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Keywords:

  • Acute kidney injury;
  • acute liver failure;
  • chronic kidney disease;
  • transplant

Abstract

  1. Top of page
  2. Abstract
  3. Methods
  4. Results
  5. Discussion
  6. Disclosure
  7. References

Renal dysfunction of acute liver failure (ALF) may have distinct pathophysiological mechanisms to hepatorenal syndrome of cirrhosis. Yet, the impact of perioperative renal function on posttransplant renal outcomes in ALF patients specifically has not been established. The aims of this study were (1) to describe the incidence and risk factors for chronic renal dysfunction following liver transplantation for ALF and (2) to compare renal outcomes with age–sex-matched patients transplanted for chronic liver disease. This was a single-center study of 101 patients transplanted for ALF. Fifty-three-and-a-half percent had pretransplant acute kidney injury and 64.9% required perioperative renal replacement therapy. After transplantation the 5-year cumulative incidence of chronic kidney disease (eGFR <60 mL/min/1.73 m2) was 41.5%. There was no association between perioperative acute kidney injury (p = 0.288) or renal replacement therapy (p = 0.134) and chronic kidney disease. Instead, the independent predictors of chronic kidney disease were older age (p = 0.019), female gender (p = 0.049), hypertension (p = 0.031), cyclosporine (p = 0.027) and nonacetaminophen-induced ALF (p = 0.039). Despite marked differences in the perioperative clinical condition and survival of patients transplanted for ALF and chronic liver disease, renal outcomes were the same. In conclusion, in patients transplanted for ALF the severity of perioperative renal injury does not predict posttransplant chronic renal dysfunction.

Abbreviations: 
ALF

acute liver failure

SIRS

systemic inflammatory response syndrome

INR

international normalised ratio

eGFR

estimated glomerular filtration rate

MDRD

Modification of Diet in Renal Disease

SD

standard deviation

IQR

interquartile range

HR

hazard ratio

CI

confidence interval

MELD

Model for End-Stage Liver Disease

CNI

calcineurin inhibitor

RRT

renal replacement therapy

CLD

chronic liver disease

Renal dysfunction is a common complication of acute liver failure (ALF) with two-thirds of patients manifesting acute kidney injury, and almost half requiring renal replacement therapy (1). Many have postulated that the pathogenesis is similar to the hepatorenal syndrome of cirrhosis (2,3). However, a growing body of evidence supports a systemic inflammatory response to ALF, and the systemic inflammatory response syndrome (SIRS) is an independent predictor of acute kidney injury in ALF patients (1,4,5). It follows that the renal dysfunction of sepsis may be a more accurate parallel than the hepatorenal syndrome (1). Additional factors that may contribute to renal dysfunction in ALF but are less likely in stable cirrhotic patients include hypovolemia, nephrotoxic drugs particularly acetaminophen, infection and disseminated intravascular coagulation (6–8).

Despite the contrasting perioperative clinical condition of patients transplanted for ALF and chronic liver disease (CLD), post-liver transplant renal outcomes have not been examined specifically in this group. Pretransplant glomerular filtration rate, pretransplant renal failure requiring renal replacement therapy and acute renal injury are consistent predictors of chronic renal dysfunction after elective liver transplantation (9,10). Given the greater baseline circulatory and neuro-humoral derangement of ALF it seems possible that the acute hemodynamic effects of the calcineurin inhibitors administered immediately following transplantation are exaggerated (11–14). On the other hand, the differing pathophysiological mechanisms could offer relative reno-protection and a reduced risk of chronic kidney disease.

The clarification of the impact of liver transplantation for ALF on posttransplant renal function has important implications for patient management. Chronic renal dysfunction is a major cause of patient morbidity and mortality and the minimization of renal injury has emerged as a priority for transplant physicians (9,15–17). Simultaneous liver–kidney transplantation is not an option in patients transplanted for ALF because of the medical urgency, but the identification of prognostic variables could help to determine those who may benefit from tailored renal sparing immunosuppressive regimens (18).

The aims of this study were first to describe the incidence and risk factors for chronic renal dysfunction following liver transplantation for ALF and second to compare renal outcome with an age–sex-matched group of patients transplanted for CLD.

Methods

  1. Top of page
  2. Abstract
  3. Methods
  4. Results
  5. Discussion
  6. Disclosure
  7. References

This was a retrospective single-center study of consecutive patients who underwent super-urgent liver transplantation for ALF (UK Transplant Super Urgent Scheme Category 1–7) between December 1992 and July 2007 (19). Eight patients had inadequate documentation available and were excluded from the analysis. A further 1 patient was lost to follow-up. Therefore, the study cohort comprised 101 patients. The causes of ALF were acetaminophen (46 patients, 45.5%), seronegative hepatitis (27 patients, 26.7%), idiosyncratic drug reaction (11 patients, 10.9%), autoimmune hepatitis (7 patients, 6.9%), hepatitis B (4 patients, 4.0%), Budd-Chiari (3 patients, 3.0%), Wilsons disease (2 patients, 2.0%) and hepatitis A (1 patient, 1.0%).

