Mical S. Campbell

Renal function after orthotopic liver transplantation is predicted by duration of pretransplantation creatinine elevation

In patients with recent onset renal insufficiency, the decision to perform combined kidney/liver transplantation (CKLT) vs. orthotopic liver transplantation alone (OLTa) can be difficult. We hypothesized that duration of renal dysfunction may correlate with creatinine elevation after liver transplantation. We retrospectively identified 69 liver transplantation patients with pretransplantation creatinine ≥1.5 mg/dL (53 OLTa, 13 CKLT). Variables analyzed were presence of hepatorenal syndrome, creatinine, Model for End‐Stage Liver Disease score, albumin, age, race, gender, cause of liver disease, diabetes mellitus, hypertension, and history of ascites, spontaneous bacterial peritonitis, variceal bleeding, hepatic encephalopathy, renal replacement therapy (RRT), and transjugular intrahepatic portosystemic shunting. Duration of pretransplantation renal dysfunction was predictive of 6‐ and 12‐month creatinine post‐OLTa. Area under the receiver operating characteristic (ROC) curve for prediction of 12‐month renal insufficiency by renal dysfunction duration was 0.71; optimal duration cutoff was 3.6 weeks. We applied a multivariable model, derived from OLTa patients, to CKLT subjects with definite or possible hepatorenal syndrome. Predicted 12‐month creatinine without renal transplantation was >2.0 mg/dL for each patient. CKLT patients as opposed to OLTa patients had longer duration of renal dysfunction (median, 18.1 vs. 2.7 weeks, P < 0.001), higher creatinine (median 4.0 versus 1.7 mg/dL, P < 0.001), and higher rate of pretransplantation RRT (62% vs. 7%, P < 0.001). Adjusting for baseline characteristics, CKLT patients had lower creatinine than OLTa patients at 6 months (P =0.15) and 12 months (P =0.01) after transplantation. In conclusion, duration, but not cause, of renal dysfunction predicts renal outcome in OLTa recipients. Prospective studies may use duration of renal dysfunction to help identify CKLT candidates. (Liver Transpl 2005;11:1048–1055.)

Screening for Wilson Disease in Acute Liver Failure: A Comparison of Currently Available Diagnostic Tests

Acute liver failure (ALF) due to Wilson disease (WD) is invariably fatal without emergency liver transplantation. Therefore, rapid diagnosis of WD should aid prompt transplant listing. To identify the best method for diagnosis of ALF due to WD (ALF‐WD), data and serum were collected from 140 ALF patients (16 with WD), 29 with other chronic liver diseases and 17 with treated chronic WD. Ceruloplasmin (Cp) was measured by both oxidase activity and nephelometry and serum copper levels by atomic absorption spectroscopy. In patients with ALF, a serum Cp <20 mg/dL by the oxidase method provided a diagnostic sensitivity of 21% and specificity of 84% while, by nephelometry, a sensitivity of 56% and specificity of 63%. Serum copper levels exceeded 200 μg/dL in all ALF‐WD patients measured (13/16), but were also elevated in non‐WD ALF. An alkaline phosphatase (AP) to total bilirubin (TB) ratio <4 yielded a sensitivity of 94%, specificity of 96%, and a likelihood ratio of 23 for diagnosing fulminant WD. In addition, an AST:ALT ratio >2.2 yielded a sensitivity of 94%, a specificity of 86%, and a likelihood ratio of 7 for diagnosing fulminant WD. Combining the tests provided a diagnostic sensitivity and specificity of 100%. Conclusion: Conventional WD testing utilizing serum ceruloplasmin and/or serum copper levels are less sensitive and specific in identifying patients with ALF‐WD than other available tests. More readily available laboratory tests including alkaline phosphatase, bilirubin and serum aminotransferases by contrast provides the most rapid and accurate method for diagnosis of ALF due to WD. (HEPATOLOGY 2008.)

A critical review of candidacy for orthotopic liver transplantation in alcoholic liver disease.

