Objectives: To date, fatigue is still poorly understood in recipients of orthotopic liver transplant and simultaneous/sequential liver and kidney transplant procedures. The present study examined the appearance of fatigue in patients who received orthotopic liver and sequential liver and kidney transplant procedures compared with the general population and the influence of various clinical and socioeconomic factors on fatigue levels.

Materials and Methods: The Multidimensional Fatigue Inventory survey was sent to all patients with a history of orthotopic liver and simultaneous/sequential liver and kidney transplant. The results were compared to data from a reference population.

Results: Our survey included 276 eligible patients: 256 recipients (92.7%) of orthotopic liver transplant and 20 recipients (7.3%) of simultaneous/sequential liver and kidney transplant. Significantly lower fatigue scores were found in the general population compared with both transplant groups (P < .001). There were also no significant differences between the transplant groups. Among the clinical and socioeconomic factors, history of hepatocellular carcinoma, chronic kidney disease, age, family status, and education had a significant impact on fatigue levels.

Conclusions: This is the first study to compare fatigue in recipients of orthotopic liver and simultaneous/-sequential liver and kidney transplant. We found that fatigue is an important but still poorly understood outcome after transplant.

Key words : Liver transplantation, MFI-20, Multidimensional Fatigue Inventory, Renal transplant

Introduction

For patients with end-stage liver disease (ESLD), orthotopic liver transplant (OLT) is currently the only curative treatment option. Orthotopic liver trans­plant offers good long-term survival, and the 10-year-survival rate is approximately 60%.¹

A challenging problem is the development of end-stage renal failure after OLT, with a probable need for renal replacement therapy.^2,3 Simultaneous or sequential kidney and liver transplant is a common and widely performed procedure.^4,5 However, this procedure is associated with a higher morbidity.⁶

Patients with ESLD are often confronted with physical restrictions, such as recurrent ascites⁷ or encephalopathy,⁸ and most of these events are potentially life-threatening.^9-11 However, survival and life-threatening complications are not the only issues to both physicians and patients. Many patients with ESLD face serious restrictions in their health-related quality of life,^12,13 with mental disorders, such as anxiety and depression, also occurring after these procedures.¹⁴ Another important impairment of patients with ESLD is the presence of fatigue.¹⁵

The term fatigue commonly expresses an everyday experience after physical exercise or inadequate sleep. As stated by Smets and associates, the term fatigue is used to describe a symptom that indicates the presence of disease.¹⁶ It is considered a multi­dimensional condition that includes both experienced fatigue and physiologic fatigue.¹⁷ Fatigue has different aspects, such as general, mental, and physical. Reduced activity and reduced motivation are also considered indicators of fatigue.¹⁸ A validated and frequently used instrument to measure fatigue levels is the Multidimensional Fatigue Inventory (MFI-20), which consists of 20 items that assess the different aspects of fatigue.¹⁹

In most cases, these psychosocial variables, including health-related quality of life, mental health, and fatigue, improve after OLT.^20,21 However, the few studies that have examined fatigue in OLT recipients have found that fatigue is still present after liver transplant and remains a major concern.^21-23 Reports about psychosocial outcome factors in recipients of liver and kidney transplant procedures are rare and have a limited number of cases.²⁴ The present cross-sectional study aimed to identify clinical factors influencing fatigue and to measure fatigue in patients with a history of OLT and patients with a history of simultaneous/sequential liver and kidney transplant (LKTX) compared with the general population.

Materials and Methods

Study design
We identified all patients who had undergone OLT or LKTX at the University Hospital (Leipzig, Germany) between 1993 and 2013. The MFI-20 survey was sent to these patients via mail with postage-paid return envelopes. We asked all patients to return the completed questionnaires within 2 weeks. After this period had expired, we contacted all patients who had not returned the survey a second time. The received questionnaires were then scanned and digitized manually and double-checked.

Before the study was started, we obtained informed consent from all patients and the consent of the local ethics committee (No. 414-12-17122012).

