Abstract
Background. Acute renal failure (ARF) is a common complication after liver transplantation (LTx). Identification of risk factors may prevent the development and attenuate the impact of ARF on patients outcome after LTX. Methods. Retrospective analysis of variables in the pre, intra, and postoperative periods of 92 patients submitted to LTx was performed in order to identify risk factors for development of ARF after LTx. ARF was defined as serum creatinine ≥2.0 mg/dL in the first 30 days after LTx. Univariate and multivariate analysis by logistic regression were performed. Results. ARF group comprised 56 patients (61%). Preoperative serum creatinine was higher in ARF group. During the intraoperative period, ARF group required more blood transfusions, developed more episodes of hypotension and presented longer anesthesia time. In the postoperative period, ARF group presented higher serum bilirubin and more episodes of hypotension. Dialysis was required in 10 patients (11%). The identified risk factors for development of ARF were: preoperative serum creatinine >1.0 mg/dL, more than five blood transfusions in the intraoperative period, hypotension during intra and postoperative periods. The identified mortality risk factors were hypotension in the postoperative period and no recovery of renal function after 30 days. Conclusions. Several factors are involved in the pathogenesis of ARF after LTx and may influence patients outcome and mortality. Pretransplant renal function and hemodynamic conditions in the operative and postoperative periods were identified as risk factors for development of ARF after LTx. Nonrenal function recovery and postoperative hypotension were identified as mortality risk factors after LTx.
Introduction
Liver transplantation (LTx) has become the standard treatment for patients with end-stage liver disease. Acute renal failure (ARF) is one of the most common complications affecting around 50% of LTx patients.Citation[[1]], Citation[[2]] Impaired preoperative and postoperative renal function reduce patient survival after LTx, especially in those patients requiring dialysis.Citation[[3]], Citation[[4]], Citation[[5]] Nonetheless, previous renal dysfunction should not be viewed as contraindication for LTx.Citation[[1]]
Renal dysfunction after LTx is multifactorial. Several preoperative, intraoperative, and postoperative patient conditions are determinant for renal function after LTx, such as baseline renal function, hemodynamic status, use of immunosuppressive or nephrotoxic drugs, graft dysfunction, and sepsis.Citation[[6]] Therefore, identification of potential risk factors for development of ARF may attenuate the impact of renal dysfunction on patient outcome after LTx. Therefore the aim of this study was to identify risk factors for development of ARF in the first 30 days after LTx.
Patients and Methods
A retrospective analysis included 92 patients submitted to first liver transplant in the period between January/1996 and December/1997 at University of Sao Paulo School of Medicine, Brazil. ARF was defined as a serum creatinine ≥2.0 mg/dL in the first 30 days after LTx. Accordingly, patients were divided in ARF and nonARF group. Recovery of renal function was characterized by serum creatinine <2.0 mg/dL after 30 days of ARF diagnosis.
Several variables in the preoperative, intraoperative, and early postoperative periods were analyzed. The preoperative parameters were: gender, age, serum creatinine (mg/dL), blood urea (mg/dL), sodium (mEq/L), potassium (mEq/L), serum albumin (g/dL), total bilirubin (mg/dL), history of ascites, encephalopathy, and esophagogastric variceal bleeding. The intraoperative factors were: surgical, anesthesia, and graft cold ischemic time (hours); diuresis (mL), blood and/or plasma transfusions (units), hypotension (mean arterial pressure below 60 mmHg), and surgical procedure of LTx (use of venovenous bypass or “piggyback” technique). The postoperative variables included: hypotension episodes during the first week, serum creatinine, blood urea, bilirubin, diuresis, use of cyclosporin A, episodes of rejection (biopsy proven), infections, and retransplantation.
Triple drug immunosuppression (cyclosporin A, azathioprine, and prednisone) was administered. Rejection episodes were treated with methylprednisolone (1 g/day/3 days) and OKT3 monoclonal antibody treatment if necessary.
Statistical analysis was performed using Student t test, chi-square, and Mann–Whitney test when appropriate. Identification of risk factors for development of ARF was performed by using multivariate analysis by logistic regression. Data are expressed as mean ± standard deviation (SD). Odds ratio (OR) and 95% confidence interval (CI) were obtained by logistic regression. Statistical significance was considered when P<0.05.
