifts, acidosis as electrolyte and coagulation abnormalities.153,154 The timing of initiation of RRT posttransplantation should be made on clinical grounds. In the early postoperative period, the balance between fluid loss and fluid administration should be carefully monitored, especially in patients with large amounts of ascites. There is no evidence that albumin is superior to other fluids. A recent controlled study has shown that posttransplant administration of terlipressin could reduce postoperative ascitic drain output.155 Nephrotoxic agents such as aminoglycosides should be avoided when alternatives exist.

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Immunosuppression Sparing Strategies

Calcineurin inhibitors remain the mainstay of post-LT immunosuppression with marked improvement in liver graft survival rates.156 However their use is associated with multiple comorbidities including development of CNI nephrotoxicity resulting in posttransplant AKI and CKD after long-term use. Various CNIs induced mechanisms of injury have been reported and these are classified into early (less than 12 months) and late (> 12 months) complications. Presumed early mechanism of CNI related injury is renal artery vasoconstriction and to a lesser extent, development of thrombotic microangiopathy.157 Meta-analyses have shown that CNI minimization can preserve and improve renal function in LT recipients.158 CNI related kidney injury is also dose dependent and hence multiple short and long-term strategies have now been developed for use of reduced dose CNIs or complete withdrawal post LT.

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Short-term Strategies (< 12 months)

One strategy to minimize CNI therapy is to combine it with a mammalian target of rapamycin (mTOR) inhibitors (Table 4). Majority of the studies have demonstrated that use of mTOR inhibitors resulted in improvement in GFR. The 2 main mTOR inhibitors studied have been sirolimus (SRL) and everolimus (EVR) with EVR demonstrating a better safety profile.159,161,162,165 Use of SRL within the first month of the immediate postoperative phase has had conflicting data with regards to preserving renal function.163,164,166 In a multicenter, open-label, randomized, prospective phase II study, LT recipients receiving standard-dose tacrolimus (TAC) versus SRL and reduced-dose TAC, had increased risk of sepsis, graft loss, and mortality at 24 months in the SRL arm. This led to early discontinuation of the study.164 A higher rate of hepatic artery thrombosis and portal vein thrombosis was also observed in the SRL arm (8% vs 3%, P = 0.065). Several studies have demonstrated that SRL beyond the first month can have renal protective effects. However the rates of acute cellular rejection (ACR) and adverse events such as new onset diabetes and cardiovascular events has been high.163,166 Administration of short-term induction therapy with monoclonal or polyclonal antibodies with delayed introduction of CNIs have also been used in the immediate post LT period as a renal protective strategy.167-170 In the larger randomized, multicenter trials daclizumab, a monoclonal antibody, was used as induction. In 1 study, patients received daclizumab and were introduced to TAC 5 days later at standard doses. Delayed introduction of TAC using standard doses was not associated with significant renal improvement.167 In other studies, however, delayed introduction of TAC along with lower trough levels was associated with significantly improved renal function.169,170 Belatacept (BELA) is a monoclonal fusion antibody that selectively inhibits T-cell activation through costimulation blockade. This molecule was also studied as a potential CNI reduction strategy. In a multicenter phase II trial, however, most BELA containing arms experienced higher rates of ACR, and the study was eventually halted due to higher rates of death in the BELA containing groups.168

TABLE 4

TABLE 4

Early introduction of EVR with reduced-exposure TAC at 1 month after LT. Use of low-dose TAC with EVR resulted in improvement in GFR compared to standard dose TAC alone. The treatment arms with TAC elimination (EVR monotherapy) however had higher ACR rates and were terminated early. Saliba et al recently demonstrated that use of induction therapy with basiliximab, a monoclonal antibody, along with addition of mycophenolic acid (MPA) may allow for elimination of CNI therapy with improvement in GFR and no increase in severe ACR rates. The follow-up for this study however was shorter at 6 months. A recent meta-analysis of randomized controlled trials of EVR with early withdrawal or CNI dose minimization has also reported on 4 such trials where EVR use with CNI minimization was associated with improvement in GFR without increase in ACR, graft loss, or mortality.171 The mTOR inhibitor containing arms however generally had higher adverse events such as infections, proteinuria, and dyslipidemia likely due to the medication itself.

