Long-term outcome of liver transplantation has. Independent Risk Factors and Natural History of Renal Dysfunction in Liver Transplant Recipients

Transcription

1 Independent Risk Factors and Natural History of Renal Dysfunction in Liver Transplant Recipients Attaphol Pawarode, * Derek M. Fine, and Paul J. Thuluvath * Renal dysfunction is common after liver transplantation. However, there are only limited data on the predictors and natural history of renal dysfunction after liver transplantation. In this study, we determined independent predictors and the natural history of renal dysfunction in 172 consecutive liver transplant recipients. Survival and time to development of permanent renal dysfunction (renal dysfunction defined as a sustained decrease in estimated glomerular filtration rate (GFR) of > 30 ml/min/1.73 m 2 from baseline for at least 6 months, severe renal failure defined as absolute GFR <30 ml/min/1.73 m 2 for at least 6 months) were determined using the Kaplan-Meier method. Cox regression analysis was used to test the independent effect of a given set of variables on time to development of such an event. Nine percent of patients required immediate dialysis, 35% developed permanent renal dysfunction, and 7% developed severe renal failure. The rate of decline in renal dysfunction was maximal, 6.5 ml/min/1.73 m 2 /mo, at 1 month after liver transplantation. Pre-existing diabetes mellitus, major surgical infection, and waiting time on the transplant list were independent risk factors for immediate dialysis. Presence of serum creatinine > 1.2 mg/dl at any time before liver transplantation and a baseline GFR <70 ml/min/1.73 m 2 were independent predictors of permanent renal dysfunction. Diabetes mellitus, coronary artery disease, and primary graft nonfunction predicted the development of severe renal failure. GFR stabilized around 9 months, and presence of decreased GFR > 30mL/min/1.73 m 2 from baseline at 9 months predicted development of permanent renal dysfunction. An absolute GFR of <30mL/min/1.73 m 2 occurring as early as 3 months after liver transplantation predicted severe renal failure. Severe renal failure was associated with a significantly lower survival by Cox regression analysis. We have identified risk factors and the natural history of permanent renal dysfunction and severe liver failure in liver transplant recipients. These observations may be useful in the development of nonnephrotoxic immunosuppressive regimens for high-risk liver transplant recipients. (Liver Transpl 2003;9: ) Long-term outcome of liver transplantation has improved over the past 2 decades because of better surgical experience, with the introduction of calcineurin inhibitors, and more importantly, because of better selection criteria. However, about 10% to 20% of long-term survivors develop permanent renal dysfunction or failure, which has been attributed to a number of factors, including the use of calcineurin inhibitors. 1,2 A significant proportion (range, 5% to 50%) of liver transplantation procedures is complicated by acute renal failure in the immediate postoperative period, with more frequent occurrence in those who have hepatorenal syndrome at the time of liver transplantation. 3-8 In the subgroup of patients who develop acute renal failure and survive, 80% to 90% regain some degree of renal function, whereas the rest develop permanent renal dysfunction or failure. 5,9 Although there have been many studies that have examined the overall prevalence of renal dysfunction, there are only limited data on the predictive risk factors and the natural history of renal dysfunction in liver transplant recipients. 1,2,10 We believe that additional information will be useful in developing strategies for preventing the development or progression of renal dysfunction in liver transplant recipients, especially because of the current availability of nonnephrotoxic immunosuppressive drugs. In this retrospective study, we determined the independent predictors and natural course of posttransplantation renal dysfunction in a cohort of patients who underwent liver transplantation at our institution. Patients and Methods We reviewed the medical records of 172 patients who underwent liver transplantation at our institution during the period from January 1994 to December 2000 and recorded data on demographics, pretransplantation and serial posttransplantation serum creatinine levels, and potential pretransplantation and posttransplantation variables that could influence renal function. We collected and analyzed data on the following potential risk factors of renal dysfunction: sex, race, age, ABO blood type, waiting time, etiology of liver disease (hepatitis B virus, hepatitis C virus, alcohol, primary sclerosing cholangitis, autoimmune disorders, and cryptogenic cirrhosis), United Network for Organ Sharing status, number of transplantations, pretransplantation comorbidity (diabetes mellitus [DM], hypertension, coronary artery disease [CAD]), From the *Division of Gastroenterology and Hepatology, and Nephrology, The Johns Hopkins University School of Medicine, Baltimore, MD. Address reprint requests to Paul J Thuluvath, MD, FRCP, Division of Gastroenterology and Hepatology, The Johns Hopkins University School of Medicine, 1830 E Monument St, Room 429, Baltimore, MD Telephone: ; FAX: ; pjthuluv@mail.jhmi.edu Copyright 2003 by the American Association for the Study of Liver Diseases /03/ $30.00/0 doi: /jlts Liver Transplantation, Vol 9, No 7 ( July), 2003: pp

