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Abstract

  1. Top of page
  2. Abstract
  3. PATIENTS AND METHODS
  4. RESULTS
  5. DISCUSSION
  6. REFERENCES

The incidence of acute kidney injury (AKI) has been reported to vary between 17% and 95% post–orthotopic liver transplantation. This variability may be related to the absence of a uniform definition of AKI in this setting. The purpose of this study was to identify the degree of AKI that is associated with long-term adverse outcome. Furthermore, to determine the best definition (for use in future studies) of AKI not requiring dialysis in post–liver transplant patients, we retrospectively reviewed the effect of 3 definitions of AKI post–orthotopic liver transplantation on renal and patient outcome between 1997 and 2005. We compared patients with AKI to a control group without AKI by each definition. AKI was defined in 3 groups as an acute rise in serum creatinine, from the pretransplant baseline, of >0.5 mg/dL, >1.0 mg/dL, or >50% above baseline to a value above 2 mg/dL. In all groups, the glomerular filtration rate was significantly lower at both 1 and 2 years post-transplant. Patient survival was worse in all groups. Graft survival was worse in all groups. The incidence of AKI was highest in the group with a rise in creatinine of >0.5 mg/dL (78%) and lowest in patients with a rise in creatinine of >50% above 2.0 mg/dL (14%). Even mild AKI, defined as a rise in serum creatinine of >0.5 mg/dL, was associated with reduced patient and graft survival. However, in comparison with the other definitions, the definition of AKI with the greatest impact on patient's outcome post–liver transplant was a rise in serum creatinine of >50% above baseline to >2 mg/dL. Liver Transpl 15:475–483, 2009. © 2009 AASLD.

Acute kidney injury (AKI) is a frequent complication post–liver transplantation. The incidence has been reported to range between 17% and 95% in different studies.1-4 The etiology of AKI post–liver transplantation is usually multifactorial. These factors include surgery-related events, blood loss, hypotension, sepsis, calcineurin inhibitor (CNI)–induced vasoconstriction, and volume depletion.4 At our institution, we tend to target a lower central venous pressure to protect the liver transplant against passive congestion with subsequent worsening of preservation injury in the immediate posttransplant period. Furthermore, renal dysfunction may be present prior to transplantation because of hepatorenal syndrome or other factors such as infections or intravascular volume depletion.5-7 Therefore, a rise in serum creatinine is common post–liver transplantation. A high burden of chronic kidney disease (CKD) and end-stage renal disease (ESRD) has been reported post–liver transplantation, most frequently due to CNI-induced nephrotoxicity.8 However, other factors may contribute to the development of this complication.8, 9 A report from our institution has shown that the incidence of ESRD is 9.5% after 13 years of follow-up post–liver transplantation.10 AKI has been proposed to be an important risk factor for the long-term development of CKD and ESRD.9 However, most of the studies have been limited to AKI requiring renal replacement therapy (RRT).11 There is a convincing body of evidence that AKI is not a transient phenomenon but a complication that may have long-lasting implications on long-term patient outcomes, including high mortality.12, 13 A better definition for early and less severe forms of AKI will assist in designing studies to prevent this complication. There is controversy in the literature about the best definition of AKI.2, 12-14 In addition, previous studies have been associated with variable and inconsistent results. In this study, we applied 3 commonly used definitions in the literature for AKI not requiring dialysis and evaluated their impact on patient outcome. We used different levels of severity of AKI, and we excluded AKI requiring RRT as it has been extensively studied. The purpose of this study was to determine the optimal definition for AKI post–liver transplantation and its impact on long-term renal function and the patient's outcome and to identify the degree of rise in serum creatinine that is associated with long-term morbidity and mortality, including chronic renal dysfunction.