ALF was defined as severe liver injury with hepatic encephalopathy in which the onset of encephalopathy was within 8 weeks for the first symptoms of illness, and in the absence of preexisting liver disease (20).

Data were collected on the following preoperative variables at the time of listing: age, gender, race, liver disease etiology, additional comorbidity, smoking status, international normalized ratio (INR), serum bilirubin, albumin, serum creatinine, serum sodium (hyponatremia; sodium <135 mmol/L) and presence of ascites (on ultrasound). SIRS was defined as ≥2 of temperature <36°C or >38°C, heart rate >90 beats per minute, white cell count <4 × 109/L or >12 × 109/L and PaCO2 < 4.3kPa at the time of admission (21). Documented perioperative variables were peak preoperative serum creatinine, preoperative renal replacement therapy, postoperative renal replacement therapy, inotropes (noradrenaline/adrenaline), bacterial sepsis and fungal sepsis. Immunosuppression was noted and calcineurin inhibitor trough levels at 1 week, 1 month and 12 months (a comparable 12-month value for the linear regression analysis was obtained for all patients regardless of calcineurin inhibitor by expressing the trough as relative to the median value). Renal function was recorded at 1 month, 6 months, 12 months and 2, 3, 4 and 5 years following transplantation. Patients still receiving renal replacement therapy at 1 month were given an arbitrary serum creatinine of 350 μmol/L and an estimated glomerular filtration rate (eGFR) of 15 mL/min/1.73 m2.

A patient was considered to have significant renal dysfunction preoperatively if they fulfilled the RIFLE criteria for acute kidney injury: peak serum creatinine ≥2 times the baseline level (22). The baseline serum creatinine was unavailable for most patients and was estimated as previously described (1,22). Following transplantation the main measure of renal function was eGFR, determined using the Modification of Diet in Renal Disease (MDRD) Study 4-variable equation (eGFR = 186 × creatinine (mg/dL)−1.154× age (years)−0.203× 1.210 (if black) × 0.742 (if female) (23). Chronic kidney disease was defined as eGFR < 60 mL/min/1.73 m2 on at least 2 occasions from 6 months posttransplant onwards: stage 3, stage 4 and stage 5 chronic kidney disease were defined as eGFR 30–59 mL/min/1.73 m2, 15–29 mL/min/1.73 m2 and <15 mL/min/1.73 m2 or on dialysis, respectively (24).

To examine whether the renal dysfunction of ALF has a different renal prognosis after transplantation to the renal dysfunction of CLD a control group of patients transplanted for CLD was identified. These patients were age-matched (to within 5 years) and sex-matched to the original cohort. The relatively young age of the patients transplanted for ALF meant that only 71 patients could be appropriately matched. The causes of CLD were primary biliary cirrhosis (18 patients, 25.4%), alcohol (10 patients, 14.1%), chronic active hepatitis (9 patients, 12.7%), sclerosing cholangitis (9 patients, 12.7%), cryptogenic cirrhosis (9 patients, 12.7%), hepatitis C (5 patients, 7.0%) and other (11 patients, 15.5%). Three patients (4.2%) were transplanted for hepatocellular carcinoma. None of the control patients had intrinsic renal disease prior to transplantation and no patient underwent combined liver–kidney transplantation.

Immunosuppression was similar for patients transplanted for ALF and for CLD, and consisted of a calcineurin inhibitor, azathioprine and prednisolone in most cases. Midway through the specified time period the unit policy for calcineurin inhibitor changed from cyclosporine to tacrolimus. Prednisolone was usually discontinued by 3 to 6 months posttransplant unless otherwise indicated. Deviation from the protocol occurred only in the setting of adverse event or graft rejection. Acute rejection was usually managed with 1 g of methyl-prednisolone intravenously for 3 days followed by reintroduction of oral steroids with or without increased dose of, or switch to, alternative calcineurin inhibitor. Chronic rejection was managed with the latter and in a small number of patients azathioprine was changed to mycophenolate. Interleukin (IL)-2 receptor antagonist induction therapy was not administered to any of the patients.