Results
Fifty-six out of 92 patients (61%) developed ARF during the first 30 days after LTx (ARF group). ARF patients presented higher preoperative serum urea, creatinine, and potassium compared with nonARF group (P<0.05). There was no difference between groups regarding gender, age, serum levels of sodium, albumin and bilirubin, history of ascites, encephalopathy or esophagogastric variceal bleeding in the preoperative period (). The most common causes of hepatic failure were hepatitis C (35%), alcoholic cirrhosis (16%), cryptogenic cirrhosis (6.5%), familial amyloid polyneuropathy (6.5%), hepatitis B, (4%), and others (32%).
Table 1. Preoperative variables in ARF and nonARF groups after LTx
During the intraoperative period, ARF group presented longer anesthesia time, developed more episodes of hypotension and needed more blood transfusions than patients without ARF. No difference between these two groups was observed regarding surgical and graft cold ischemia time, diuresis, requirement of plasma, platelets or cryoprecipitate transfusions, and venovenous bypass use in the intraoperative period ().
Table 2. Intraoperative variables in ARF and nonARF group after LTx
Patients with ARF developed more episodes of hypotension during the first week post LTx and presented higher serum bilirubin in the 5th day after LT (onset of ARF). The mean serum level of cyclosporin A (CyA) in the 5th day after LT was similar in both groups (270 ± 145 vs. 271 ± 117 µg/mL, NS) but the proportion of patients receiving CyA was lower in ARF group (39% vs. 83%, P<0.001). The occurrence of infections, transplant rejection, and retransplants were not different between the two groups (). Oliguria was observed in 8 patients while 36 patients were nonoliguric and 1 patient was anuric at the time of diagnosis of ARF (data not available in 11 patients). Hemodialysis was required in 10 patients (11%). Dialysis indications were hypervolemia (5 patients), uremia (1 patient), and both in 4 patients. Employed dialysis modalities were slow continuous ultrafiltration (1 patient) and continuous venovenous hemodialysis (9 patients). After 30 days of ARF, recovery of renal function was observed in 32 patients (57%).
Table 3. Postoperative variables in ARF and nonARF group after LTx
Mortality rate during the entire follow-up (3 to 27 months) was 8.3% in the non-ARF group, 9.4% in ARF patients with renal function recovery and 47.8% in ARF patients who did not recover renal function. During the first 30 days after LTx mortality rate was similar between ARF and nonARF group (12.5% and 5.5%, NS) whereas in patients submitted to dialysis mortality rate was 30%.
As risk factors for development of ARF, the following parameters were identified: preoperative serum creatinine higher than 1.0 mg/dL, transfusion of more than five red blood cell packs in the intraoperative and hypotension in the intraoperative and postoperative periods (). The identified risk factors for death after LTx were: hypotension in the postoperative and no recovery of renal function after 30 days of diagnosis of ARF ().
Table 4. Risk factors for development of ARF after LTx
Table 5. Risk factors for mortality after LTx
Discussion
Development of ARF is a serious and early complication after LTx. The absence of universal criteria for definition of ARF after LTx has made inter-center comparisons difficult in the literature. The incidence of renal dysfunction may vary from 25 to 70%, according to the employed definition of ARF.Citation[[7]], Citation[[8]], Citation[[9]] In this study, a 61% incidence of ARF after LTx was observed. Renal insufficiency was usually diagnosed in the fifth day after LTx. In some patients, ARF was observed only during the second or third week after LTx. The etiology of ARF after LTx is multifactorial, involving preoperative, intraoperative, and postoperative variables such as previous renal function, hemodynamic status, immunosuppressive drugs, graft dysfunction, sepsis, and nephrotoxic drugs.Citation[[3]], Citation[[6]], Citation[[7]], Citation[[8]], Citation[[10]]
Preoperative renal insufficiency is usually considered as risk factor for development of ARF after LTx and as a mortality risk factor in several studies.Citation[[4]], Citation[[11]], Citation[[12]], Citation[[13]] Although, Gonwa et al. have shown that pre-transplant renal dysfunction, other than hepatorenal syndrome had no effect on patient survival after LTx.Citation[[14]] In the present study, patients who developed ARF after LTx presented higher levels of serum creatinine, urea, and potassium in the preoperative period. However, by logistic regression analysis, only serum creatinine higher than 1.0 mg/dL was associated with development of ARF after LTx. Similarly, Lafayette et al.Citation[[4]] analyzed the effect of pre-transplant renal function on patient outcome and they have shown that serum creatinine above 1.0 mg/dL was the strongest predictor for ARF and death after LTx. In cirrhotic patients, serum creatinine is not the best marker of glomerular filtration rate (GFR), since it is often low because of poor nutritional status and decreased muscle mass. BUN or serum urea levels are also used to assess GFR in cirrhotic patients, but they are also unreliable as GFR measurements. BUN and serum urea are reduced due to low dietary intake, impaired hepatic synthesis, or serum levels may be elevated because of gastrointestinal bleeding and/or increased catabolism. Therefore, renal preoperative evaluation is problematic and clearance studies (inulin or radionuclide) may be necessary for an accurate evaluation.