PATIENTS AND METHODS

  1. Top of page
  2. Abstract
  3. PATIENTS AND METHODS
  4. RESULTS
  5. DISCUSSION
  6. REFERENCES

The sources of our data included chart review and our prospectively maintained database of liver transplant recipients.15 We reviewed our experience with AKI post–liver transplantation between 1997 and 2005. The database has information regarding recipient hemodynamic status, cause of liver disease, transplant or retransplant status, United Network for Organ Sharing status, Model for End-Stage Liver Disease score, and intraoperative and postoperative clinical data. All patients were included in the study, regardless of their initial serum creatinine. Patients on dialysis prior to liver transplantation were excluded from the study. For this study, we used three definitions commonly used in the literature to define AKI and evaluated the influence of each on serum creatinine at 1 and 2 years, the glomerular filtration rate (GFR) at 1 and 2 years with iothalamate clearance, the incidence of ESRD at 1 and 2 years, and patient and graft survival. In addition, we evaluated the incidence of acute rejection. The selection of AKI definitions was made to represent changes in renal function from mild to more severe changes in renal function occurring within 1 week at any time during the first 3 months post–orthotopic liver transplantation. The 3 definitions for AKI were as follows:

  • 1
    Rise in serum creatinine of >0.5 mg/dL above baseline.
  • 2
    Rise in serum creatinine of >1.0 mg/dL above baseline.
  • 3
    Rise in serum creatinine of >50% above baseline to above 2 mg/dL.

These definitions were applied to serum creatinine levels obtained at regular intervals in the posttransplant period. The baseline serum creatinine level is the one measured immediately prior to liver transplantation. Patients with AKI were compared to a control group without AKI by each definition.

The Institutional Review Board for Human Protection at the Baylor University Medical Center approved this retrospective study. Combined liver/kidney transplants and pretransplant dialysis patients were excluded from the analysis. All liver transplants were performed with venovenous bypass. The donor allografts were implanted by caval interposition or piggyback techniques. Venovenous bypass was performed through an access placed in the patient's internal jugular, left femoral, and portal vein. Piggyback transplants used venovenous bypass or intraoperative portocaval shunts when hypotension occurred during portal vein occlusion.

Immunosuppression

Our standard immunosuppression for patients with acute renal insufficiency post-transplant (manifested with oliguria/anuria) is to withhold CNI for the first 72 hours post-transplant. The patient receives a regimen of steroids and mycophenolate mofetil during that time. If urine output improves and is associated with a rise in serum creatinine, CNI is commenced at a low dose to aim for low levels (cyclosporine, 100-150 ng/mL, and tacrolimus, 3-5 ng/mL) to enhance renal function recovery. If it seems that renal function is unlikely to recover within 72 hours, antibody therapy is initiated with either OKT3 (5 mg/day) to a maximum of 14 days or thymoglobulin (1.5 mg/kg/day) for up to 14 days, and CNI is withheld until the recovery of renal function occurs.

Infection

When patients developed symptoms suggesting infection, blood and urine cultures were obtained. Sepsis was defined as hemodynamic instability associated with a positive blood culture. Positive cytomegalovirus (CMV) antigenemia or CMV polymerase chain reaction was regarded as CMV infection. All infections were treated with appropriate therapy.

Rejection

All episodes of acute cellular rejection (ACR) of the liver were diagnosed on the basis of core needle liver biopsy. ACR was treated with steroid pulse therapy administered as methylprednisolone (1 g daily for 2 days and then tapered over 5-7 days). Steroid-resistant ACR confirmed by biopsy was treated with OKT3 or thymoglobulin.

Kidney Function

Kidney function was assessed by GFR. Glofil-125 (sodium iothalamate I-125 injection) was used for GFR estimation. GFR was measured during the initial preoperative evaluation and postoperatively at 2 months, 1 year, 2 years, 3 years, 5 years, and then every 5 years thereafter. Serum creatinine in real time was downloaded to the database at defined time periods from the Department of Pathology.