Statistical analyses

Cumulative incidence of chronic kidney disease was estimated using the Kaplan–Meier method. Survival was estimated using Kaplan–Meier plots with log-rank test for differences, and age-adjusted survival was determined using Cox proportional hazards analyses. Normally distributed continuous variables and nonparametric continuous variables were compared using the Student's t-test and Mann–Whitney test, respectively. Chi-squared analysis or Fisher's exact test were used for comparison of categorical data. A multivariate linear regression analysis was performed to explore the relationship between perioperative renal dysfunction and long-term renal function following transplantation. Clinically relevant factors were included simultaneously with 12-month eGFR as the dependent variable. Cox proportional hazards analysis was then used to identify variables predictive of chronic kidney disease by 5-years posttransplant. Three multivariate models were constructed with all clinically relevant factors entered simultaneously. Variables entered into Model 1 were age, gender, pretransplant diagnosed hypertension, category of ALF (acetaminophen-induced vs. nonacetaminophen-induced), SIRS, calcineurin inhibitor at time of hospital discharge and pretransplant acute kidney injury. In Models 2 and 3 acute kidney injury was replaced by the other measures of perioperative renal dysfunction, peak preoperative change in serum creatinine and immediate posttransplant renal replacement therapy, respectively. All three measures of perioperative renal dysfunction were not included in the same model because of collinearity. None of the multivariate models was adjusted for the presence of pretransplant diabetes mellitus secondary to small patient numbers. p < 0.05 was considered statistically significant unless otherwise stated. Data were analyzed using the SPSS 15 package (SPSS Inc., Chicago, IL, USA).

All values are expressed as mean and standard deviation (SD), and median and interquartile range (IQR) as appropriate.

Results

  1. Top of page
  2. Abstract
  3. Methods
  4. Results
  5. Discussion
  6. Disclosure
  7. References

Patient characteristics

The median jaundice to encephalopathy time for patients with nonacetaminophen-induced ALF was 14 (IQR 11–31) days. In patients with acetaminophen-induced ALF the median time from overdose to listing for liver transplantation was 69 (IQR 54–72) h. Patient characteristics at the time of listing are outlined in Table 1. The median time from listing to transplantation was 1 (IQR 1–2) day. The estimated 1-month, 12-month and 5-year posttransplant patient survival was 83%, 75% and 68%, respectively.

Table 1.  Clinical characteristics of acute liver failure patients at time of listing for liver transplantation (n = 101)
Clinical characteristics 
  1. Values expressed as mean (standard deviation), median (inter-quartile range) and number (percent) where appropriate.

  2. ALF = acute liver failure; INR = international normalised ratio; MELD = Model for End-Stage Liver Disease; SIRS = systemic inflammatory response syndrome.

Baseline demographics
 Age (years)36.3 (14.1)
 Male : Female  1:1.5
 Caucasian99 (98)
Comorbidity
 Diagnosed hypertension6 (5.9)
 Type I diabetes mellitus2 (2.0)
 Type II diabetes mellitus1 (1.0)
 Dyslipidaemia1 (1.0)
Cause of ALF
 Acetaminophen46 (45.5)
 Seronegative hepatitis27 (26.7)
 Idiosyncratic drug reaction11 (10.9)
 Autoimmune hepatitis7 (6.9)
 Hepatitis B4 (4.0)
 Budd-Chiari3 (3.0)
 Wilsons disease2 (2.0)
 Hepatitis A2 (1.0)
Clinical characteristics at listing
 Bilirubin (μmol/L)193 (80–463)
 INR8.3 (3.2–11.7)
 Albumin (g/L)30.8 (10.2)
 Creatinine (μmol/L)160 (94–298)
 Sodium (mmol/L)135 (5)
 MELD score43 (35–52)
 Ascites24 (23.8)
 SIRS59 (70.2)
 Grade III/IV encephalopathy57 (59.4)
 Inotropes36 (37.9)

Perioperative renal function

Actual baseline renal function was available in 21 patients: the median baseline serum creatinine was 75 (IQR 60–93) μmol/L and the mean baseline eGFR was 106 (SD 45) mL/min/1.73 m2.

During the immediate preoperative period the median peak serum creatinine of the entire cohort was 203 (IQR 102–362) μmol/L. Fifty-four patients (53.5%) fulfilled the criteria for acute kidney injury, of whom 72.2% underwent renal replacement therapy. A further five patients were commenced on hemofiltration in the absence of a creatinine rise. Following transplantation 64.9% (n = 63) received renal replacement therapy. By 1-month posttransplant the median serum creatinine was 97 (IQR 83–136) μmol/L and the mean eGFR was 67 (SD 40) mL/min/1.73 m2. Four of the surviving patients (4.8%) were still on renal replacement therapy at this time point.