2 742 Pawarode, Fine, and Thuluvath Table 1. Demographics of Transplant Recipients Characteristics Percent Male 62 Caucasian/black/other 77.0 / 18.4 / 4.6 Number of transplantations: 1/ / 11.0 United Network for Organ Sharing status: 1/2a/2b/ / 21.4 / 60.7 / 5.7 Donor types: cadaver/living 88.3 / 11.7 Pre-TX diabetes mellitus 29.7 Pre-TX hypertension 17.4 Pre-TX coronary artery disease 5.8 Abbreviations: Pre-TX, pretransplantation. peripheral vascular disease, hypercholesterolemia), encephalopathy, ascites, regrafting, baseline glomerular filtration rate (GFR), pre-existing renal disease (hepatorenal syndrome, presence of serum creatinine 1.2 mg/dl at any time before transplantation), preoperative and intraoperative nephrotoxic agent exposure, surgical trauma, intraoperative profound shock, other intraoperative and postoperative complications, number of posttransplantation nephrotoxic agent(s) exposure, primary graft nonfunction, graft failure, rejection episodes, and immunosuppressive regimens. We used the following defintions for the potential risk factors. Presence of DM was diagnosed if patients had symptoms and had a random blood glucose concentration 200 mg/dl or if fasting plasma glucose was 126 mg/dl on at least two separate measurements. Hypertension was defined as the presence of elevated systolic blood pressure of either 140 mm Hg or diastolic 90 mm Hg. CAD or peripheral vascular disease was present if the patient had clinical manifestations with or without imaging studies, and hypercholesterolemia was present if the serum total cholesterol was 200 mg/dl on at least two separate measurements. The potential nephrotoxic agents that we included were calcineurin inhibitors, aminoglycosides, amphotericin B, nonsteroidal anti-inflammatory drugs and other less common nephrotoxic agents. Major surgical infection was defined as intra-abdominal abscess or wound infection that required extensive debridement. GFR was estimated by a simplified version of the Modification of Diet in Renal Disease Study prediction equation (GFR 186 Plasma creatinine age [if black] [if female]). 11,12 Permanent renal dysfunction was defined as a persistent decrease in median GFR of more than 30 ml/min/1.73 m 2 from baseline for at least 6 months. The need for immediate posttransplantation dialysis was defined as the need for dialysis within 1 month after liver transplantation in those who were not on pretransplantation dialysis. Severe renal failure was defined as the presence of median GFR 30 ml/min/1.73 m 2 for at least 6 months or the need for long-term dialysis for patients without pretransplantation dialysis. Patients who died within a 6-month posttransplantation period and those who had combined liver kidney transplantation were excluded from renal function analysis. Statistical Analysis Time to renal dysfunction and patient survival were calculated according to the Kaplan-Meier method, and comparisons were made by log-rank test. The Kaplan Meier method or 2 test was used as appropriate to identify potential variables for inclusion in the multivariate models. Cox regression survival analysis was performed to adjust survival for confounding risk factors. We excluded from the analysis patients whose renal functions were maintained by renal replacement therapies and patients who died within a 6-month posttransplantation period. A Cox regression analysis was used to evaluate the effect of a given set of independent and dependent variables on the development of renal dysfunction. Dependent variables, including presence of more than a 30mL/min/ 1.73 m 2 decrease in GFR at various postoperative periods, were tested separately from independent variables. Risk factors for the need for immediate dialysis were analyzed using a logistic regression model. All analyses were performed using the SPSS statistical package (SPSS, Inc, Chicago, IL). All reported P values are two-sided. Results The patient demographics are shown in Table 1. The median age was 52.2 years (range, 15.4 to 68.2 years), median duration of follow-up was 72.4 months (range, 6.5 to months), and mean posttransplantation survival was 90.4 months (95% confidence interval (CI), 84.6 to 96.2 months). Baseline renal function is shown in Table 2. The median baseline GFR was 80.3 ml/min/1.73 m 2. A summary of intraoperative and Table 2. Baseline Renal Function of Transplant Recipients Percent Pretransplantation glomerular filtration rate* or dialysis 11.0 Pretransplantation renal replacement therapy None 94.1 Hemodialysis 3.3 Continuous venovenous hemodialysis 2.6 Pretransplantation hepatorenal syndrome 5.4 Pretransplantation nephrotoxic agent(s) exposure 22.8 *ml/min Within 3 months before liver transplantation.