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Long Term (>12 months)

Most data indicate that early nephroprotective strategies are more effective than late interventions. Introduction of mTOR inhibitors, both SRL and EVR, to replace CNIs beyond the first year of transplant has not shown to be substantially beneficial.12,85 There are some indications that reducing CNI doses with continued use of mycophenolate mofetil (MMF) may be beneficial in terms of improving renal function with no increase in ACR rates.172 Use of MMF alone however with complete withdrawal of CNIs, while protective of the kidneys is associated with increased rates of ACR and possible graft loss.172 Beyond immunosuppression management, LT recipients are at an increased risk of development of hypertension and diabetes. Therefore, adequate control of these comorbid conditions is of utmost importance in minimizing development of CKD.12

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AKI AFTER LT IN SPECIAL POPULATIONS

Live Donor LT

Living donor LT was developed to supplement the critically short supply of organs available for transplant. Advantages of LDLT include performing a planned elective procedure where the recipient is optimized and the potential to receive a healthy donor graft with minimal cold ischemia time. Given the optimization and selection of recipients for LDLT one would expect there to be less AKI after LDLT. Several studies have shown that the development of AKI after LDLT has a negative impact on patient and graft survival.173-175 Those patients that developed renal dysfunction secondary to their liver disease did well after LDLT as the kidney injury recovered after transplant. This is in comparison to those patients that developed severe AKI posttransplant requiring initiation of RRT. The initiation of RRT after LDLT has been shown to be associated with decreased patient and graft survival.173,174 A single-center study showed that those undergoing LDLT (n = 100) had significantly less AKI (23.3% vs 44.2%) in the postoperative period as compared to those who underwent deceased donor LT (n = 424) without any difference in patient survival.176

Risk factors for AKI after LDLT are similar to that of deceased donor LT.177 Lee et al. assessed for AKI immediately after LDLT and found that in addition to increased MELD score and preoperative renal dysfunction, small for size graft syndrome (SFS) significantly contributed to postoperative renal dysfunction.178 Graft-recipient body weight ratio (GRWR) less than 0.8% is known risk factor for SFS and 66% of patients with GRWR less than 0.8% developed postoperative AKI compared to only 27% of patients that received a GRWR greater than 0.8% graft.178 Another study assessing the risks factors for developing AKI after LDLT had similar findings but also showed that significant intraoperative blood loss (>55 mL/kg) and preoperative diabetes were related to AKI.44

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Pediatric Population

Most of the publications on kidney function after LT in children assess chronic renal dysfunction and how it relates to long-term use of CNIs. After LT, renal function will continue to decline with incidences of CKD at 10 years posttransplant ranging from 25% to 38%.179 There has been only one recently published study investigating the incidence and impact of AKI after pediatric LT. Hamada et al180 found that AKI defined according to the KDIGO Guidelines, developed in 46% of pediatric patients immediately after LT. Risk factors for AKI were elevated perioperative bilirubin and increased intraoperative blood loss. The development of postoperative AKI was shown to prolong hospital stay and did not impact in hospital mortality. This study does not mention graft or patient survival beyond the hospital stay. More prospective studies are needed before a conclusion can be reached about the clinical significance of AKI after pediatric LT.

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SIMULTANEOUS LIVER-KIDNEY TRANSPLANTATION

The priority in allocation to LT candidates with renal dysfunction has coincided with a dramatic increase in the number of SLK transplants, up to 739 in 2017, representing 10% of all LTs (Figure 2). Furthermore, approximately 5% of transplanted deceased donor kidneys are drawn away from kidney transplant alone (KTA) candidates. The rationale for SLK includes eliminating dialysis dependence after LT alone (LTA), easier perioperative management, and mitigating adverse long-term effects of CNIs on renal function. Although studied extensively over the past decade, it remains difficult to predict renal recovery after LTA. Selection criteria are grounded in a weak evidence base and guidance has been primarily consensus recommendations.181-183 Hence, there is variability in selection practices, and a strong reliance on the kidney transplant in borderline situations.184

FIGURE 2

FIGURE 2

Clinical selection for SLK revolves around the determination of reversibility of renal dysfunction.5,56,185-187 On one end of the spectrum are candidates with end-stage renal disease (ESRD), where the choice of SLK is obvious. On the other end are those with pure HRS, for whom renal recovery has been reliably demonstrated.5 In between, however, are those with varying degrees of CKD and AKI, which may be difficult to accurately characterize and often coexist, thus prediction of renal recovery is difficult. The magnitude, trajectory and duration of renal dysfunction are all relevant. Prior diagnosis of CKD and CKD risk factors may provide additional insight, but absent a preexisting diagnosis or extensive renal function history (which is often absent), accurately attributing the contribution of CKD can be challenging. Although use of biopsy has been promoted, this has not been widely adopted due to procedural risk.34,35,69,188 Predictive models and equations are not sufficiently accurate to have been widely used.