When patients with and without acetaminophen-induced ALF were compared the former were more likely to demonstrate perioperative renal dysfunction. Acetaminophen-induced ALF patients had a greater median peak preoperative serum creatinine (acetaminophen-induced-ALF, 332 (217–415) μmol/L, n = 47; nonacetaminophen-induced ALF, 108 (86–187) μmol/L, median (IQR), n = 54; p < 0.001), a greater frequency of acute kidney injury (acetaminophen-induced ALF, 83%; nonacetaminophen-induced ALF, 28%; p < 0.001) and a greater frequency of pre- (acetaminophen-induced ALF, 74%; nonacetaminophen-induced ALF, 15%; p < 0.001) and postoperative renal replacement therapy (acetaminophen-induced ALF, 95%; nonacetaminophen-induced ALF, 38%; p < 0.001). At 1-month posttransplant mean eGFR was similar for the two groups (acetaminophen-induced ALF, 57 (30) mL/min/1.73 m2, n = 36; nonacetaminophen-induced ALF, 74 (44) mL/min/1.73 m2; mean (SD), n = 48; p = 0.053).

Postoperative renal function

In most patients renal function demonstrated maximal recovery by 6- to 12-months following transplantation. The mean 12-month eGFR was 70 (SD 21) mL/min/1.73 m2, and 21.1% (n = 16) of patients had stage 3–5 chronic kidney disease by this time point. In those patients with follow-up up to 5 years after transplantation the mean eGFR remained stable at 70 (SD 20) mL/min/1.73 m2, and the prevalence of stage 3–5 chronic kidney disease was 29.5% (n = 13). Twelve-month eGFR demonstrated a close correlation with 5-year eGFR (r = 0.809, p < 0.001). The cumulative incidence of stage 3–5, and stage 4–5 chronic kidney disease by 5 years was 41.5% and 2.6%, respectively.

Relationship between perioperative renal dysfunction and posttransplant mortality

ALF patients who fulfilled the criteria for acute kidney injury prior to transplantation had greater mortality post transplant (log-rank p = 0.061: age-adjusted HR 2.09; 95% CI 1.01–4.34, p = 0.048; Figure 1). Similarly, patients who required postoperative renal replacement therapy demonstrated an increased risk of death (age-adjusted HR 6.22; 95% CI 2.01–19.26, p = 0.002).

image

Figure 1. Kaplan–Meier plot of the probability of survival following liver transplantation for acute liver failure subdivided based on the presence or absence of preoperative acute kidney injury.

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Relationship between perioperative renal dysfunction and posttransplant renal function

To explore the relationship between perioperative renal dysfunction and long-term renal function following transplantation for ALF a multiple linear regression analysis was performed, therefore, allowing adjustment for other relevant clinical factors such as age, gender and immunosuppressive therapy. Given the close correlation between 12-month eGFR and 5-year eGFR, 12-month eGFR was used as the dependent variable (Table 2). The analysis revealed no significant association between pretransplant acute kidney injury and 12-month posttransplant eGFR (p = 0.098). Instead, increasing age (p = 0.012), female gender (p = 0.005), preoperative SIRS (p = 0.041) and cyclosporine as primary immunosuppression (p = 0.021) were associated with worse renal function. Patients with acetaminophen-induced ALF had a higher 12-month eGFR compared with patients with nonacetaminophen-induced ALF (p = 0.027).

Table 2.  Multivariate linear regression analysis of variables associated with eGFR 12-months following liver transplantation for acute liver failure
VariableB(95% CI)βp-Value
  1. Reference group (relative risk 1.00): male gender, past medical history: no hypertension, nonacetaminophen-induced ALF, no preoperative SIRS, no preoperative acute kidney injury, CNI: tacrolimus (at time of 12-month eGFR). Bold indicates statistical significance.

  2. ALF = acute liver failure; B = unstandardized regression coefficient; β= standardized regression coefficient; CNI = calcineurin inhibitor; SIRS = systemic inflammatory response syndrome.