Preoperative and Postoperative Data

Database information from pretransplant admission, intraoperative monitoring, and posttransplant care was reviewed. Data included age, gender, race, serum blood urea nitrogen and creatinine, GFR, length of hospital and intensive care unit (ICU) stay, rehospitalization, episodes of AKI, incidence of acute rejection, patient and graft survival, CNI levels, sepsis, infection, use of intravenous contrast, and pretransplant hepatorenal syndrome. Cardiovascular events included myocardial infarction, arrhythmias, congestive heart failure, angina, and cardiogenic shock.

Statistical Analysis

All data for this study were obtained from our prospectively maintained database and chart review if necessary. Categorical data were analyzed with the 2-tailed Fisher's exact test for 2-by-2 tables and the likelihood ratio chi-square test for larger tables. Continuous data were reported as mean ± standard deviation and compared with the Wilcoxon 2-sample tests. Actuarial survival was estimated with the Kaplan-Meier method and compared with the log rank test. P values less than 0.05 were considered to be significant. Statistical analyses were performed with SAS software, version 9.1.3

RESULTS

  1. Top of page
  2. Abstract
  3. PATIENTS AND METHODS
  4. RESULTS
  5. DISCUSSION
  6. REFERENCES

The incidence of AKI was variable, depending on the definition applied for AKI (see Tables 1–3). The tables show demographic and outcome data comparing the AKI patients and control group.

Table 1. Rise in Serum Creatinine of >0.5 mg/dL
CriteriaAKIControlP Value
  1. Abbreviations: CMV, cytomegalovirus; Cr, creatinine; GFR, glomerular filtration rate; ICU, intensive care unit; MELD, Model for End-Stage Liver Disease; PRBC, packed red blood cell; W/B/O, white/black/other.

Demographics   
 Number815235 
 %78%22% 
 Age (years)51 ± 950 ± 100.2780
 Sex (male/female)63%/37%58%/42%0.1957
 Race (W/B/O)89%/8%/3%84%/10%/6%0.0885
 Hepatitis C34%32%0.5846
 Hepatorenal syndrome8%6%0.2083
 Hypertension19%24%0.1154
 Diabetes33%27%0.0801
 Cyclosporine/tacrolimus27%/73%28%/72%0.7096
Outcome   
 Acute rejection in 0–3 months45%43%0.7658
 Cardiac events in 0–12 months11%7%0.1378
 MELD score18 ± 715 ± 70.0001
 PRBC transfusion5 ± 114 ± 40.0001
 ICU days4 ± 102 ± 20.0001
 Length of stay13 ± 159 ± 60.0001
 GFR at 1 year (mL/minute)63 ± 2778 ± 280.0001
 GFR at 2 years (mL/minute)62 ± 2673 ± 310.0001
 GFR < 30 mL/minute at 1 year7%2%0.0036
 GFR < 30 mL/minute at 2 years7%1%0.0006
 Preoperative Cr (mg/dL)1.2 (0.3–7.2)1.0 (0.4–7.2)0.005
 Cr at 1 year (mg/dL)1.5 ± 0.71.2 ± 0.40.0001
 Cr at 2 years (mg/dL)1.5 ± 0.61.3 ± 0.70.0001
 Cr > 2 mg/dL at 1 year12%3%< 0.0001
 Cr > 2 mg/dL at 2 years12%5%0.0102
 Sepsis in 0–3 months12%4%0.0002
 CMV infection in 0–3 months19%12%0.0141
 Dialysis in 1–2 years1%00.3625
 Readmission in 0–3 months60%44%< 0.0001
 Reoperation in 0–3 months21%11%0.0001
Table 2. Rise in Serum Creatinine of >1.0 mg/dL
CriteriaAKIControlP Value
  1. Abbreviations: CMV, cytomegalovirus; Cr, creatinine; GFR, glomerular filtration rate; ICU, intensive care unit; MELD, Model for End-Stage Liver Disease; PRBC, packed red blood cell; W/B/O, white/black/other.

