Manuel Lombardero

Donor age and outcome of liver transplantation.

To evaluate the effect of donor age on graft and patient outcome after liver transplantation an analysis of a large‐scale cohort study was performed at three tertiary referral liver transplant centers. Between April 1990 and June 1994, 772 adults underwent an initial single‐organ liver transplantation. The age of the donors averaged 35 years;193 (25%) were 50 or above, the age used to define “older” donors. Groups were compared for demographic, clinical, and biochemical features. Outcome was measured using results of biochemical tests after transplantation and by graft and patient survival. Compared with younger donors, older donors were more commonly women (59% vs. 33%:P ≤ .001) and died of central nervous system causes (79% vs. 28%) as opposed to trauma (13% vs. 63%:P ≤ .001). The recipients of the two groups of donor livers did not differ in important respects. However, intraoperatively, livers from older donors were more likely to be assessed as either “poor” or “fair” as opposed to “good” (17% vs. 4%:P ≤ .001) by the harvesting surgeon and to have initial “poor” or “fair” bile production (29% vs. 18%:P ≤ .001). During the first week postoperatively, the serum aminotransferase and bilirubin levels and prothrombin times were higher in recipients of older than those of younger donor livers. During follow‐up, graft survival was less for recipients of older donor livers at 3 months (81% vs.91%:P = .0001) and at 1 (76% vs. 85%:P = .007) and 2 years (71% vs. 80%:P = .005); patient survival showed similar though less marked differences. This association of donor age and poorer graft survival persisted after adjusting for many variables using bivariate and multivariate analyses. Importantly, however, the association with poor graft survival was largely among recipients of older donor livers, the quality of which was assessed as fair or poor by the harvesting surgeon; recipients of older donor livers assessed as good had a retransplant‐free survival similar to that of younger donor livers (87% vs. 91% at 3 months). Thus, use of older donor livers, the quality of which are judged to be good by the harvesting surgeon, is not associated with a decrease in patient or graft survival after liver transplantation. differences. This association of donor age and poorer graft survival persisted after adjusting for many variables using bivariate and multivariate analyses. Importantly, however, the association with poorer graft survival was largely among recipients of older donor livers, the quality of which was assessed as fair or poor by the harvesting surgeon; recipients of older donor livers, the quality of which was assessed as fair or poor by the harvesting surgeon; recipients of older donor livers assessed as good had a retransplant‐free survival similar to that of younger donor livers (87% vs. 91% at 3 months). Thus, use of older donor livers, the quality of which are judged to be good by the harvesting surgeon, is not associated with a decrease in patient or graft survival after liver transplantation.

The Effect of Previous Coronary-Artery Bypass Surgery on the Prognosis of Patients with Diabetes Who Have Acute Myocardial Infarction

BACKGROUND Acute myocardial infarction in patients with diabetes is associated with high mortality. We studied whether previous revascularization by coronary-artery bypass grafting (CABG), as compared with percutaneous transluminal coronary angioplasty (PTCA), influences the prognosis in such patients. METHODS We classified all patients eligible for the Bypass Angioplasty Revascularization Investigation who underwent coronary revascularization within three months after entry into the study according to whether they had diabetes and whether they had undergone CABG, either initially or after PTCA. The protective effect of CABG with regard to mortality in the presence and in the absence of subsequent spontaneous Q-wave myocardial infarction was estimated with the use of Cox regression models. RESULTS Among the 641 patients with diabetes and the 2962 without diabetes, the cumulative five-year rates of death were 20 percent and 8 percent, respectively (P<0.001), and the five-year rates of spontaneous Q-wave myocardial infarction were 8 percent and 4 percent (P<0.001). CABG greatly reduced the risk of death after spontaneous Q-wave myocardial infarction in the patients with diabetes (relative risk, 0.09; 95 percent confidence interval, 0.03 to 0.29). Among patients with diabetes who had undergone CABG but did not have spontaneous Q-wave myocardial infarctions, the corresponding relative risk of death was 0.65 (95 percent confidence interval, 0.45 to 0.94). Among the patients without diabetes, no protective effect of CABG was evident. CONCLUSIONS Among patients with diabetes, previous coronary bypass surgery, as compared with coronary angioplasty, has a highly favorable influence on prognosis after acute myocardial infarction and a smaller beneficial effect among patients who do not have infarction. These findings should influence the type of coronary revascularization procedure selected for patients with diabetes who have multivessel coronary artery disease.

Outcome of patients with renal insufficiency undergoing liver or liver-kidney transplantation.