3 Independent Risk Factors and Natural History of Renal Dysfunction 743 Table 3. Summary of Complications, Drugs, and Outcome Characteristics Percent Surgical complications 3.2 Intraoperative shock requiring aggressive resuscitation 10.7 Intraoperative nephrotoxic agent(s) exposure 5.0 Overall graft failure 12.9 Primary graft nonfunction 8.7 Acute rejection 46.4 Immediate postoperative dialysis 16.1 New-onset chronic dialysis 6.8 Immunosuppression Cyclosporin-based 20.2 Tacrolimus-based 50.4 Tacrolimus and Mycophenolate Mofetil 27.1 Cyclosporin and Mycophenolate Mofetil or others 2.4 Status dead 22.6 posttransplantation complications, nephrotoxic drug exposure(s), and clinical course is shown in Table 3. Thirty-five percent (54 of 154) of patients who survived at least 6 months or more developed permanent renal dysfunction, with a 5-year cumulative incidence of 41% (Fig. 1A). Nine percent (15 of 172) of patients required immediate postoperative dialysis. Seven percent (11 of 154) of patients developed severe renal failure, with a 5-year cumulative incidence of 8% (Fig. 1B). Of the 11 patients who developed severe renal failure, 9 patients survived 6 months or longer. Two (2 of 9) of these patients required chronic dialysis, and in one them, severe renal failure developed 6 months after liver transplantation. The maximal median rate of progression of renal dysfunction occurred at 1 month after transplantion at 6.5 ml/min/1.73m 2 /mo (range, 31.2 to 37.2 ml/min/1.73m 2 /mo) (Fig. 2). The mean time to permanent renal dysfunction and severe renal failure was 42.4 months (95% CI, 36.6 to 48.1 months) and 88.7 months (95% CI, 84.1 to 93.9 months), respectively. Median time, which seems to be longer than mean time, could not be computed because fewer than 50% of the patients were estimated to develop these events by 100 months of follow-up. Of the 42 potential risk factors that were tested, serum creatinine 1.2 mg/dl at any time before transplantation (P.029) and baseline GFR (P.001) were independent prognostic factors for the development of permanent renal dysfunction (Table 4). Presence of a decrease in posttransplantation GFR of 30 ml/min/1.73 m 2 from baseline at 9 months was a significant predictor for the development of permanent renal dysfunction (P.001). Pre-existing DM (P.035), major surgical infection (P.011), and waiting time on the transplantation list (P.019) were independent predictors for the need for immediate (within 1 month) posttransplantation dialysis. DM (P.016), CAD (P.004), and primary graft nonfunction (P.005) independently predicted the need for chronic dialysis (Table 4). Presence of an absolute decrease in GFR to below 30 ml/min/1.73 m 2 at 3 months after transplantation predicted the development of severe renal failure. According to the estimated relative risk(e ), a Figure 1. (A) Actuarial cumulative incidence of permanent renal dysfunction (defined as decrease in glomerular filtration rate > 30 ml/min/1.73 m 2 from baseline). (B) Actuarial cumulative incidence of severe renal failure (glomerular filtration rate <30 ml/min/1.73 m 2 ).