Age (years)−0.516−0.916, −0.116−0.3180.012
Female gender−14.500−24.358, −4.643−0.3320.005
Past medical history: hypertension−20.354−59.134, 18.426−0.1230.297
Acetaminophen-induced ALF16.1761.889, 30.4630.3710.027
Preoperative SIRS−12.780−24.991, −0.570−0.2700.041
Preoperative acute kidney injury−10.204−22.369, 1.960−0.2350.098
CNI: cyclosporine−12.465−22.947, −1.983−0.2630.021
12-month CNI trough0.583−7.662, 8.8320.0160.887

Predictors of chronic kidney disease following transplantation

Recognizing the significant morbidity and mortality of chronic kidney disease, as well as concerns regarding the influence of early deaths after transplantation on the 12-month data, Cox regression was then performed to identify perioperative variables predictive of posttransplant chronic kidney disease. Variables associated with the development of chronic kidney disease following transplantation on univariate analysis are outlined in Table 3. A subsequent multivariate regression analysis including all clinically relevant variables simultaneously (Model 1 Table 3) identified older age (overall p = 0.019), female gender (p = 0.049), pretransplant diagnosed hypertension (p = 0.031) and cyclosporine immunosuppressive therapy (p = 0.027) to be predictors of chronic kidney disease after transplantation. Patients transplanted for acetaminophen-induced ALF were at lower risk of chronic kidney disease than patients transplanted for nonacetaminophen-induced ALF (p = 0.039).

Table 3.  Univariate and multivariate cox regression analysis of variables as predictors of chronic kidney disease (eGFR <60 mL/min/1.73m2) by 5-years following liver transplantation for acute liver failure
  UnivariateMultivariate Model 1Multivariate Model 2Multivariate Model 3
  1. Reference group (relative risk 1.00): male gender, past medical history: no hypertension, no SIRS, no acute kidney injury, no RRT. Bold indicates statistical significance.

  2. ALF = acute liver failure; CNI = calcineurin inhibitor; eGFR = estimated glomerular filtration rate; peak Δ creatinine = peak change in serum creatinine (peak serum creatinine / baseline serum creatinine); RRT = renal replacement therapy during immediate postoperative period; SIRS = systemic inflammatory response syndrome.

  HR (95% CI)pHR (95% CI)pHR (95% CI)pHR (95% CI)p
   
Age<30 years1.00 1.00 1.00 1.00 
 30–44 years 3.59 (1.10–11.67)0.034 4.14 (1.18–14.50)0.0264.18 (1.19–14.65)0.0264.32 (1.27–14.62)0.019
 ≥45 years11.35 (3.63–35.51)<0.001 5.94 (1.62–21.74)0.0076.11 (1.67–22.36)0.0068.15 (2.08–31.96)0.003
Female gender 2.23 (0.95–5.25)0.0672.94 (1.00–8.64)0.0492.86 (0.96–8.58) 0.0602.92 (1.02–8.34) 0.045
Diagnosed hypertension  2.39 (0.57–10.11)0.23614.16 (1.28–156.2)0.03112.17 (1.12–131.89)0.04012.95 (1.20–140.22)0.035
ALFNon POD1.00 1.00 1.00 1.00 
 POD0.42 (0.18–0.95)0.0370.23 (0.06–0.93)0.0390.26 (0.07–1.01) 0.0520.22 (0.06–0.81) 0.022
Preoperative:         
 SIRS 1.41 (0.56–3.52)0.4672.11 (0.63–7.12)0.2292.09 (0.63–7.01) 0.2311.93 (0.57–6.52) 0.288
 Acute kidney injury 0.91 (0.43–1.91)0.7961.70 (0.64–4.51)0.288    
 Peak Δ creatinine 0.97 (0.75–1.26)0.838  1.14 (0.81–1.61) 0.457  
 Postoperative:         
 CNI on dischargeTacrolimus1.00 1.00 1.00 1.00 
  Cyclosporine2.00 (0.95–4.19)0.0672.67 (1.12–6.37) 0.0272.67 (1.12–6.36)0.0262.20 (0.88–5.48) 0.091
 RRT 0.74 (0.35–1.55)0.420    2.39 (0.77–7.44) 0.134
 1 month eGFR (mL/min/1.73 m2)≥901.00       
 60–8911.63 (1.50–90.24)0.019      
 30–5912.02 (1.52–95.17)0.018      
 <3018.95 (2.33–154.4)0.006      

Pretransplant AKI both on univariate analysis (p = 0.796), and after adjusting for confounding factors (p = 0.288), was not predictive of posttransplant chronic kidney disease. Similarly, no relationship was demonstrated between peak preoperative change in serum creatinine (univariate analysis, p = 0.838; multivariate analysis, p = 0.457, Model 2 Table 3), or renal replacement therapy during the immediate posttransplant period (univariate analysis, p = 0.420; multivariate analysis, p = 0.134, Model 3 Table 3) and chronic renal dysfunction.