Etiology of renal dysfunction post LTx varies according to the period of transplantation. Renal dysfunction in the immediate postoperative period is often related to intraoperative hemodynamic conditions, delayed liver function, inadequate fluid replacement, and/or drug nephrotoxicity. Several factors can lead to hemodynamic instability during LTx, such as blood loss due to hemorrhage during surgical procedure or coagulation disturbances and hypotension after graft reperfusion.Citation[[15]], Citation[[16]] In this study, ARF patients presented more episodes of hypotension, required more blood transfusions and had longer anesthesia time compared with patients in the nonARF group. These data were confirmed by multivariate analysis, in which intraoperative hypotension and transfusion of more than five units of blood packs were identified as risk factors for the development of ARF after LTx.
Use of venovenous bypass (VVBP) or preservation of recipient inferior vena cava (“piggyback” technique) are surgical technical modifications that were introduced to reduce hemodynamic instability during LTx. VVBP allows blood return from inferior vena cava and portal vein territories to superior vena cava, attenuating hemodynamic disturbances caused by clamping of those vessels during the anhepatic phase of LTx. Grande et al.,Citation[[17]] in a prospective controlled study, observed no relationship between development of severe postoperative renal failure and use of VVBP. In the “piggyback” technique, venous return is maintained since the inferior vena cava is not cross-clamped. Thus, in this situation kidneys are better preserved because of sustained renal venous outflow.Citation[[18]] Recent prospective trial comparing VVBP with “piggyback” technique for support of LTx demonstrated that patients in the VVBP group presented a 31% incidence early postoperative renal dysfunction vs. 0% for those supported by the latter technique.Citation[[19]] However, no relationship was identified between the technical procedure and postoperative ARF in this study.
Cyclosporine has been considered one of the most potential harmful drugs in the early postoperative period.Citation[[4]], Citation[[8]], Citation[[10]] The number of patients in the ARF group using CyA was lower compared with the nonARF group (39% vs. 81%, P<0.001) at the 5th postoperative day (initiation of ARF). This low frequency may have occurred because CyA administration was suspended when serum creatinine started to rise.
Patients who require dialysis after LTx usually present an increased mortality rate.Citation[[3]], Citation[[5]] In our study, dialysis was required in 11% of patients after LTx. These patients also presented higher mortality rate (30%) compared with nondialysis ARF patients (12.5%) and nonARF patients (5.5%) in the first 30 days after LTx. Contreras et al. have recently shown that patients who required dialysis during the first week after LTx (11%) also presented elevated hospital mortality and need of early dialysis was related to preoperative renal dysfunction.Citation[[20]]
Finally, despite of the retrospective nature of the present study, a reasonable number of patients was enrolled allowing a multivariate analysis by logistic regression to be performed which identified risk and mortality risk factors (Tables and ) for the development of ARF after LTx. Identification of these risk factors may help clinicians in the management of LTx patients in order to reduce morbidity and mortality.
In conclusion, ARF is a common complication after LTx. Several factors during the preoperative period are involved in the development of ARF and may decisively influence patient outcome and mortality. Pre-transplant renal function and hemodynamic conditions in the operative and postoperative periods were identified as risk factors for development of ARF after LTx. Nonrenal function recovery after 30 days and postoperative hypotension were identified as mortality risk factors after LTX.
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