Renal insufficiency (RI) is a common finding with end-stage liver disease. RI is generally not regarded as a contraindication to liver transplantation. However, the impact of RI on outcome following transplantation and the role of combined liver-kidney transplant are not well understood. The effect of RI on patients with fulminant hepatic failure (FHF) or chronic liver disease (cirrhosis) was investigated using the National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) Liver Transplantation Database. Patients were analyzed based on the presence of RI, defined as creatinine >1.6 mg/dl, or on dialysis. Patients undergoing liver-kidney transplantation were analyzed separately. For patients with FHF, the RI group had a lower patient survival rate at 1 year (50% vs. 83%, P=0.04) and tended to have a lower graft survival rate (50% vs. 71%). Stay in the intensive care unit (ICU) was prolonged in the RI group but hospital stay was not. Among patients with cirrhosis, RI did not affect patient survival, except for patients on dialysis or those with liver-kidney transplants. One-year patient and graft survival rates were 65% and 60% for the dialysis group, 74% and 70% for the liver-kidney transplant group, 89% and 86% for RI patients not on dialysis, and 89 and 84% for non-RI patients. ICU and hospital stays were prolonged for all of the RI groups compared with the non-RI patients. Patients with RI had higher rates of posttransplant dialysis; however, the differences tended to equalize after 4 weeks. We conclude that RI in FHF and RI requiring dialysis or liver-kidney transplantation in cirrhosis predict lower posttransplant patient and graft survival rates. Patients with RI have longer hospital and ICU stays and an increased need for dialysis, which likely increases the cost of transplantation. Whether liver-kidney transplantation improves outcome and thus represents an appropriate use of cadaver kidneys requires further study.

Biopsy of marginal donor kidneys: correlation of histologic findings with graft dysfunction.

BACKGROUND Kidney biopsies are being used to evaluate marginal donors, but rigorous statistical validation of this practice with multivariate analysis has not been performed. METHODS To analyze histologic parameters in 78 donor biopsies for their ability to predict graft dysfunction, we used a proportional odds model that included both donor and recipient factors. Glomerulosclerosis was categorized into grades 0, 1, 2, and 3, corresponding to 0, 1-10%, 11-20%, and 21-30% global sclerosis, respectively. The degrees of interstitial fibrosis, tubular atrophy, arteriosclerosis, and arteriolar hyalinosis were graded from 0 to 3+, using definitions suggested by the Banff Schema of allograft pathology. RESULTS Increasing donor age was associated with higher glomerulosclerosis, tubular atrophy, and arteriosclerosis. Kidneys with any degree of interstitial fibrosis were 2.6 times [odds ratio (OR)] more likely to experience a worse outcome at 6 months (P = 0.02). This association held up after correction for acute rejection (OR 2.5, P = 0.03) and high panel-reactive antibody (OR 3.4, P = 0.006), However, the OR was reduced to 1.9 (P = 0.15) after controlling for recipient age. With each increment in the grade of glomerulosclerosis, the odds for a worse outcome at 12 months increased to 2.3 (P = 0.005). The value for OR became 2.0 (P = 0.03) when controlling for recipient age (P = 0.01), 2.4 (P = 0.005), when controlling for acute rejection, and 2.3 (P = 0.006) when controlling for high panel-reactive antibody. CONCLUSIONS Histopathological parameters present in donor biopsies can independently predict post-transplant graft function. Implications for the pool of donor organs available for transplantation are discussed.

Increased waiting time for liver transplantation results in higher mortality

BACKGROUND Waiting time to liver transplantation (LTx) has dramatically lengthened, but the proportion of candidates who die awaiting transplantation has not increased. We evaluated whether longer waiting time for LTx candidates increases mortality. METHODS A cohort of candidates listed for LTx between 1990 and 1993 by three large transplantation programs was followed for 2 years. The exposure measure was ABO blood type, which is not inherently related to outcome, but is a major determinant of waiting time. The main outcome measure was 2-year mortality, as evaluated by logistic regression analysis that controlled for differences in clinical status at the time of evaluation for LTx. RESULTS The 308 candidates with type O blood waited longer for LTx (median 109 days) than the 399 candidates with other blood types (median 58 days) (P=0.001). Candidates listed for LTx with type O blood had better clinical status at evaluation, but then had higher pretransplantation mortality (13.3%) than other candidates (7.0%) (P=0.005). Blood group O candidates had higher 2-year mortality (26.6%) than other candidates (22.1%), which on multivariate analysis resulted in a mortality odds ratio at 2 years of 1.52 (95% confidence interval=1.04-2.23). With the difference in median waiting time between blood groups increasing from 44 days in the first year to 108 days in the third year, the 2-year mortality odds ratio also rose from 0.94 to 1.97. CONCLUSIONS When compared with LTx candidates with other blood types, blood type O candidates have longer waiting times and higher pretransplantation mortality, which results in higher 2-year mortality.

A controlled analysis of the transjugular intrahepatic portosystemic shunt in liver transplant recipients

BACKGROUND The transjugular intrahepatic portosystemic shunt (TIPS) is an important treatment for complications of portal hypertension. As some authors have suggested that TIPS may facilitate liver transplantation technically, the objective of this study was to determine the impact of TIPS on the liver transplant operation and its outcome. METHODS The analysis was designed as a retrospective cohort study using a multicenter database. Fifty-five patients with TIPS were matched with 55 controls on the basis of 10 pretransplant laboratory, clinical, and demographic features. TIPS patients and control patients were compared with regard to duration of surgery, intraoperative blood product usage, liver and renal function, volume of ascites, survival, and hospital stay. For confirmatory purposes, a parallel analysis using linear regression methods was performed. RESULTS By matched analysis, TIPS patients had less ascites at surgery (mean 0.9+/-0.20 vs. 2.2+/-0.37 L, P=0.005) and a slightly shorter time from incision to cross-clamp (mean 2.1+/-0.10 vs. 2.5+/-0.15 hr, P=0.03). However, there were not significant differences for total operative time (mean 6.0+/-0.17 vs. 6.3+/-0.25 hr, P=1.00), blood product usage, or any other outcome variable. Regression analysis confirmed these results. CONCLUSIONS TIPS does not significantly impact the course of liver transplantation surgery. Therefore, preoperative portal decompression solely to facilitate liver transplantation is not an appropriate indication for TIPS.

Rosiglitazone and Outcomes for Patients With Diabetes Mellitus and Coronary Artery Disease in the Bypass Angioplasty Revascularization Investigation 2 Diabetes (BARI 2D) Trial

Background— Rosiglitazone improves glycemic control for patients with type 2 diabetes mellitus, but there remains controversy regarding an observed association with cardiovascular hazard. The cardiovascular effects of rosiglitazone for patients with coronary artery disease remain unknown. Methods and Results— To examine any association between rosiglitazone use and cardiovascular events among patients with diabetes mellitus and coronary artery disease, we analyzed events among 2368 patients with type 2 diabetes mellitus and coronary artery disease in the Bypass Angioplasty Revascularization Investigation 2 Diabetes (BARI 2D) trial. Total mortality, composite death, myocardial infarction, and stroke, and the individual incidence of death, myocardial infarction, stroke, congestive heart failure, and fractures, were compared during 4.5 years of follow-up among patients treated with rosiglitazone versus patients not receiving a thiazolidinedione by use of Cox proportional hazards and Kaplan–Meier analyses that included propensity matching. After multivariable adjustment, among patients treated with rosiglitazone, mortality was similar (hazard ratio [HR], 0.83; 95% confidence interval [CI], 0.58–1.18), whereas there was a lower incidence of composite death, myocardial infarction, and stroke (HR, 0.72; 95% CI, 0.55–0.93) and stroke (HR, 0.36; 95% CI, 0.16–0.86) and a higher incidence of fractures (HR, 1.62; 95% CI, 1.05–2.51); the incidence of myocardial infarction (HR, 0.77; 95% CI, 0.54–1.10) and congestive heart failure (HR, 1.22; 95% CI, 0.84–1.82) did not differ significantly. Among propensity-matched patients, rates of major ischemic cardiovascular events and congestive heart failure were not significantly different. Conclusions— Among patients with type 2 diabetes mellitus and coronary artery disease in the BARI 2D trial, neither on-treatment nor propensity-matched analysis supported an association of rosiglitazone treatment with an increase in major ischemic cardiovascular events. Clinical Trial Registration— URL: http://www.clinicaltrials.gov. Unique identifier: NCT00006305.

Favorable Effects of Insulin Sensitizers Pertinent to Peripheral Arterial Disease in Type 2 Diabetes: Results from the Bypass Angioplasty Revascularization Investigation 2 Diabetes (BARI 2D) trial

OBJECTIVE The aim of this manuscript was to report the risk of incident peripheral arterial disease (PAD) in a large randomized clinical trial that enrolled participants with stable coronary artery disease and type 2 diabetes and compare the risk between assigned treatment arms. RESEARCH DESIGN AND METHODS The Bypass Angioplasty Revascularization Investigation 2 Diabetes (BARI 2D) trial randomly assigned participants to insulin sensitization (IS) therapy versus insulin-providing (IP) therapy for glycemic control. Results showed similar 5-year mortality in the two glycemic treatment arms. In secondary analyses reported here, we examine the effects of treatment assignment on the incidence of PAD. A total of 1,479 BARI 2D participants with normal ankle-brachial index (ABI) (0.91–1.30) were eligible for analysis. The following PAD-related outcomes are evaluated in this article: new low ABI ≤0.9, a lower-extremity revascularization, lower-extremity amputation, and a composite of the three outcomes. RESULTS During an average 4.6 years of follow-up, 303 participants experienced one or more of the outcomes listed above. Incidence of the composite outcome was significantly lower among participants assigned to IS therapy than those assigned to IP therapy (16.9 vs. 24.1%; P < 0.001). The difference was significant in time-to-event analysis (hazard ratio 0.66 [95% CI 0.51–0.83], P < 0.001) and remained significant after adjustment for in-trial HbA1c (0.76 [0.59–0.96], P = 0.02). CONCLUSIONS In participants with type 2 diabetes who are free from PAD, a glycemic control strategy of insulin sensitization may be the preferred therapeutic strategy to reduce the incidence of PAD and subsequent outcomes.

Association Between Albuminuria and Duration of Diabetes and Myocardial Dysfunction and Peripheral Arterial Disease Among Patients With Stable Coronary Artery Disease in the BARI 2D Study

OBJECTIVE To evaluate the effect of prior duration of diabetes, glycated hemoglobin level at study entry, and microalbuminuria or macroalbuminuria on the extent and severity of coronary artery disease (CAD) and peripheral arterial disease. PATIENTS AND METHODS We studied baseline characteristics of the 2368 participants of the BARI 2D (Bypass Angioplasty Revascularization Investigation 2 Diabetes) study, a randomized clinical trial that evaluates treatment efficacy for patients with type 2 diabetes and angiographically documented stable CAD. Patients were enrolled from January 1, 2001, through March 31, 2005. Peripheral arterial disease was ascertained by an ankle-brachial index (ABI) of 0.9 or less, and extent of CAD was measured by presence of multivessel disease, a left ventricular ejection fraction (LVEF) of less than 50%, and myocardial jeopardy index. RESULTS Duration of diabetes of 20 or more years was associated with increased risk of ABI of 0.9 or less (odds ratio [OR], 1.54; 95% confidence interval [CI], 1.04-2.26), intermittent claudication (OR, 1.61; 95% CI, 1.10-2.35), and LVEF of less than 50% (OR, 2.03; 95% CI, 1.37-3.02). Microalbuminuria was associated with intermittent claudication (OR, 1.53; 95% CI, 1.16-2.02) and ABI of 0.9 or less (OR, 1.31; 95% CI, 0.98-1.75), whereas macroalbuminuria was associated with abnormal ABI, claudication, and LVEF of less than 50%. There was a significant association between diabetes duration and extent of CAD as manifested by number of coronary lesions, but no other significant associations were observed between duration of disease, glycated hemoglobin levels, or albumin-to-creatinine ratio and other manifestations of CAD. CONCLUSION Duration of diabetes and microalbuminuria or macroalbuminuria are important predictors of severity of peripheral arterial disease and left ventricular dysfunction in a cohort of patients selected for the presence of CAD.

The prevalence and predictors of an abnormal ankle-brachial index in the Bypass Angioplasty Revascularization Investigation 2 Diabetes (BARI 2D) trial.

OBJECTIVE To examine ankle-brachial index (ABI) abnormalities in patients with type 2 diabetes and coronary artery disease (CAD). RESEARCH DESIGN AND METHODS An ABI was obtained in 2,240 patients in the Bypass Angioplasty Revascularization Investigation 2 Diabetes (BARI 2D) Trial. ABIs were classified as: normal, 0.91–1.3; low, ≤0.9; high, >1.3; or noncompressible artery (NC). Baseline characteristics were examined according to ABI and by multivariate analysis. RESULTS ABI was normal in 66%, low in 19%, and high in 8% of patients, and 6% of patients had NC. Of the low ABI patients, 68% were asymptomatic. Using normal ABI as referent, low ABI was independently associated with smoking, female sex, black race, hypertension, age, C-reactive protein, diabetes duration, and lower BMI. High ABI was associated with male sex, nonblack race, and higher BMI; and NC artery was associated with diabetes duration, higher BMI, and hypertension. CONCLUSIONS ABI abnormalities are common and often asymptomatic in patients with type 2 diabetes and CAD.