4 744 Pawarode, Fine, and Thuluvath Figure 2. (A) Rate of decrease in posttransplantation glomerular filtration rate. Maximal decline was seen within 1 month after transplantation. (B) Decline in median glomerular filtration rate after liver transplantation. patient with DM was eight times (eight-fold increase) as likely to develop severe renal failure and four times (four-fold increase) more likely to require immediate dialysis compared with those without DM. Similarly, patients with CAD had 16-fold higher risk of developing severe renal failure compared with those without CAD. A patient with a history of elevated serum creatinine (creatinine 1.2 mg/dl at any time before transplantation) or a baseline GFR 70 ml/min/1.73 m 2 was associated with a three-fold or 12-fold increased Table 4. Independent Predictors by Multivariate Analyses Variable Risk (95% Confidence Interval) P Value Renal dysfunction Independent History of renal insufficiency HR 3.2 ( ).029 Baseline GFR 70 HR 12.7 ( ).001 Dependent Decrease in GFR 30 ml/min/1.73 m 2 * At month At month At month At month 9 HR 12.1 ( ).001 Immediate dialysis Diabetes mellitus OR 3.8 ( ).035 Major surgical infection OR 5.1 ( ).011 Waiting time (in months) OR 1.06 ( ).019 Severe renal failure Independent Diabetes mellitus HR 8.0 ( ).016 Coronary artery disease HR 15.7 ( ).004 Primary nonfunction HR 64.4 ( ).005 Dependent Absolute GFR 30 ml/min/1.73 m 2 At month At month 3 HR 22.0 ( ).030 Abbreviations: HR, hazard ratio; GFR, glomeral filtration rate; OR, odds ratio. *Decrease in glomerular filtration rate 30 ml/min/1.73 m 2 from baseline. By logistic regression analysis, and others by Cox regression analysis.

5 Independent Risk Factors and Natural History of Renal Dysfunction 745 Figure 3. Cox regression survival in patients with (broken line) and without (unbroken line) severe renal failure after adjusting for other independent variables. Patients who survived longer than 6 months are not included in this analysis. risk respectively of developing permanent renal dysfunction than one without such risk factors. A patient with renal dysfunction at posttransplantation month 9 had a 16-fold greater chance of developing permanent renal dysfunction than one without renal dysfunction, after adjusting for the other factors in the model (P.0005). Similarly, an absolute decrease in GFR below 30 ml/min/1.73 m 2 at posttransplantation month 3 was associated with the development of permanent severe renal failure requiring chronic dialysis. There was no difference in survival between patients who did and did not develop permanent renal dysfunction; however, patients with severe renal failure had a significantly shorter survival after adjusting (Cox regression) for other independent variables (P.004, Fig. 3). Discussion In this study, we have shown that renal dysfunction is common in liver transplant recipients and have identified potential risk factors, other than calcineurin inhibitors, that predicted the need for immediate dialysis and the development of renal dysfunction or severe renal failure. We have also shown that most patients who develop renal dysfunction and failure can be identified within 1 year after liver transplantation. In addition, our study confirmed that posttransplantation renal failure was associated with a poor survival even after adjusting for other confounding risk factors. Previous studies have also reported significant renal dysfunction in liver transplant recipients and long-term survivors. In one study, the median estimated creatinine clearance was 54 ml/min/1.73 m 2 before transplantation and only 28 ml/min/1.73 m 2 at the last follow-up visit (13). In another study, about 8.6% and 9.5% of patients who survived more than 6 months developed chronic renal failure (sustained serum creatinine 2.5 mg/dl) and end-stage renal disease, respectively. 14 In a retrospective study, Cohen et al reported that 27.5% of patients had severe renal dysfunction (measured GFR 40 ml/min/1.73 m 2 ) at 5 years, with a cumulative incidence of end-stage renal disease of 6.25% at 7 years and 10% at 10 years. 10 In our study, 41% and 8% developed renal dysfunction and severe renal failure at 5 years, respectively, and 9% required immediate dialysis. We probably have underestimated the risk of renal dysfunction and severe renal failure because we excluded patients who survived fewer than 6 months from our analysis. There are many factors, including increased bile acids, endotoxins, circulating immune complexes and various cytokines, nephrotoxic drugs, and hitherto unrecognized factors that predispose patients with cirrhosis to renal dysfunction and hepatorenal syndrome. 1,15-21 Some of these factors may also play a role in the progression of renal disease after liver transplantation. 1,22,23 Previous studies have attempted to identify risk factors for the development of posttransplantation renal failure. The Pittsburgh group found that posttransplantation alcohol use and DM were independent predictors of late-onset renal failure, especially in patients with hepatitis C virus. 24 In our study, we have identified risk factors that independently predicted the need for immediate dialysis and the development of permanent renal dysfunction and severe renal failure after liver transplantation. A documented history of renal insufficiency (creatinine 1.2 mg/dl) or a baseline GFR 70 ml/min/1.73 m 2 predicted the development of permanent renal dysfunction as we have defined it. DM, CAD, and primary graft nonfunction predicted the development of chronic renal failure. From these observations, it seems that susceptible patients with microvascular disease (DM, CAD) are more likely to develop renal failure. It is possible that many of these patients may have had unrecognized pre-existing renal disease that progressed with time after liver transplantation. Currently, there is no gold standard for determining renal function in patients with advanced liver disease. Although directly measured GFR would be optimal, it is difficult to obtain a baseline GFR by this method because the waiting period for receiving cadaver transplantation is unpredictable.