Demographics   
 Number487563 
 %46%54% 
 Age (years)51 ± 950 ± 100.7340
 Sex (male/female)67%/33%57%/43%0.0028
 Race (W/B/O)88%/9%/3%88%/8%/4%0.4441
 Hepatitis C32%36%0.1912
 Hepatorenal syndrome9%6%0.1588
 Hypertension20%20%0.8776
 Diabetes33%30%0.2866
 Cyclosporine/tacrolimus24%/76%30%/70%0.0608
Outcome   
 Acute rejection in 0–3 months44%45%0.7559
 Cardiac events in 0–12 months13%7%0.0019
 MELD score18 ± 716 ± 70.0001
 PRBC transfusion6 ± 134 ± 40.0001
 ICU days5 ± 122 ± 3<0.0001
 Length of stay15 ± 1810 ± 7<0.0001
 GFR at 1 year (mL/minute)61 ± 2771 ± 280.0001
 GFR at 2 years (mL/minute)61 ± 2668 ± 280.0016
 GFR < 30 mL/minute at 1 year9%3%<0.0001
 GFR < 30 mL/minute at 2 years8%4%0.0108
 Preoperative Cr (mg/dL)1.3 (0.5–7.2)1.0 (0.3–7.2)0.0001
 Cr at 1 year (mg/dL)1.6 ± 0.71.3 ± 0.60.0001
 Cr at 2 years (mg/dL)1.5 ± 0.71.3 ± 0.60.0001
 Cr > 2 mg/dL at 1 year15%6%<0.0001
 Cr > 2 mg/dL at 2 years14%8%0.0038
 Sepsis in 0–3 months16%6%<0.0001
 CMV infection in 0–3 months19%16%0.2526
 Dialysis in 1–2 years1%<1%0.2508
 Readmission in 0–3 months60%54%0.0638
 Reoperation in 0–3 months26%13%<0.0001
Table 3. Rise in Serum Creatinine of >50% Above 2.0 mg/dL
CriteriaAKIControlP Value
  1. Abbreviations: CMV, cytomegalovirus; Cr, creatinine; GFR, glomerular filtration rate; ICU, intensive care unit; MELD, Model for End-Stage Liver Disease; PRBC, packed red blood cell; W/B/O, white/black/other.

Demographics   
 Number151899 
 %14%86% 
 Age (years)49 ± 951 ± 100.0518
 Sex (male/female)74%/26%60%/40%0.0011
 Race (W/B/O)87%/10%/3%88%/8%/4%0.7555
 Hepatitis C32%34%0.7110
 Hepatorenal syndrome10%7%0.2422
 Hypertension15%21%0.1241
 Diabetes38%30%0.0581
 Cyclosporine/tacrolimus24%/76%27%/73%0.5061
Outcome   
 Acute rejection in 0–3 months44%45%0.8599
 Cardiac events in 0–12 months18%9%0.0011
 MELD score19 ± 817 ± 70.0001
 PRBC transfusion5 ± 45 ± 100.0265
 ICU days8 ± 193 ± 5<0.0001
 Length of stay20 ± 2411 ± 10<0.0001
 GFR at 1 year (mL/minute)57 ± 2568 ± 280.0008
 GFR at 2 years (mL/minute)57 ± 2366 ± 280.0398
 GFR < 30 mL/minute at 1 year15%4%0.0001
 GFR < 30 mL/minute at 2 years15%5%0.0018
 Preoperative Cr (mg/dL)1.4 (0.5–7.2)1.1 0.3–7.2)0.0001
 Cr at 1 year (mg/dL)1.8 ± 1.01.4 ± 0.60.0001
 Cr at 2 years (mg/dL)1.7 ± 0.71.4 ± 0.60.0001
 Cr > 2 mg/dL at 1 year25%8%<0.0001
 Cr > 2 mg/dL at 2 years24%9%<0.0001
 Sepsis in 0–3 months23%9%<0.0001
 CMV infection in 0–3 months28%16%0.0004
 Dialysis in 1–2 years3%<1%0.0493
 Readmission in 0–3 months67%55%0.0092
 Reoperation in 0–3 months40%16%<0.0001