The many observational studies comparing outcomes of SLK and LTA recipients are all limited by the selection bias that funnels SLK to those with CKD and prolonged AKI, and LTA to those with HRS and lesser degrees of AKI. While these differences may not contribute to differences in outcomes, they make it impossible to ascertain the precise benefit of SLK, or whether one exists at all in populations other than those with ESRD. These analyses are limited by the lack of granular registry data and are not sufficiently powered in single-center analyses. Most analyses have found outcomes between SLK and LTA to be comparable or to favor SLK, although few have found superior outcomes for SLK for those candidates not on dialysis.6,189-191 In general, the survival advantage in SLK tends to parallel the degree to which those with ESRD or prolonged dialysis are included in the cohort. While controlling for MELD appears reasonable, there is strong sentiment that a candidate with ESRD is not as acutely ill as one with similar MELD whose renal failure is a result of hepatic decompensation, which has implications for transplant outcomes.181 The benefit of a functioning kidney in the peri and early postoperative period compared with RRT is difficult to assess, and evidence for this benefit is lacking. It should also be recognized that there is a substantial incidence of DGF (up to 40%) and futile kidney transplant due to early graft failure, primary nonfunction or death (up to 20%) in this population, so this potential benefit is by no means assured.192

SLK candidates and recipients present additional challenges. The additional kidney transplant procedure carries extra operative risk. As organ procurement organizations (OPOs) sharing of a kidney to SLK recipients is optional, centers may be left with a choice of accepting a liver alone for a high-MELD SLK candidate with borderline indications for kidney transplant or to try to wait for SLK. The liver is immunoprotective for the kidney when both organs are transplanted in combination.193 However, SLK candidates who are sensitized have additional restrictions on access; while the impact of sensitization on kidney outcomes in SLK recipients is less than KTA, it is not negligible, and quantitative DSA thresholds have not been firmly established.194 The widespread adoption of machine perfusion for recovered kidneys has potential to improve management and outcomes of SLK recipients; it has been recently demonstrated that excellent patient and kidney outcomes can be achieved with delayed kidney transplant (as a second operation) up to 81 hours utilizing hypothermic perfusion.195 This allows for potential stabilization of the recipient after LT, and even for returning the kidney back to the pool in cases of perioperative mortality or rapid renal recovery.

Two recent allocation modifications by the OPTN have the potential to have an impact on practice and SLK volumes nationally. New listing criteria for SLK include elements such as duration, need for dialysis, and evidence of CKD (Table 5). They are moderately liberal in recognition of the difficulty of predicting renal recovery after LTA, and thus the predicted impact on SLK activity is controversial.96,196 In conjunction with these listing requirements, a “safety net” was established that gives high priority for LT recipients with advanced renal dysfunction if listed within 1 year of LT. Kidney transplant recipients with a previous LT (kidney after liver transplantation) have been demonstrated to have survival outcomes superior to remaining on dialysis, superior to SLK recipients and similar to KTA recipients if transplanted within 3 years.197 From the kidney utilization perspective kidney after liver transplantation represents a better use of organs compared to SLK, and is therefore more palatable to the kidney transplant community. These measures are intended to reduce SLK both by restricting access and providing incentive for clinicians to elect LTA for candidates with borderline indications.

TABLE 5

TABLE 5

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CONCLUSIONS

Acute kidney injury is common post-LT and is likely multifactorial due to prolonged hypotension, infection, reoperation, and nephrotoxic medications for immunosuppression. Presence of pretransplant AKI increases the risk of persistent renal dysfunction post LT. Strategies to prevent pretransplant AKI are paramount to ensure favorable postoperative outcomes for patients undergoing LT. Insults, such as bleeding, reoperation, sepsis, and nephrotoxicity, from immunosuppression medications contribute to AKI in the posttransplant period. Novel biomarkers may in the future provide further information on the potential of renal recovery post-LT (along with cause) and potentially affect the decision to allocate an SLK.

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