The majority of candidates with end-stage alcoholic liver disease (ESALD) in the United States who are eligible for referral for liver transplantation (LT) are not being referred. There is a lack of firm consensus for the duration of abstinence from alcohol as well as what constitutes good psychosocial criteria for listing for LT. Evidence shows that the general public and the practicing physicians outside the transplant community perceive that patients with a history of alcohol abuse will make poor transplant candidates. However, physicians in the transplant community perceive selected patients with ESALD as good candidates. When considering patients for listing for LT, 3 months of alcohol abstinence may be more ideal than 6 months. Patients with a lack of social support, active smoking, psychotic or personality disorders, or a pattern of nonadherence should be listed only with reservation. Those who have a diagnosis of alcohol abuse as opposed to alcohol dependence may make better transplant candidates. Patients who have regular appointments with a psychiatrist or psychologist in addictions treatment training also seem to do more favorably.

Transplantation : Impact of Pretransplant Renal Insufficiency

Pre–liver transplant renal dysfunction is associated with decreased survival following transplantation and is also a prognostic indicator of posttransplant chronic kidney disease. Selection of patients for combined liver/kidney transplantation versus orthotopic liver transplantation alone (OLTa) is often difficult given the lack of a reliable method to predict which patients will have ongoing severe renal dysfunction in the absence of concomitant kidney transplantation. We hypothesized that most patients with pretransplant renal dysfunction (serum creatinine ≥ 1.5 mg/dL for at least 2 weeks prior to and at time of transplant) will not experience a rapid decline in estimated glomerular filtration rates (eGF) post‐OLTa to the point of necessitating consideration for kidney transplantation, even in the setting of calcineurin inhibitor–based immunosuppression. We performed a single‐center retrospective study of 60 OLTa patients with pretransplant renal dysfunction transplanted between 2000 and 2005. Kaplan‐Meier analysis was performed of the time interval to develop eGFR < 20 mL/minute post‐OLTa. At OLTa, the mean patient age was 59 years, and median serum creatinine was 1.8 mg/dL; 42% patients were hepatitis C–positive, 32% were diabetic, 38% had kidney dysfunction > 12 weeks, and 5% were receiving hemodialysis. After 36 months median follow‐up post‐OLTa, only 8 patients (13%) with significant renal dysfunction pre‐OLTa achieved eGFR < 20 mL/minute. Patients with pretransplant kidney dysfunction > 12 weeks were at increased risk for eGFR < 20 mL/minute (hazard ratio = 5.3, P = 0.04), a risk that escalated after adjustment for age and serum creatinine at transplant (hazard ratio = 8.9, P = 0.01). Significant predictors of eGFR < 20 mL/minute post‐OLTa in this patient cohort were the presence of diabetes and the serum creatinine level at transplant. In conclusion, few patients with preexisting renal dysfunction, especially if <12 weeks duration, experience a significant drop in eGFR post‐OLTa. Liver Transpl 14:665–671, 2008.

Association Between Model for End-Stage Liver Disease and Spontaneous Bacterial Peritonitis

OBJECTIVE:To determine whether a greater Model for End-Stage Liver Disease (MELD) score is associated with a greater risk of spontaneous bacterial peritonitis (SBP).METHODS:Our retrospective case-control study enrolled 271 consecutive patients with cirrhosis and ascites who underwent diagnostic paracentesis upon hospital admission (2002–2005). After excluding immunosuppressed patients, those recently exposed to antibiotics, those with a potential confounding etiology for ascites, and those with a prior history of SBP, 111 were included in the study. SBP was defined as a paracentesis yielding ≥250 neutrophils/mL ascites fluid. Multivariable logistic regression was performed to determine the odds ratio for the development of SBP associated with MELD score and grouped MELD score (≤15, 16–24, ≥25). Potential confounders assessed included age, diabetes mellitus, gender, race, alcohol use, serum sodium, and etiology of liver disease.RESULTS:Twenty-nine of 111 hospitalized patients with cirrhosis were found to have SBP. Patient characteristics were similar between groups with and without SBP. The mean MELD score for patients with SBP was 24 and for those without 18 (P = 0.0003). The odds ratio for developing SBP by each MELD point was 1.11 (1.05–1.19, P = 0.001). Patients with MELD ≥25 had an odds ratio of 9.67 (2.35–39.82, P = 0.002) for SBP, compared to subjects with MELD ≤15. None of the potential confounders substantially altered the relationship between MELD and SBP.CONCLUSIONS:Increasing MELD score is independently associated with a greater risk of SBP. For every point increase in the MELD score, the risk of developing SBP increases by 11%. Our finding has important implications for increasing the suspicion of SBP in patients with elevated MELD scores.