6 746 Pawarode, Fine, and Thuluvath Another possibility is that the susceptible subjects are more prone to renal failure because of surgical complications or because of the nephrotoxicity of calcineurin inhibitors. We could not test the independent effect of calcineurin inhibitors because all of our patients were on either cyclosporine or tacrolimus. The prevalence of renal dysfunction was equally common in patients who received tacrolimus or cyclosporine. Although we can only speculate on the pathogenesis of renal dysfunction and failure, we believe that our findings are important because we may be able to tailor the immunosuppressive regimen to reduce nephrotoxicity in patients with these risk factors. We have shown that the majority of patients who develop permanent renal dysfunction can be identified at 9 months after transplantation. Gonwa et al 14 showed that postoperative creatinine level at 4 weeks, 3 months, and 1 year, but not preoperative ones, were independent predictors for chronic renal failure and end-stage renal disease. However, unlike in our study, they did not find any relationship between pretransplantation serum creatinine level and posttransplantation renal failure. Another recent study had also reported that pretransplantation GFR (measured) was not a predictor of posttransplantation renal failure. 10 Although measured GFR is definitely superior to estimated GFR, in their study, the baseline GFR was done at the time of listing and not any time close to liver transplantation. Because there is considerable delay, which may range from months to many years, between listing and transplantation (waiting period), the relevance of their observation is questionable. Nevertheless, these investigators as well as other have identified elevated 1-year serum creatinine levels as a risk factor for chronic renal dysfunction and failure. 10,14,25 These observations along with our findings are useful for developing nonnephrotoxic immunosuppressive regimens or trials in liver transplant recipients who are most likely to benefit from it. In our study, the maximum rate of decline of renal function was seen within the first month after transplantation, which was possibly related to surgery or to induction therapy, which invariably included nephrotoxic drugs. Pre-existing DM, major surgical infection, and a longer waiting time on the transplant list were independent predictors for the need of immediate (within 1 month) posttransplantation dialysis. Although some of these factors are beyond our control, it is important to consider prospective trials of novel induction therapy for these high-risk subjects to reduce renal failure or the need for immediate dialysis. This is especially important in the current Model of End stage Liver Disease era, in which many patients who undergo transplantation have pre-existing renal insufficiency. Pretransplantation renal failure has been shown to decrease the survival of liver transplant recipients 26 and to predict the risk of posttransplantation renal failure and infection. 3,6-9,24-31 In this study, patients who developed severe renal failure after transplantation had a significantly shorter survival compared with those without, even after adjusting for other confounding variables such as DM and CAD. These findings underscore the importance of preventing severe renal failure in liver transplant recipients. As we enter the third decade of successful liver transplantation, a procedure that revolutionized the management of end-stage liver disease, our focus should be changed to improving the quality of life and long-term survival of liver transplant recipients. References 1. Davis CL, Gonwa TA, Wilkinson AH. Pathophysiology of renal disease associated with liver disorder: Implications for liver transplantation: Part I. Liver Transpl 2002;8: Davis CL, Gonwa TA, Wilkinson AH. Identification of patient best suited for combined liver-kidney transplantation: Part II. Liver Transpl 2002;8: Jeyarajah GR, Gonwa TA, Mcbride M, Testa G, Abbasoglu O, Husberg BS, et al. Hepatorenal syndrome: Combined liver kidney transplantations versus isolated liver transplant. Transplantation 1997;64: Brown RS, Lombardero M, Lake JR. Outcome of patients with renal insufficiency undergoing liver or liver kidney transplantation. Transplantation 1996:62: Gonwa TA, Mai ML, Melton LB, Hays SR, Goldstein RM, Levy MF, Klintmalm GB. Renal replacement therapy (RRT) and orthotopic liver transplantation (OLTX): The role of continuous veno-venous hemodialysis (CVVHD). Transplantation 2001; 71: 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: Gonwa TA, Klintmalm G, Levy M, Jennings L, Goldstein R, Husberg B. Impact of pretransplantation renal function on survival after liver transplantation. Transplantation 1995;59: Singh N, Gayowski T, Wagener MM. Posttransplant dialysis associated morbidity and impact on outcome in liver transplant recipients. Liver Transpl 2001;7: 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: Cohen AJ, Stegall MD, Rosen CB, Wiesner RH, Leung N, Kremers WK, Zein NN. Chronic renal dysfunction late after liver transplantation. Liver Transpl 2002;8: Levey AS, Greene T, Kusek JW, Beck GJ, MDRD Study Group. A simplified equation to predict glomerular filtration rate from serum creatinine [abstract]. J Am Soc Nephrol 2000;11:155A.