Comparison of posttransplant renal function in patients transplanted for ALF and age–sex matched patients transplanted for CLD

To determine whether ALF per se is associated with renal function following transplantation age–sex-matched patients transplanted for CLD were introduced into the statistical analysis. Pre- and perioperative characteristics of patients with ALF and with CLD are compared in Table 4. The median waiting-list time was 1 (IQR 1–2) day for ALF patients and 52 (IQR 20–136) days for CLD patients (p < 0.001). Median listing serum creatinine was higher (p < 0.001), mean listing eGFR lower (p < 0.001) and the frequency of ascites less (p < 0.001) in the ALF group. Furthermore, the ALF patients were more likely to receive pre- (p < 0.001) and postoperative renal replacement therapy (p < 0.001). The estimated 1-month, 12-month and 5-year survival was 78%, 69% and 62%, respectively, for ALF patients and 96%, 90% and 79% for patients with CLD (Figure 2, log-rank p = 0.029).

Table 4.  Pre- and perioperative clinical characteristics of patients transplanted for acute liver failure and age–sex-matched patients transplanted for chronic liver disease
CharacteristicALF patients (n = 71)CLD patients (n = 71)p-Value
  1. Values expressed as mean (standard deviation), median (interquartile range) and number (percent) where appropriate.

  2. ALF = acute liver failure; CLD = chronic liver disease; CNI = calcineurin inhibitor; eGFR = estimated glomerular filtration rate; INR = international normalized ratio; MELD = Model for End-Stage Liver Disease; RRT = renal replacement therapy.

Age (years)42.2 (12.4)42.5 (12.1)0.918
Male:Female1:1.31:1.31.000
Time on waiting list (days)1 (1–2)52 (20–136)<0.001 
Comorbidity
 Diagnosed hypertension6 (8.5)2 (2.8)0.137
 Type I diabetes mellitus0 (0)(0)1.000
 Type II diabetes mellitus1 (1.4)5 (7.0)0.104
 Dyslipidemia1 (1.4)4 (5.6)0.183
 Hepatitis C1 (1.4)6 (8.5)0.058
 Active smoker37 (56.9)20 (29.4)0.001
At listing
 INR5.8 (2.8–11.1)1.2 (1.1–1.5)<0.001
 Bilirubin (μmol/L)227 (81–486)67 (35–172)<0.001
 Albumin (g/L)30.8 (11.4)30.0 (5.6)0.582
 MELD score41 (33–52)16 (12–19)<0.001
 Creatinine (μmol/L)148 (94–298)81 (71–97)<0.001
 eGFR (mL/min/1.73 m2)49 (42)83 (30)<0.001
 Hyponatremia27 (38.0)19 (26.8)0.151
 Ascites18 (25.4)41 (57.7)<0.001
Perioperative
 Peak creatinine (μmol/L)200 (99–384)  
 Pre RRT30 (42.3)0 (0)<0.001
 Post RRT41 (61.2)12 (16.9)<0.001
 Fungal sepsis5 (7.5)3 (4.2)0.327
 Bacterial sepsis35 (52.2)25 (35.2)0.044
 Super-urgent retransplant4 (5.6)4 (5.6)0.641
 Early acute cellular rejection17 (25.4)28 (39.4)0.078
CNI on discharge: cyclosporin16 (28.1)27 (39.1)0.192
image

Figure 2. Kaplan–Meier plot of the probability of survival following liver transplantation for acute liver failure and chronic liver disease.

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By 1 month following transplantation the median serum creatinine (ALF, 92 [83—127]μmol/L; CLD, 88 [79–101]μmol/L, median [IQR]; p = 0.103) and the mean eGFR (ALF, 69 [42] mL/min/1.73 m2; CLD, 74 [27] mL/min/1.73 m2, mean [SD]; p = 0.451) were similar in ALF and CLD patients. Figure 3 illustrates the mean pre- and posttransplantation eGFR in patients with ALF and CLD surviving to 12 months. The accompanying table (Table 5) documents relevant pre- and posttransplant clinical variables of these surviving patients. Despite significantly lower listing eGFR in the ALF group renal function was similar at all time points in the postoperative period. The cumulative incidence of stage 3–5 (ALF, 48.7%; CLD, 49.6%; p = 0.930) and stage 4–5 chronic kidney disease (ALF, 4.1%; CLD, 8.7%; p = 0.615) by 5 years was also no different between ALF and CLD groups.

image

Figure 3. Mean estimated glomerular filtration rate (eGFR) and 95% confidence intervals at the time of listing for liver transplantation and at 1, 6 and 12 months following transplantation in all patients surviving to 12 months subdivided into acute liver failure and chronic liver disease groups. p-value <0.013 considered significant. The median time from listing to transplantation for acute liver failure patients was 1 (IQR 1–2) day and for chronic liver disease patients was 52 (20–136) days.