Patient selection
All patients over 18 years old with a complete medical history available in our database were included in the study. The included patients were divided into 2 groups: (1) patients with a history of OLT (OLT group) and (2) patients with a history of LKTX (LKTX group). Fatigue scores were assessed in both groups. Moreover, we analyzed the impact of several clinical and psychosocial variables of fatigue in these patients.

Control groups
Results from transplant patients were compared with reference data from the German general population. These original data were obtained from an earlier investigation performed by one of the authors of this manuscript.²⁵ To create a representative sample that was comparable to the patient cohorts of the present study, individuals in the general population cohort were matched according to age and sex.

Multidimensional fatigue inventory
The MFI-20 is a self-reported questionnaire to measure fatigue that was first described by Smets and colleagues.¹⁶ It contains 20 items divided into 5 subscales: general fatigue, physical fatigue, reduced activity, reduced motivation, and mental fatigue. For each item, there are 5 possible answers (5-point Likert scale). For each subscale, a score ranging from 4 to 20 can be calculated. The total fatigue score is calculated by adding up the scores from the 5 subscales (range, 20-100). Higher scores indicate high fatigue levels. The MFI-20 has been shown to have a high internal consistency and validity.²⁶

In addition to the MFI-20, we asked the patients to describe their current health status compared with the year before. The question was a 5-point Likert-scale item with the following possible answers: “much better,” “slightly better,” “equal,” “slightly worse,” and “much worse.”

Statistical analyses
For data collection and statistical analysis, Microsoft Excel (Microsoft, Redmond, WA, USA) and SPSS version 17.0 (IBM, Armonk, NY, USA) were used. The MFI-20 questionnaires were first digitized and computed by the Evasys system (Electric Paper Evaluations Systems GmbH, Lüneburg, Germany) and then imported into Excel and SPSS. To guarantee consistency, all data were manually controlled.

For the analysis of statistical differences between the different groups, we used nonparametric tests like the Mann-Whitney U test and the Kruskal-Wallis test. Continuous variables are displayed as mean and standard deviation.

Categorical variables, including sex, age group, underlying disease, comorbidities, time since transplant, family and relationship status, and religion, were compared using cross tables, chi-square tests, or t tests. Results were considered statistically significant if P was less than .05.

The data presented are part of a large cross-sectional study of transplant candidates and transplant recipients. So far, data have been previously published in parts.^27-30 Nonetheless, these publications focused on different inclusion criteria and used a different patient subset (eg, patients who have history of liver transplant vs patients on wait lists). Here, we initially report on the recipients of a liver and kidney transplant, thus providing crucial new insights in this field.

Results

Patient characteristics
In total, 689 OLT and LKTX recipients who were still alive were identified. These 689 patients received the MFI-20 survey. Twenty-seven patients (3.9%) had to be excluded since their relatives informed us about the death of the patient. In total, there were 276 eligible surveys (41.5%): 255 OLT recipients (92.8%) and 20 LKTX recipients (7.2%).

With regard to time since transplant, there were 142 patients (51.6%) whose OLT was performed less than 5 years before the study time, 68 (26.6%) who received OLT 5 to 10 years before the study time, and 46 patients (18.0%) who received OLT more than 10 years before the study time. In the LKTX group, time since transplant was as follows: 7 patients (35.0%) with transplant less than 5 years, 10 (50.0%) with transplant 5 to 10 years, and 3 (15.0%) with transplant > 10 years before study enrollment.

There were no significant differences regarding age, religion, family status, or relationship status (P > .05) between the 3 groups.

When we analyzed for associations regarding the underlying disease, there were significant differences between the groups (P < .001). Moreover, there were significantly more patients with a history of hepatocellular carcinoma (HCC) in the OLT group than in the LKTX group. The baseline characteristics, including relevant comorbidities, are summarized in Table 1. These medical conditions were not further subclassified. Chronic kidney disease was defined as a permanent reduction of glomerular filtration rate to < 90 mL/min/1.73 m² (stage II according to “Kidney Disease Improving Global Outcomes” or higher31). Among the patients with chronic kidney disease, no patients had end-stage renal failure.

The matched MFI-20 group of the reference population consisted of 1309 individuals of which 816 patients (62.3%) were men and 493 (37.7%) were women. The mean age was 57.5 years.