Rise in Serum Creatinine of >0.5 mg/dL

Defining AKI as a rise in serum creatinine of >0.5 mg/dL resulted in the highest incidence of AKI (78%). Patients with AKI defined as a rise in serum creatinine of >0.5 mg/dL were associated with lower GFR at 1 year (63 ± 27 versus 78 ± 28 mL/minute, P = 0.0001) and at 2 years (62 ± 26 versus 73 ± 31 mL/minute, P = 0.0001) in comparison with the control group. Patients with AKI also had higher serum creatinine at 1 year (1.5 ± 0.7 versus 1.2 ± 0.4 mg/dL, P = 0.0001) and at 2 years (1.5 ± 0.6 versus 1.3 ± 0.7 mg/dL, P = 0.0001) in comparison with the control group. Furthermore, patient survival and graft survival were both lower in the AKI group, with 2-year patient survival of 84% versus 91% (P = 0.0272) and 2-year graft survival of 81% versus 88% (P = 0.0262), in comparison with the control group (Table 1 and Fig. 1).

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Figure 1. Patient and graft survival when acute kidney injury (AKI) is defined as a rise in serum creatinine of >0.5 mg/dL.

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Rise in Serum Creatinine of >1.0 mg/dL

The second definition of AKI was a rise in serum creatinine of >1.0 mg/dL. GFR was significantly lower in the AKI group at 1 year (61 ± 27 versus 71 ± 28 mL/minute, P = 0.0001) and at 2 years (61 ± 26 versus 68 ± 28 mL/minute, P = 0.0016) in comparison with the control group. Serum creatinine was significantly higher in the AKI group at 1 year (1.6 ± 0.7 versus 1.3 ± 0.6 mg/dL, P = 0.0001) and at 2 years (1.5 ± 0.7 versus 1.3 ± 0.6 mg/dL, P = 0.0001) in comparison with the control group. There was no difference in the incidence of chronic dialysis at 1 and 2 years with this definition. Patient survival was reduced in the AKI group to 80% versus 90% at 2 years (P < 0.0001), and there was a reduction in graft survival at 2 years of 77% versus 88% (P = 0.0005). With this definition, the incidence of AKI was 46% (Table 2 and Fig. 2).

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Figure 2. Patient and graft survival when acute kidney injury (AKI) is defined as a rise in serum creatinine of >1.0 mg/dL.

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Rise in Serum Creatinine of >50% Above 2.0 mg/dL

When AKI was defined as a rise of serum creatinine of >50% from baseline to above 2 mg/dL within 1 week, AKI was associated with a lower GFR at 1 year (57 ± 25 versus 68 ± 28 mL/minute, P = 0.0008) and at 2 years (57 ± 23 versus 66 ± 28 mL/minute, P = 0.0398) in comparison with the control group. Serum creatinine was higher in the AKI group at 1 year (1.8 ± 1.0 versus 1.4 ± 0.6 mg/dL, P = 0.0001) and at 2 years (1.7 ± 0.7 versus 1.4 ± 0.6 mg/dL, P = 0.0001) in comparison with the control group. Furthermore, graft survival was lower at 2 years in the AKI group at 69% versus 85% (P < 0.0025), and patient survival was also reduced at 2 years versus the control group at 75% versus 87% (P = 0.0104). With this definition, the incidence of AKI was 14%. Cardiac events were more frequent with AKI (18% versus 9%, P = 0.0011; Table 3 and Fig. 3). CKD was more frequent with AKI when we used the three definitions with a larger number of patients with GFR < 30 mL/minute at 1 and 2 years (see Tables 1–3).

thumbnail image

Figure 3. Patient and graft survival when acute kidney injury (AKI) is defined as a rise in serum creatinine of >50% to >2.0 mg/dL.

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DISCUSSION

  1. Top of page
  2. Abstract
  3. PATIENTS AND METHODS
  4. RESULTS
  5. DISCUSSION
  6. REFERENCES

The incidence of AKI post–liver transplantation was variable in previous studies.1-4 This variation in the incidence of AKI has been documented in other clinical settings such as postcardiac surgery or critically ill patients in the ICU, ranging from 1% to 25%.16-18 This variability is in large part due to different definitions, case mix, and the setting and severity of AKI. More than 30 definitions have been previously applied in the literature for AKI, making interpretation, comparison, and intervention results confusing.12 This is more critical post–liver transplantation because of the high incidence of AKI. In this study, we examined 3 commonly used definitions ranging from mild AKI (rise in serum creatinine of >0.5 mg/dL) to the most severe AKI (rise in serum creatinine to >2.0 mg/dL and at least 50% above baseline). Some investigators have suggested applying additional criteria other than serum creatinine to the definition of AKI, such as urine output, race, age, and gender.12, 19, 20 However, in this study, we used changes in serum creatinine from baseline as the main marker for AKI. It is important to note that serum creatinine is less reliable in patients with liver disease in estimating actual renal function. Although a single measurement of serum creatinine is not an accurate reflection of GFR, changes in serum creatinine from baseline reflect changes in renal function. Furthermore, serum creatinine is more reliable than other markers such as urea.

A recent study reported that cystatin C is a reliable marker of kidney function during the immediate post–liver transplant period compared to serum creatinine and creatinine clearance.21 Furthermore, plasma cystatin C was found to be a more accurate marker of GFR in patients with cirrhosis, whereas serum creatinine and creatinine clearance were not of pertinent value.22 This finding may be due to the fact that serum cystatin C is determined by GFR regardless of age, gender, muscle mass, or the presence of an inflammatory state.23, 24 We did not measure cystatin C in this study, but the use of this marker has shown superiority in patients with liver cirrhosis and post–liver transplantation.

Until better markers are discovered and validated, serum creatinine will remain the main criterion used for the diagnosis of AKI.25 Developing a uniform validated definition will allow the design of consistent studies to examine the best methods to prevent this serious complication. The lack of universally recognized definitions of AKI has posed significant limitations. The Acute Kidney Injury Network (AKIN) is an independent collaborative network composed of experts selected by several societies.13 The goal of this network is to facilitate international, interdisciplinary, and intersocietal collaborations to ensure progress in the field of AKI. The definition of AKI proposed by AKIN is based on alteration and serum creatinine and urine output.13 AKI is defined as an abrupt and absolute increase in serum creatinine of ≥0.3 mg/dL, a percentage increase in serum creatinine of ≥50%, or a reduction in urine output of ≤0.5 mL/kg/hour for more than 6 hours.13 We did not have urine output recorded in our database and therefore were unable to apply the AKIN criteria. We have used 3 definitions of AKI, which include a wide range of severity specific to our population. The acronym RIFLE defines 3 grades of increasing severity of AKI (risk, injury, and failure) and 2 outcome variables (loss and end-stage kidney disease).26-28 AKIN has proposed refinements to increase the sensitivity of the RIFLE criteria.13 In a study by Bagshaw et al.,29 the AKIN criteria do not materially improve the sensitivity and prediction ability of the RIFLE criteria in defining AKI in ICU patients.29 To our knowledge, the AKIN and RIFLE criteria have not been validated in patients with liver disease. In this study, we did not use AKIN or RIFLE criteria as we did not have urine output data available and because of the small number of our study population.

Our study demonstrated variability in the incidence of AKI with different definitions. Furthermore, there was difference in outcome. Another finding was low incidence of AKI, with more severe AKI defined as a rise in creatinine of >50% above baseline to >2.0 mg/dL, but there was a more significant impact on outcome with higher incidence of cardiovascular events and ESRD.