Recurrence of Diseases Following Orthotopic Liver Transplantation

Long-term graft survival and mortality after liver transplantation continue to improve. However, disease recurrence remains a major stumbling block, especially among patients with hepatitis C. Chronic hepatitis C recurs to varying degrees in nearly all patients who undergo transplantation. Transplantation for hepatitis C is associated with higher rates of graft failure and death compared with transplantation for other indications, and retransplantation for hepatitis C related liver failure remains controversial. Recurrence of hepatitis B has been markedly reduced with improved prophylactic regimens. Further, rates of hepatocellular carcinoma recurrence have also decreased, as improved patient selection criteria have prioritized transplantation for those with a low risk of recurrence. Primary biliary cirrhosis recurs in some patients, but it is often relatively mild. Autoimmune liver disease has also been shown to have a relatively benign post-transplantation course, but some studies have indicated that it slowly progresses in most recipients. It has been recently reported that alcoholic liver disease liver transplant recipients who return to drinking have worsened mortality. In such patients worse outcomes are not due to graft failure, but instead to other comorbidities. Recurrences of other diseases, including nonalcoholic steatohepatitis and primary sclerosing cholangitis, are now being recognized as having potentially detrimental effects on graft survival and mortality. Expert clinical management may help prevent and treat complications associated with disese recurrence.

Elevated troponin I levels in acute liver failure: Is myocardial injury an integral part of acute liver failure?

Although rare instances of cardiac injury or arrhythmias have been reported in acute liver failure (ALF), overall, the heart is considered to be spared in this condition. Troponin I, a sensitive and specific marker of myocardial injury, may be elevated in patients with sepsis and acute stroke without underlying acute coronary syndrome, indicating unrecognized cardiac injury in these settings. We sought to determine whether subclinical cardiac injury might also occur in acute liver failure. Serum troponin I levels were measured in 187 patients enrolled in the US Acute Liver Failure Study Group registry, and correlated with clinical variables and outcomes. Diagnoses were representative of the larger group of >1000 patients thus far enrolled and included 80 with acetaminophen‐related injury, 26 with viral hepatitis, 19 with ischemic injury, and 62 others. Overall, 74% of patients had elevated troponin I levels (>0.1 ng/ml). Patients with elevated troponin I levels were more likely to have advanced hepatic coma (grades III or IV) or to die (for troponin I levels >0.1 ng/ml, odds ratio 3.88 and 4.69 for advanced coma or death, respectively). Conclusion: In acute liver failure, subclinical myocardial injury appears to occur more commonly than has been recognized, and its pathogenesis in the context of acute liver failure is unclear. Elevated troponin levels are associated with a significant increase in morbidity and mortality. Measurement of troponin I levels may be helpful in patients with acute liver failure, to detect unrecognized myocardial damage and as a marker of unfavorable outcome. (HEPATOLOGY 2007;45:1489–1495.)

Quality of life in refractory ascites: Transjugular intrahepatic portal‐systemic shunting versus medical therapy