Multidimensional Fatigue Inventory questionnaire and general health question
The comparison of the 5 subscales and the summation score showed significant differences between both groups and the general population (general fatigue, physical fatigue, reduced activity, mental fatigue, and summation score: all P < .001; Figures 1 and 2). The lowest fatigue scores in each subscale were found in the general population. In the OLT and LKTX groups, scores did not differ significantly (general fatigue: P = .660; physical fatigue: P = .537; reduced activity: P = .874; reduced motivation: P = .852; mental fatigue: P = .994; summation score: P = .861). The reference population showed significantly lower values for general, physical, and mental fatigue; reduced activity; and summation score (all P < .001) than the OLT patients. For reduced motivation, no significant differences were found (P = .524). When compared with the LKTX recipients, there were significantly lower scores for general fatigue (P < .001), physical fatigue (P = .008), and summation score (P = .036). Reduced activity (P = .111), reduced motivation (P = .999), and mental fatigue (P = 0.157) did not differ significantly.

As shown in Figure 3, of the 276 patients, 146 (52.9%) answered the general health question (OLT group: 132 responses; LKTX group: 14 responses; P = .085).

Impact of clinical factors on fatigue
As shown in Table 2, patients in the OLT and LKTX groups who had chronic kidney disease had significantly higher fatigue summation scores than patients without chronic kidney disease (mean [standard deviation] of 47.2 [14.8] vs 54.1 [17.6]; P = .001). The scores for general and physical fatigue (P = .001 for both), reduced activity (P < .001), and reduced motivation (P = .011) were also significantly increased. Patients with a history of HCC had significantly lower general fatigue (P = .017) than patients without history of HCC. The summation score (mean [standard deviation] of 47.3 [16.0] vs 51.9 [16.8]; P = .074) was also lower but without statistical significance. All other clinical factors, including the underlying disease, the presence of arterial hyper­tension and diabetes mellitus, and the time since transplant, had no significant effect on fatigue scores.

Impact of socioeconomic factors on fatigue
The impact of socioeconomic factors on fatigue is shown in Table 3. The variables sex, relationship status, and religiousness had no impact on the fatigue subscales and summation score (P > .05). When compared with regard to age, significantly lower scores for general, physical, and mental fatigue (P < .05 for all 3) and summation scores (P = .012) were found in patients younger than 50 years and patients between 65 and 69 years old compared with patients who were between 50 and 54, 55 and 59, 60 and 64, and over 70 years old.

When different groups were compared regarding family status, statistically significant differences were found for physical fatigue (P = .031). Post hoc tests revealed significant differences between divorced and unmarried patients. The highest scores were found in the divorced who, compared with unmarried patients, had significantly higher scores for general fatigue (P = .004), physical fatigue (P = .002), mental fatigue (P < .021), and summation score (mean [standard deviation] of 57.5 [16.2] vs 47.7 [13.7]; P = .009).

Patients with higher secondary school quali­fications had significantly lower scores in the mental scales of reduced activity (P = .014) and mental fatigue (P = .010).

Discussion

The present study showed that OLT and LKTX recipients have significantly higher fatigue scores than the general population. It is, to the authors’ best knowledge, the first study to compare fatigue in the above-mentioned patient groups. Recipients of LKTX showed equal fatigue scores versus OLT recipients. The comparison of the findings of the present study with the current literature is difficult as only a few studies have compared OLT and LKTX recipients versus the general population.

Similar to van den Berg-Emons and associates, we found a considerable amount of fatigue symptoms in our study collective.²² The nature of fatigue was mainly due to physical limitations, with higher fatigue scores for physical fatigue and reduced activity. Moreover, Berg-Emons and colleagues revealed an association between fatigue and age. Kalaitzakis and associates compared patients before and after liver transplant and found reduced fatigue scores after transplant. However, physical fatigue, in particular, was still present among OLT recipients.²¹ These findings are comparable with the results found in the present study. In contrast to these studies, we found no association between fatigue and sex and time since transplant. Fatigue appears to be a chronic problem after OLT with no change after 2 years, and there is a relation between fatigue and the physical domains of health-related quality of life.²³ It is well-known that these domains of health-related quality of life are reduced after liver transplant.³² A possible explanation for the presence of fatigue after OLT might be that these patients have multiple comor­bidities related to immunosuppressive therapy, such as osteoporosis, arterial hypertension, and chronic kidney disease.^33-35 Fatigue is common in patients with chronic disease,36 and OLT recipients with chronic kidney disease appear to have increased fatigue scores.²¹ As described in the literature, we found higher fatigue scores in patients with kidney disease,³⁷ so this could be a factor contributing to the increased fatigue scores compared with the general population.