7 Independent Risk Factors and Natural History of Renal Dysfunction Manjunath G, Sarnak MJ, Levey AS. Prediction equations to estimate glomerular filtration rate: An update. Curr Opin Nephrol Hypertens 2001;10: Sheiner PA, Magliocca JF, Bodian CA., Kim-Schluger L, Altaca G, Guarrera JV, et al. Long-term medical complications in patients surviving 5 years after liver transplantation. Transplantation 2000;69: Gonwa TA, Mai ML, Melton LB, Hays SR, Goldstein RM, Levy MF, Klintmalm GB. End stage renal disease (ESRD) following orthotopic liver transplantation (OLTX) utilizing calcineurin based immunotherapy: Risk of development and treatment. Transplantation 2001;72: Sakisaka S, Koga H, Sasatomi K, Mimura Y, Kawaguchi T, Tanikawa K. Biliary secretion of endotoxin and pathogenesis of primary biliary cirrhosis. Yale J Biol Med 1997;70: Yokoyama I, Gavaler JS, Todo S, Mitaya T, Van Thiel DH, Starzl TE. Endotoxemia is associated with renal dysfunction in liver transplantation recipients during the first postoperative week. Hepatogastroenterology 1995;42: Ding JW, Andersson R, Soltesz V, Willen R, Bengmark S. Obstructive jaundice impairs reticuloendothelial function and promotes bacterial translocation in the rat. J Surg Res 1994;57: Milner LS, Houser MT, Kolbeck PC, Antonson DL, McDonald TL, Markin RS, Shaw BW Jr. Glomerular injury in end-stage liver disease Role of circulating IgG and IgM immune complexes. Pediatr Nephrol 1993;7: Triger DR, Wright R. Hyperglobulinemia in liver disease. Lancet 1973;1: Feizi T. Immunoglobulins in chronic liver disease. Gut 1968;9: Thompson RA, Carter R, Stokes RP, Geddes AM, Goodall JA. Serum immunoglobulins, complement component levels and autoantibodies in liver disease. Clin Exp Immunol 1973;14: Becker GJ, Hewitson TD. The role of tubulointerstitial injury in chronic renal failure. Curr Opin Nephrol Hypertens 2000;9: Nakamura T, Obata J, Kimura H, Ohno S, Yoshida Y, Kawashi H, Shimizu F. Blocking angiotensin II ameliorates proteinuria and glomerular lesions in progressive mesangioprolifereative glomerulonephritis. Kidney Int 1999;55: Gayowski T, Singh N, Keyes L, Wanstedt CF, Wagener MM, Vargus H, Laskus T. Late-onset renal failure after liver transplantation: Role of posttransplant alcohol use. Transplantation 2000; 3: Fisher NC, Nightingale PG, Gunson BK, Lipkin GW, Neuberger JM. Chronic renal failure following liver transplantation. Transplantation 1998;66: Nair S, Verma S, Thuluvath PJ. Pretransplant renal function predicts survival in patients undergoing orthotopic liver transplantation. Hepatology 2002;35: Dimartini A, Jain A, Irish W, Fitzgerald MG, Fung J. Outcome of liver transplantation in critically ill patients with alcoholic cirrhosis: Survival according to medical variables and sobriety. Transplantation 1998;66: Lafayette RA, Pare G, Schmid CH, King AJ, Rohrer RJ, Nasraway SA. Pretransplant renal dysfunction predicts poorer outcome in liver transplantation. Clin Nephrol 1997;48: Seu P, Wilkinson AH, Shaked A, Busuttil RW. The hepatorenal syndrome in liver transplant recipients. Am Surg 1991;57: McCauley J, Van Thiel DH, Starzl TE, Puschett JB. Acute and chronic renal failure in liver transplantation. Nephron 1990;55: Rimola A, Gavaler JS, Schade RS, El-Lankany S, Starzl TE, Van Thiel DH. Effects of renal impairment on liver transplantation. Gastroenterology 1987;93: