Results
Recipient and Donor Characteristics
A total of 598 adult KPNC patients underwent either primary liver (n = 542) or simultaneous liver–kidney (n = 56) transplantation between January 1, 1997 and June 30, 2009. Donors were 40.4 ± 16.1 years old, 90% deceased (brain and cardiac death), more likely to be male (54%) and Caucasian (63%). Cerebrovascular accident was the most frequent cause of donor death (43%), followed by trauma (39%) (Table 1).
Recipients were 53.4 ± 9.5 years old, predominantly male (62%) and Caucasian (43%). HCV (49%) was the most common etiology of liver disease; approximately one-third of recipients (32%) had hepatocellular carcinoma (Table 1). A total of 117 deaths were recorded, 71 of which occurred more than 1-year after transplant. Allograft failure due to recurrent HCV was the most common cause of death (31%) followed by malignancy (28%), cardiovascular events (10%) and infection (8%; Table 2). Overall 5-year survival was 80% (Figure 1).
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Figure 1.
Kaplan–Meier survival curve for adult liver transplantation recipients. Both total follow-up time and the number of patients at risk are provided on the x-axis.
Prevalence, Duration and Treatment of Diabetes, Hypertension and Hyperlipidemia Over Time
On the basis of physician-entered diagnostic codes alone, diabetes (22%), hypertension (30%) and hyperlipidemia (12%) were common before transplantation in our population (Table 3). The prevalence of each condition increased steadily until 7 years after transplant when 35% had diabetes, 56% had hypertension and 22% had hyperlipidemia. The prevalence of all three conditions decreased between 7 and 10 years after transplant. It should, however, be noted that the 10-year data is based on only 43 recipients.
Recipients with diabetes had a mean duration of 6.98 ± 4.79 years with a maximum duration of 15.2 years. Sixty percent of diabetic recipients had pretransplant diabetes whereas 40% developed diabetes after transplantation. We did not encounter any patients with pretransplant diabetes that did not have persistent diabetes after transplant. Similarly, recipients with hypertension had a mean duration of 6.34 ± 4.35 years with a maximum duration of 15.44 years. Finally, the duration of hyperlipidemia was shorter; 4.52 ± 4.07 years with a maximum duration of 14.76 years.
Treatment of these conditions also varied before and after transplant. Overall, 79% of diabetic recipients received insulin at some point either before or after liver transplantation. Among recipients with pretransplant diabetes, 27% required insulin before transplantation whereas 67% required insulin 6 months or more after transplant. Among recipients who developed diabetes after transplantation, 56% required insulin. Antihypertensive medications, excluding propranolol and nadolol, were administered to 17% of all recipients before transplant. Six months or more after transplant, 48% of all recipients were treated with antihypertensive medications. Finally, 8% of all recipients received antilipemic medication before transplant whereas 20% were treated 6 months or more after transplant.
Predictors of Long-term Survival
We examined donor, recipient, transplant and posttransplant factors to identify predictors of long-term mortality in recipients who survived at least 1 year. For the three conditions of interest, we examined the duration of each using both our primary and secondary definitions (see Methods) as well as simple presence or absence. Univariate analysis identified recipient age at transplant (hazard ratio [HR] 1.03 per year increment; 95% confidence interval [CI] 1.00–1.06; p = 0.02) and HCV liver disease (HR 2.86; 95% CI 1.72–4.77; p < 0.01; Table 4) as strongly associated with long-term mortality for liver transplant recipients. As for diabetes, hypertension and hyperlipidemia, the duration of diabetes was a highly potent predictor of long-term mortality. When diabetes was defined by diagnostic code alone, the HR was 1.08 per year increment (95% CI 1.02–1.13; p < 0.01); when diabetes was defined by diagnostic code plus prescription requirement, the HR was 1.10 per year (95% CI 1.00–1.21; p = 0.05). Notably, the less precise definition of diabetes, simply absence or presence, did not demonstrate a significant association (HR 1.18; 95% CI 0.74–1.88; p = 0.50). Neither hypertension nor hyperlipidemia, assessed as duration or presence/absence, were statistically significant predictors of long-term survival (Table 4).
To further explore the impact of recipient diabetes, we analyzed whether the need for insulin had an impact on long-term survival (Table 5). Neither insulin use at any point during the study period (HR 1.06; 95% CI 0.66–1.72; p = 0.80) nor after transplant was a predictor of long-term survival (HR 1.33; 95% CI 0.81–2.18; p = 0.25). Furthermore, when insulin therapy was incorporated into bivariate models with duration of diabetes, duration of diabetes remained a significant predictor of mortality while insulin therapy was actually protective, though this relationship did not reach statistical significance (insulin use ever HR 0.54; 95% CI 0.28–1.06; p = 0.08; insulin use after transplant HR 0.82; 95% CI 0.43–1.57; p = 0.55).
When all predictors with a p value of <0.10 in univariate analysis were entered into a multivariate model, recipient age (HR 1.03 per year increment; 95% CI 1.00–1.06; p = 0.02), HCV liver disease (HR 2.85; 95% CI 1.71–4.75; p < 0.01) and diabetes duration (HR 1.07 per year increment; 95% CI 1.01–1.13; p = 0.02) again emerged as significant negative predictors of long-term survival (Table 6). The interaction between HCV liver disease and diabetes duration was explored by adding it to the above multivariate model. The interaction was not statistically significant (HR 0.93, 95% CI 0.82–1.03, p = 0.14); recipient age at transplant (HR 1.03 per year increment, 95% CI 1.00–1.06, p = 0.02), HCV liver disease (HR 3.81, 95% CI 1.97–7.36, p = 0.01) and duration of diabetes (HR 1.13 per year increment, 95% CI 1.04–1.24, p = 0.01) remained statistically significant. Therefore, this interaction was not presented in our final multivariate model.
Finally, we explored the association between diabetes, hypertension and hyperlipidemia and specific causes of death. There were few late deaths due to cardiovascular disease and duration of diabetes (HR 1.09, 95% CI 0.93–1.28, p = 0.29), hypertension (HR 1.01, 95% CI 0.84–1.22, p = 0.92), or hyperlipidemia (HR 1.12, 95% CI 0.92–1.38, p = 0.25) were not statistically significant predictors on univariate analysis. However, duration of diabetes was a significant predictor of long-term mortality due to the combination of recurrent HCV, cardiovascular events and infection (HR 1.08, 95% CI 1.00–1.16, p = 0.05). Duration of hypertension (HR 1.02, 95% CI 0.92–1.11, p = 0.68) and hyperlipidemia (HR 1.06, 95% CI 0.95–1.20, p = 0.31) were not significant predictors.