Patients who underwent LKTX showed fatigue scores higher than the general population but not higher than OLT recipients. This appears to be surprising since the overall results and outcomes of LKTX procedures are acceptable but inferior to those of patients who undergo single-organ transplant procedures.^38,39 Thus, the fatigue scores found in the present study do not mirror the physical challenge that is represented by a double-organ transplant. However, almost 20% of patients from the OLT group stated that their health status had improved, whereas there were no patients from the LKTX group who marked a response of healthier than the year before. This finding potentially shows the negative effect of combined liver and kidney transplant procedures on general health status. It is also probable that the underlying renal disease in LKTX patients has a negative influence on fatigue and general health. Kirchner and associates demonstrated that fatigue is reduced significantly in patients with polycystic liver and kidney disease after transplant.²⁴

In the present study, we examined the influence of clinical and psychosocial variables on fatigue. As already mentioned, comorbidities, especially chronic kidney disease, negatively influence fatigue. Chronic disease and morbidity in general greatly affect fatigue, and this is also mirrored by the fact that there was a strong correlation between the current self-reported health status and the assessment of fatigue symptoms.

Moreover, there appears to be some age depen­dency of fatigue syndrome.^22,25 Unlike other studies, we could not find a relation between sex and fatigue.^22,25 There was no association between the underlying disease and fatigue except for history of HCC. Transplant recipients with a history of HCC had significantly lower scores than patients without a history of HCC. At first, these findings seem to be paradoxical, since most cancer patients struggle with fatigue syndrome.^40,41 However, a possible ex­planation could be the fact that HCC potentially results in less impairment of liver function than shown in patients with cirrhosis when the transplant is performed. This is because the urgency of OLT in HCC patients is not assessed using the laboratory Model for End-Stage Liver Disease score, which is a good indicator for liver function,⁴² but with an exceptional Model for End-Stage Liver Disease score,⁴³ which does not rely on the actual laboratory findings. A second possible explanation is the presence of a response shift effect. This effect is common in health-related quality of life assessments, which can lead to a change in a person’s values, internal standards, and conceptualization.⁴⁴ The cure of the underlying cancer can potentially lead to a subjectively stronger effect of OLT in HCC patients than in patients without HCC.

Among the social factors, family status (especially being divorced) and education were found to be significantly associated with different levels of fatigue; these observations were also reported in previous studies.^45,46

A strength of our study is the large sample size, which leads to representative results. Moreover, we were able to compare our findings with those of a large reference population. However, the group sizes of our study collective were not homogenous, which may be a potential bias. Another shortcoming is the fact that we did not evaluate fatigue syndrome prospectively. Thus, the identification of factors influencing fatigue would be easier to evaluate in prospective studies.

In summary, we found significantly increased fatigue scores, except reduced motivation, in both posttransplant groups compared with the reference population. However, fatigue was not increased in LKTX patients compared with OLT patients.

Both OLT and LKTX are associated with relevant comorbidities, which led to an increased amount of fatigue symptoms compared with the reference population. Various psychosocial factors, such as education and family status, are related to different levels of fatigue. However, causality can only be suggested since the study design was cross-sectional.

Conclusions

Although patients who received both a liver and kidney transplant are potentially confronted with an increased physical and psychologic stress compared with OLT recipients, both groups of recipients have similar fatigue scores. Nevertheless, fatigue is present in both groups and needs to be taken into account. Fatigue in transplant patients is still poorly understood, and there are many factors influencing fatigue levels.

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