Objectives: The preferred modality for renal replace-ment therapy is renal transplantation. Marked improvements in early graft survival and long-term graft function have made renal transplantation a more cost-effective alternative to dialysis. The presence of liver disease in the posttransplant period adversely affects graft function and survival. Determining the cause of deranged liver function tests can be helpful in treating the underlying cause, leading to improved graft survival and overall quality of life in patients after renal transplant. Here, we determined the frequency of hepatotropic viral infections leading to deranged liver function tests in renal transplant recipients.
Materials and Methods: Our study included 132 patients with deranged liver function tests who had undergone renal transplant within the past 6 months. Reactivity and nonreactivity of hepatotropic viruses leading to deranged liver function tests were recorded.
Results: Average age of patients was 37.17 ± 8.75 years. There were 84 male (63.64%) and 48 female (36.36%) patients. Rates of hepatitis C virus antibodies and hepatitis B surface antigen were 62.88% (83/132) and 37.12% (49/132), respectively, whereas no patients had hepatitis E virus immunoglobulin M antibodies or hepatitis A virus immunoglobulin M antibodies.
Conclusions: Among the hepatotropic viral infections leading to deranged liver function tests in renal transplant recipients, hepatitis B virus accounted for a small fraction. In contrast, hepatitis C virus was highly prevalent in transplant recipients who developed deranged liver function tests. Renal transplant recipients with hepatic viral infections have worse patient and allograft survival after transplant compared with noninfected renal transplant recipients. We recommend that transplant candidates be screened for hepatitis B and C virus infection, thus allowing increased graft survival and improved quality of life in renal transplant recipients.
Key words : Hepatitis B virus, Hepatitis C virus, Hepatotropic viral infections, Kidney transplant
The superiority of renal transplantation in prolonging the longevity of patients with end-stage renal disease is well established.1 Around the world over the past 3 to 4 decades, thousands of renal transplants have been performed, yet the wait list has increased threefold.2 Marked improvements in early graft survival and long-term graft function have made renal transplantation a more cost-effective alternative to dialysis.
Liver disease has emerged as an important cause of morbidity and mortality in renal transplant recipients.3 Various studies have reported liver dysfunction in 7% to 67% of kidney transplant recipients.4-7 Moreover, liver insufficiency is the cause of death in up to 28% of long-term survivors after renal transplant.8 The causes of liver dysfunction after renal transplant can be classified broadly into viral and nonviral causes. Viral infections are important causes of hepatic complications in renal transplant recipients. In developing countries, these viral infections are more common due to many risk factors, including malnutrition, poverty, and tropical climate.9
Hepatotropic viruses, including hepatitis A (HAV), hepatitis B (HBV), hepatitis C (HCV), and hepatitis E virus (HEV), cause persistent hepatic dysfunction. Hepatitis C virus infection is found to be the most common factor responsible for hepatic dysfunction and graft loss. Its prevalence in renal transplant recipients is reported to be 65% with hepatic impairment shown in 28.5% of these patients.10 The prevalence of HBV is relatively low due to effective vaccination during hemodialysis. The prevalence of HBV is reported to be 0.8% with elevated liver enzymes in renal transplant patients.11 Regarding HEV, 1 study showed that 12 patients of 1200 solid-organ transplant recipients were infected with HEV; bilirubin levels were elevated in 45.5% of these patients.12
The presence of liver disease after renal transplant adversely affects graft function and survival. Determining the cause of deranged liver function tests (LFTs) can be helpful in treating the underlying cause, thus increasing graft survival and improving the overall quality of life of renal transplant recipients. In this study, we aimed to determine the frequency of hepatotropic viral infections leading to deranged LFTs in renal transplant recipients.
Materials and Methods
This cross-sectional study was conducted in the Department of Hepatogastroenterology, Sindh Institute of Urology and Transplantation (Karachi, Pakistan). Ethical approval was given by our institutional ethics committee.