Three endpoints were examined to test these three proposed definitions. These included long-term renal function as measured by serum creatinine and GFR as well as graft and patient survival. The definition of AKI as a rise in serum creatinine of >0.5 mg/dL was associated with a significant rise in serum creatinine and decline in GFR and reduced patient and graft survival, which underscored the importance of AKI post–liver transplantation. This definition has been extrapolated from that used in the diagnosis of intravenous contrast–induced AKI.25 Recent reports have suggested that even a milder renal insufficiency with a rise in serum creatinine of >0.3 mg/dL may have a negative impact on patient outcome.12, 13 Therefore, this study confirms that mild AKI, defined as a rise in serum creatinine of >0.5 mg/dL, is sensitive, has a significant impact on long-term outcome, and warrants attention and strategies for prevention. In this study, we have not examined a rise in creatinine of >0.3 mg/dL because of the high incidence of AKI in this setting. However, the impact on patient outcome appears to be less pronounced than definitions indicating more severe AKI, such as a rise in serum creatinine of >1.0 mg/dL or a rise in serum creatinine more than 50% above baseline to >2.0 mg/dL. Previous studies have been largely focused on AKI requiring RRT post–liver transplant and associated with high mortality.2, 11, 30 However, this study demonstrated a significant impact of mild AKI on long-term outcome.

The definition of AKI as a rise in serum creatinine of >0.5 mg/dL is sensitive with an incidence of 78%, with a reduction in patient and graft survival. In contrast, the definition of AKI as a rise in serum creatinine of >50% to above 2.0 mg/dL was associated with a lower incidence of 14%. In other patient populations, this phenomenon of varying degrees of AKI has been suggested.16-18 We propose that 1 definition for AKI cannot be universally applied as a patient with postcardiac surgery may be different from patients with intravenous contrast-induced AKI. It is of interest that AKI in patients post–liver transplantation can influence mortality even 5 years after the event. It is conceivable that this is related to a higher incidence of CKD and cardiovascular events, as shown in this study.11, 31, 32 Further studies are needed to prove that AKI is causally related to increased mortality.

Our data showed increased incidence of sepsis and cardiovascular events with AKI. It is conceivable that infections and cardiac events explain the increased mortality in patients with AKI. A previous study suggested that high mortality in AKI is related to infections and cardiovascular events.32 Furthermore, investigators have shown that CKD is associated with increased incidence of cardiovascular events.33 Moreover, AKI is associated with an increase in inflammatory markers such as C-reactive protein.34 Likewise, CKD has been reported to be associated with traditional and novel cardiovascular risk factors such as higher levels of C-reactive protein, homocysteine, and fibrinogen.35, 36 Subtle impairment in renal function was shown to be a potent marker of cardiovascular disease.37 In an epidemiological study, investigators noted that increased serum creatinine within the normal range is a marker for cardiovascular events in both normotensive and hypertensive subjects.37 In the hypertension detection and follow-up trial, it has been suggested that creatinine acts as a marker for vascular disease.38 In this study, we have shown higher serum creatinine and lower GFR over the long term in patients with AKI. The high incidence of CKD post–liver transplantation underscores the importance of preventing risk factors such as AKI to reduce the incidence of cardiovascular events.

It is of interest that risk of ESRD was significantly increased with AKI defined as a rise of serum creatinine of >50% above 2.0 mg/dL, but not with the other definitions. Moreover, cardiovascular events were increased with this definition, and this explained the increased mortality. Gonwa et al.10 showed increased incidence of ESRD in patients with acute renal failure requiring RRT.10 Similarly, Paramesh et al.8 reported that 23% of patients requiring dialysis developed ESRD. Retrospective studies of predictors of ESRD post–liver transplantation include acute renal failure requiring RRT.10 Our study is the only study that has shown increased ESRD incidence with AKI not requiring dialysis. It is clear that ESRD is associated with more severe AKI. These findings underscore the importance of strategies to prevent AKI.