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Table 5.  Relevant pre- and posttransplant clinical characteristics of all patients transplanted for acute liver failure and patients transplanted for chronic liver disease surviving to 12 months after transplant
 ALF patientsCLD patientsp-
Characteristic(n = 49)(no = 62)Value
  1. Values expressed as mean (standard deviation) and number (percent) where appropriate.

  2. *p-value <0.017 considered significant.

  3. ALF = acute liver failure; CLD = chronic liver disease; CNI = calcineurin inhibitor.

Age at listing (years)41.8 (12.4)42.5 (12.4)0.772
Male:Female1:11:1.30.569
Comorbidity at 12-month posttransplant
 Diagnosed hypertension14 (28.6)17 (27.4)0.893
 Type II diabetes mellitus7 (14.3)7 (11.3)0.637
 Insulin-dependent diabetes mellitus1 (2.0)6 (9.7)0.103
CNI on discharge: cyclosporine16 (32.7)25 (40.3)0.406
1 week CNI trough:
 Cyclosporine181 (57)145 (52) 0.157*
 Tacrolimus8.5 (3.3)10.1 (3.1) 0.195*
1 month CNI trough:
 Cyclosporine151 (39)162 (48) 0.492*
 Tacrolimus10.8 (4.6)8.1 (3.2)0.006*
12 month CNI trough:
 Cyclosporine133 (40)160 (40) 0.073*
 Tacrolimus8.0 (3.3)7.9 (2.8) 0.974*

Discussion

  1. Top of page
  2. Abstract
  3. Methods
  4. Results
  5. Discussion
  6. Disclosure
  7. References

In this large single-center study we have described for the first time the risk factors for chronic renal dysfunction following emergency liver transplantation for ALF. Importantly, we have shown that perioperative kidney injury does not appear to have negative consequences for long-term renal function in this population. Contrary to observations in CLD patients pretransplant acute kidney injury and renal replacement therapy were not associated with chronic kidney disease. Only failure to recover renal function, as evidenced by eGFR at 1-month posttransplant, was a predictive factor. Despite marked differences in the perioperative clinical condition of patients transplanted for ALF and CLD long-term renal outcome following transplantation was the same.

The rate of chronic kidney disease after transplantation for ALF was similar to that reported by Aberg et al., the single other publication of renal function in this setting (25). Although half of our patients fulfilled the criteria for acute kidney injury pretransplant, and more than 60% required renal replacement therapy during the immediate postoperative period, only 21% had an eGFR less than 60mL/min/1.73 m2 12 months thereafter. This dramatic renal recovery echoes clinical observations in spontaneous survivors of ALF. By 5-years posttransplant the cumulative incidence of chronic kidney disease was 42%.

The identical posttransplant renal function of ALF and CLD patients was unexpected when considering our current understanding of the underlying mechanisms (11–14,26). Based on the traditional hypothesis of hepatorenal syndrome one might predict that severe perioperative renal vasoconstriction would exacerbate calcineurin-inhibitor mediated kidney dysfunction (11–14,26). Cyclosporine and tacrolimus cause an initially hemodynamic dose-dependent renal impairment that is feasibly exaggerated in patients with greater baseline circulatory and neuro-humoral derangement (11–14). Our results support an alternative patho-physiological process underlying the renal injury that occurs in ALF.

We have previously demonstrated that SIRS predicts the development of acute kidney injury in patients with nonacetaminophen-induced ALF, a relationship that appears to be independent of the severity of liver injury (1). Consequently, we have postulated that the renal dysfunction of sepsis may be a more accurate parallel than the hepatorenal syndrome of cirrhosis (1). In fulminant hepatic failure the systemic inflammatory response may be the key mediator of renal impairment. Patients with subfulminant ALF are more likely to have clinically significant portal hypertension, and may develop ascites (27). Therefore, this group may share some of the hemodynamic and neuro-humoral features of hepatorenal syndrome (1). In sepsis, kidney injury may occur in the setting of preserved or even increased renal perfusion, which is in contrast to the intense renal vasoconstriction of hepatorenal syndrome (26,28). We propose that relative renal hyperemia may help to minimize the renal hemodynamic response to calcineurin inhibitors and explain the comparable long-term posttransplant renal function demonstrated by ALF patients (14).

Alternatively, the failure of perioperative renal dysfunction to impact on long-term posttransplant renal outcomes may reflect the duration of renal impairment. In patients transplanted for CLD renal dysfunction duration appears to be a key determinant of chronic renal impairment. Campbell et al. demonstrated that renal dysfunction duration of greater than 3.6 weeks pretransplant was an appropriate cut-off to identify patients at risk of renal insufficiency 12-months thereafter (29). In our cohort the renal injury, although more severe, was on the contrary short-lived.