Deranged LFTs were considered when any 1 or more of the following were present13-16: total bilirubin > 1.2 mg/dL, direct bilirubin > 0.3 mg/dL, alkaline phosphatase > 140 IU/L, gamma-glutamyltransferase > 50 IU/L, aspartate aminotransferase > 40 IU/L, and alanine aminotransferase > 40 IU/L.
Exclusion criteria included the following: patients with preexisting liver disease before kidney trans-plant, renal transplant recipients known to have choledochal cysts or any other congenital anomalies, and ultrasonograph-documented dilatated common bile duct due to any reason.
Male and female patients between 18 and 60 years old with deranged LFTs who had undergone renal transplant within the past 6 months were included in the study. Written informed consent was obtained from each patient. History was taken for age, residence, level of education, and compliance. Height and weight were checked to calculate body mass index (BMI). Liver function tests consisting of total bilirubin, direct bilirubin, alanine aminotransferase, aspartate aminotransferase, alkaline phosphatase, and gamma-glutamyltransferase were conducted using the Beckman Coulter Synchron Clinical System (model DXC 800 Unicell; Beckman Coulter, Fullerton, CA, USA). Deranged LFT patterns were recorded. Anti-HCV antibody and HBV surface antigen tests were performed by enzyme-linked immunosorbent assay. The reactivity and nonreactivity results of hepatotropic viruses leading to deranged LFTs were recorded.
With an estimated patient population of 200 renal transplants during the previous 6 months and an estimated average prevalence of 50% of elevated liver enzymes in renal transplant recipients and applying the Rao soft sample size calculator (d = 8.5% and confidence interval = 95%), our estimated sample size was 132.
Statistical analysis was performed using SPSS software version 20.0 (SPSS Inc., Chicago, IL, USA). Frequencies and percentages were calculated for binary variables (patient sex, presence of hepato-tropic viruses, residence, compliance, and level of education). Measures of central tendency (including mean and SD) were calculated for continuous variables (including age and duration since renal transplant, height, weight, and BMI). Modifiers like age, level of education, residence, sex, duration since renal transplant, and BMI were stratified to see the effects of these on outcome. After stratification, chi-square tests were applied. P < .05 was significant.
Our study included 132 patients with deranged LFTs who had undergone renal transplant within the past 6 months. Demographic characteristics of patients are shown in Table 1.
Of total patients, 84 (63.6%) were male. Most recipients (n = 53; 40.15%) were 41 to 50 years old, 47 (35.61%) were 31 to 40 years old, and 32 (24.24%) were ≤ 30 years old. Duration from renal transplant to presentation of deranged LFTs was 3.13 ± 1.2 months.
Fifty-three patients (40.1%) were from urban residential areas. Most patients (n = 78; 59.09%) were illiterate (Table 2), and 105 renal transplant recipients were compliant with immunosuppression prescription and follow-up.
Rates of anti-HCV antibody and HBV surface antigen were 62.88% (83/132) and 37.12% (49/132), respectively. No patients showed anti-HEV immuno-globulin M (IgM) or anti-HAV IgM.
Rates of hepatotropic viral infections leading to deranged liver function were significantly associated with duration since transplant and education status of the study population. Stratification analyses showed no significant association with patient age, sex, residence, and BMI (Table 3).
A high prevalence of hepatic dysfunction in the posttransplant period has been noted from the earliest days of renal transplantation,17,18 and many articles have since been written attempting to define the incidence and cause of these abnormalities of liver function.19 Most often incriminated in this setting have been infections with either HBV20,21 or Cytomegalovirus13 and azathioprine therapy.14,15 The degree to which each of these agents has been held responsible varies from report to report. Equally variable has been the reported incidence of hepatic dysfunction, the clinical severity of the liver disease, and the risk of its progression to massive hepatic necrosis or postnecrotic cirrhosis. Although patient survival after renal transplant has improved, it has been associated with medical complications that both impair the quality of life of transplant recipients and substantially add to societal health care costs. Infection is one of the most important medical complications of transplantation. Over time, the pattern and severity of various infections have changed, with noticeably reduced severity. Along with reduction in incidence, mortality due to infections has decreased from 40% to less than 5%.16
The average age of patients with end-stage renal disease has increased each year worldwide. In our study, 40.15% of patients were 41 to 50 years of age, 35.61% were 31 to 40 years old, and 24.24% were ≤ 30 years of age.