A recent consensus conference on AKI has suggested that a milder definition should be used for AKI to detect this problem early and to intervene before it is severe and established.13 Our study is in agreement with the concept that mild AKI results in a significant impact on patient outcome. Post–liver transplantation changes in serum creatinine are very common because of hemodynamic factors in the peritransplant period.3 The definition of AKI as a rise in serum creatinine of >50% to >2 mg/dL has the greatest negative impact on patient and graft outcome in comparison with the other definitions used in this study. The incidence of AKI with this definition was the lowest at 14%, but it was associated with higher incidence of ESRD and cardiac events. This study has demonstrated that the definitions of AKI prior to a requirement for RRT are important for future intervention trials.

In conclusion, mild AKI has a significant impact on patient outcome. The definitions with greatest impact on the outcome of renal function and patient and graft survival were (1) a rise in serum creatinine above 2 mg/dL and at least 50% above baseline and (2) a rise in serum creatinine of >1 mg/dL. This study shows that AKI, appropriately defined, has an important impact on long-term renal function and patient and graft survival post–liver transplantation. The high incidence of AKI post–liver transplantation is an important risk factor for long-term renal dysfunction and its associated morbidity and mortality. Using the appropriate definition for AKI post–liver transplantation will allow progress in the field of prevention of AKI. Whether AKI is the direct cause of poor outcome or is simply associated with it will need further study.

REFERENCES

  1. Top of page
  2. Abstract
  3. PATIENTS AND METHODS
  4. RESULTS
  5. DISCUSSION
  6. REFERENCES
  • 1
    Fraley DS, Burr R, Bernardini J, Angus D, Kramer DJ, Johnson JP. Impact of acute renal failure on mortality in end-stage liver disease with or without transplantation. Kidney Int 1998; 54: 518-524.
  • 2
    McCauley J, Van Thiel DH, Starzl TE, Puschett JB. Acute and chronic renal failure in liver transplantation. Nephron 1990; 55: 121-128.
  • 3
    Lima EQ, Zanetta DM, Castro I, Massarollo PC, Mies S, Machado MM, Yu L. Risk factors for development of acute renal failure after liver transplantation. Ren Fail 2003; 25: 553-560.
  • 4
    Bilbao I, Charco R, Balsells J, Lazaro JL, Hidalgo E, Llopart L, et al. Risk factors for acute renal failure requiring dialysis after liver transplantation. Clin Transplant 1998; 12: 123-129.
  • 5
    Gonwa TA, Morris CA, Goldstein RM, Husberg BS, Klintmalm GB. Long-term survival and renal function following liver transplantation in patients with and without hepatorenal syndrome—experience in 300 patients. Transplantation 1991; 51: 428-430.
  • 6
    Johnson JP, Johnston JR, Flick R, Singh A, Angus D, Greenberg A. Acute renal failure in recipients of organ transplantation and nontransplantation patients: comparison of characteristics and mortality. Ren Fail 1997; 19: 461-473.
  • 7
    Ring-Larsen H, Palazzo U. Renal failure in fulminant hepatic failure and terminal cirrhosis: a comparison between incidence, types, and prognosis. Gut 1981; 22: 585-591.
  • 8
    Paramesh AS, Roayaie S, Doan Y, Schwartz ME, Emre S, Fishbein T, et al. Post-liver transplant acute renal failure: factors predicting development of end-stage renal disease. Clin Transplant 2004; 18: 94-99.
  • 9
    Fisher NC, Nightingale PG, Gunson BK, Lipkin GW, Neuberger JM. Chronic renal failure following liver transplantation: a retrospective analysis. Transplantation 1998; 66: 59-66.
  • 10
    Gonwa TA, Mai ML, Melton LB, Hays SR, Goldstein RM, Levy MF, Klintmalm GB. End-stage renal disease (ESRD) after orthotopic liver transplantation using calcineurin based treatment. Transplantation 2001; 72: 1934-1939.
  • 11
    Lütkes P, Lutz J, Loock J, Daul A, Broelsch C, Philipp T, Heemann U. Continuous venovenous hemodialysis treatment in critically ill patients after liver transplantation. Kidney Int Suppl 1999; 72: S71S74.
  • 12
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