Uncontrolled studies suggest that transjugular intrahepatic portal‐systemic shunting (TIPS) may improve quality of life in patients with refractory ascites. We hypothesized that any improvement of quality of life in patients with TIPS would be matched in controls due to the competing effects of improved ascites and worsened hepatic encephalopathy. Thus, an analysis of quality of life was performed using original data from the North American Study for the Treatment of Refractory Ascites, a multicenter trial of 109 patients randomized to TIPS or repeated large volume paracentesis (LVP) for refractory ascites. Short form 36 (SF‐36) surveys were completed at baseline and at 6‐ and 12‐month follow‐up. Variables analyzed were: randomization group, number of LVP performed, cumulative volume from LVP, shortness of breath, abdominal distention, abdominal pain, diuretic usage, confusion, hospitalizations, and emergency room visits. Outcomes were changes in physical component scale (PCS) and mental component scale (MCS) of SF‐36 results. We constructed multivariable, mixed effects models, including randomization group and baseline MCS and PCS. Changes in PCS and MCS from baseline were similar between the two randomization groups. In multivariate analysis, PCS improvement was associated with lack of confusion, improved ascites, and lack of hospitalizations, but not directly with randomization group. Improvement in MCS was associated with randomization to TIPS and lack of confusion. In conclusion, patients with refractory ascites randomized to TIPS or repeated LVP had similar changes in quality of life. Competing effects of hepatic encephalopathy, requirement for repeated LVP, and need for hospitalizations explain similar changes in quality of life between the two groups. (HEPATOLOGY 2005.)

Predictive value of actin‐free Gc‐globulin in acute liver failure

Serum concentrations of the actin scavenger Gc‐globulin may provide prognostic information in acute liver failure (ALF). The fraction of Gc‐globulin not bound to actin is postulated to represent a better marker than total Gc‐globulin but has been difficult to measure. We tested a new rapid assay for actin‐free Gc‐globulin to determine its prognostic value when compared with the Kings College Hospital (KCH) criteria in a large number of patients with ALF. A total of 252 patients with varying etiologies from the U.S. ALF Study Group registry were included; the first 178 patients constituted the learning set, and the last 74 patients served as the validation set. Actin‐free Gc‐globulin was determined with a commercial enzyme‐linked immunosorbent assay kit. The median (range) actin‐free Gc‐globulin level at admission for the learning set was significantly reduced compared with controls (47 [0‐183] mg/L vs. 204 [101‐365] mg/L, respectively, P < 0.001). Gc‐globulin levels were significantly higher in spontaneous survivors than in patients who died or were transplanted (53 [0‐129] mg/L vs. 37 [0‐183] mg/L, P = 0.002). A receiver operating characteristic curve analysis showed that a 40 mg/L cutoff level carried the best prognostic information, yielding positive and negative predictive values of 68% and 67%, respectively, in the validation set. The corresponding figures for the KCH criteria were 72% and 64%. A new enzyme‐linked immunosorbent assay for actin‐free Gc‐globulin provides the same (but not optimal) prognostic information as KCH criteria in a single measurement at admission. Liver Transpl 13:1324–1329, 2007.

Effects of sirolimus vs. calcineurin inhibitors on renal dysfunction after orthotopic liver transplantation

Abstract:  Small uncontrolled series have suggested that sirolimus favorably impacts renal function after orthotopic liver transplantation (OLT). We sought to retrospectively compare renal dysfunction between cohorts exposed to sirolimus‐based and calcineurin inhibitor‐based immunosuppression. We retrospectively studied 79 patients converted to sirolimus‐based immunosuppression and 100 control subjects continued on calcineurin inhibitor‐based immunosuppression after OLT at our institution from 2000 to 2005. We collected clinical, demographic, and medication history. Renal dysfunction was defined as two or more wk of creatinine ≥2.0 mg/dL. Cohorts were compared using Kaplan–Meier survival analysis and Cox proportional hazards modeling. Patients began sirolimus a median 83 d post‐OLT and were followed on the medication for median 359 d. Patients in both the sirolimus and calcineurin inhibitor cohorts had median creatinine 1.2 mg/dL at study entry. Sirolimus‐based immunosuppression was associated with a 1.8 (0.8–4.3, p = 0.17) hazards ratio for renal dysfunction. Adjusting for presence of hepatocellular carcinoma, combined kidney/liver transplantation, and age, the hazards ratio was 2.0 (0.8–4.8, p = 0.13). These point estimates were not substantially altered after subgroup analysis of sirolimus as the lone immunosuppressant, duration of exposure, and time between OLT and sirolimus conversion. In conclusion, our retrospective, controlled study showed that conversion to sirolimus after OLT did not protect against renal dysfunction. The effect of sirolimus on renal function will need to be prospectively evaluated in a prospective, randomized trial.