In Europe, most dialysis patients are men, whereas there is only a small difference between sexes in the United States.22 Male sex is associated with a more rapid progression of renal injury in nondiabetic kidney disease.23 In the 2005 annual report from Norway, 64.5% of patients who received renal replacement therapy were men.24 Similarly, in our study, 63.64% of patients were male and 36.36% were female. Due to difference in sociocultural and economic roles, inconsistent knowledge may be present between men and women, and women have been considered less informed regarding trans-plantation. However, another important factor should be considered to explain the above-reported gender bias. Specifically, potential mechanisms for related protection in women include differences in renal structure, including glomerular number and size, renal hemodynamics, and different effects of estrogen or androgen on the synthesis and release of vasoactive substances, growth factors, and cytokines.25
Hepatotropic viral infections occur frequently in allograft recipients and may be caused by a number of different viruses. Of these, the most important infectious agents are HBV and HCV, which can cause both acute and chronic hepatitis. In addition, HEV, thought previously to only cause acute hepatitis in the developing world, has emerged as an increasing cause of chronic hepatitis and even cirrhosis in solid-organ transplant recipients in industrialized countries.26,27 In our study, the frequency of hepatotropic viral infections leading to deranged LFTs in renal transplant recipients, as shown by incidence of anti-HCV antibody and HBV surface antigen, was 62.88% and 37.12%, respectively. Anti-HEV IgM and anti-HAV IgM were not found in this study. The prevalence of HBV surface antigen seropositive status among renal transplant recipients varies among countries28 and has been decreasing over time.29-31 Mathurin and associates reported that HBV surface antigen prevalence has significantly decreased (from 24.2% before 1982 to 9.1% after 1982; P < .001).29 Recently, Santos and associates30 showed a marked decline in HBV infections over the past 15 years (from 6.2% in 1994 to 2.3% in 2006). Among renal transplant recipients, the reported prevalence of HCV infection ranged from approximately 1.8% to 8%.32,33 Most HCV-infected transplant recipients are infected before transplant while on dialysis.34 Transmission of HCV through kidney transplant is rare due to donor screening.34 A more recent analysis showed that HCV alone may be prevalent in 40% of renal transplant recipients.35
Among hepatotropic viral infections leading to deranged LFTs after renal transplant, HBV accounts for a small fraction. In contrast, HCV is highly prevalent in transplant recipients who develop deranged LFTs. Renal transplant recipients with hepatic viral infections have worse patient and allograft survival after transplant than noninfected renal transplant recipients. We recommend that transplant candidates be screened for HCV and HBV infections to hence increase graft survival and improve overall quality of life after renal transplant.
Volume : 17
Issue : 1
Pages : 202 - 206
DOI : 10.6002/ect.MESOT2018.P66
From the Department of Hepatogastroenterology, Sindh Institute of Urology and
Transplantation (SIUT), Karachi, Pakistan
Acknowledgements: The authors have no sources of funding for this study and have no conflicts of interest to declare.
Corresponding author: Farina Muhammad Hanif, 48/2, Lane 15, Khayaban-e-Badban, DHA phase VII, Karachi, Pakistan
Phone: +92 3002171785
Table 1. Descriptive Statistics and Demographic Data of Patients (N = 132)
Table 2. Frequency of Hepatotropic Viral Infections Leading to Deranged Liver Function Tests as Classified by Education Level
Table 3. Frequency of Hepatotropic Viral Infections Leading to Deranged Liver Function Tests as Classified by Duration Since Renal Transplant