In the nontransplant population acute kidney injury is a risk factor for chronic renal dysfunction. For example, in patients who undergo major vascular surgery the occurrence of perioperative acute kidney injury is associated with an increased risk of chronic kidney disease (30). Furthermore, patients requiring dialysis for acute kidney injury who are dialysis-independent at the time of hospital discharge are three times more likely to develop end-stage renal failure (31). Animal studies have confirmed that acute kidney injury can cause permanent structural kidney damage with progressive tubulo-interstitial fibrosis and long-term implications for renal function (32). Our failure to show a relationship between perioperative renal dysfunction and posttransplant chronic kidney disease is not in accordance with these observations. Acute kidney injury is an independent predictor of mortality in patients with ALF, and following transplantation for ALF (1). Yet, our findings suggest that beyond hospital discharge acute renal impairment, if short-lived, does not impact particularly on chronic renal function.

Acetaminophen as the cause of ALF was associated with a higher absolute eGFR at 12-months following transplantation and a reduced risk of chronic kidney disease. Acetaminophen is an independent predictor of acute kidney injury in patients with ALF and there are case reports of renal failure following acetaminophen overdose in the absence of significant hepatic injury (1,33,34). Animal models support a direct nephrotoxic effect although the mechanism remains unclear (33). It has been hypothesized that a locally produced metabolite induces proximal tubular cell necrosis while functional renal effects may also contribute (33,35,36). Our findings support the reversibility of acetaminophen-induced nephrotoxicity (37,38).

The study has some potential limitations that should be mentioned. First, baseline renal function was only available in a small number of ALF patients and it is possible that a proportion could have had undiagnosed intrinsic renal disease. The patients studied were of a relatively young age and it is assumed that premorbid renal function was normal. Second, nephrotoxic medications could have influenced the severity of perioperative renal dysfunction. Our unit avoids nephrotoxic drugs, yet this does not preclude exposure prior to transfer. Third, although our study consists of one of the largest single center cohorts of patients transplanted for ALF it remains possible that the relatively small numbers may have influenced our results.

With regards the CLD group, only 70% of the ALF patients could be matched because of the young age range. Furthermore, the pretransplant eGFR was only available at the time of listing and not immediately prior to transplantation. Pretransplant kidney function may, therefore, have been over represented in the CLD patients if there was a significant deterioration on the list. Nevertheless, no CLD patient required preoperative renal replacement therapy or reassessment for combined liver–kidney transplantation and, given the relatively short median waiting-list time of 52 days, it seems unlikely that this data would have influenced the results. The lack of pretransplant renal impairment in the control arm may also raise some concerns about its generalizability for a standard population of liver transplant recipients. This largely reflects the younger age of the patients. However, those with intrinsic renal disease or who received a simultaneous liver–kidney transplant were also deliberately excluded; we wished to examine whether the physiological differences between ALF and CLD would influence renal outcomes. Of course, it is well recognized that eGFR is not an accurate measure of renal function in patients listed for elective liver transplantation, tending to overestimate when the true GFR is reduced (39). Sixty percent of the CLD patients had ascites and one-third had hyponatraemia, indicating a high prevalence of portal hypertensive-related renal impairment (40). Finally, it is difficult to ensure retrospectively that ALF and CLD patients received similar immunosuppressive regimes. However, during the period studied our unit had a single protocol that was rarely deviated from with calcineurin inhibitor administration within 24 h of transplantation. The similar posttransplant calcineurin inhibitor trough levels support this claim.

The findings of our study have important implications for patient management. Patients who undergo liver transplantation for ALF should not be considered a high-risk group for developing chronic kidney disease even when perioperative acute renal impairment is severe. Consequently, we do not support the routine use of interleukin-2 receptor antagonists and delayed introduction of the calcineurin inhibitor in this setting (18). Renal sparing immunosuppression such as mycophenolate and reduced dose tacrolimus could be considered in select patients, for example older females transplanted for nonacetaminophen-induced ALF (41).

In conclusion, in this large single-center study of patients transplanted for ALF we have shown that the severity of perioperative renal dysfunction was not predictive of posttransplant chronic kidney disease. Despite greater perioperative physiological derangement in ALF patients when compared with an age–sex-matched cohort transplanted for CLD renal function following transplantation was the same.

Disclosure

  1. Top of page
  2. Abstract
  3. Methods
  4. Results
  5. Discussion
  6. Disclosure
  7. References

The authors of this manuscript have no conflicts of interest to disclose as described by the American Journal of Transplantation.

References

  1. Top of page
  2. Abstract
  3. Methods
  4. Results
  5. Discussion
  6. Disclosure
  7. References