Objectives: The clinical effects of hepatitis C virus infection acquired after transplant have not been thoroughly studied. We aimed to study hepatitis C virus-related morbidity and mortality with de novo hepatitis C virus infection after renal transplant.
Materials and Methods: Data from mortality files were retrospectively collected from January 2011 to January 2015. Patients were divided into 2 groups: hepatitis C virus positive (group A) and hepatitis C virus negative (group B).
Results: Eighty-one patients were included, with median duration of survival of 39 months after transplant. In group A (32 patients), 78.1% of patients were males, with mean age of 36.83 ± 9.15 years. The mean survival duration was better in group A than in group B (67.59 ± 67.1 vs 58.10 ± 59.6 mo; P = .58). Acute cellular rejection was 25% in group A versus 20.4% in group B, whereas chronic allograft nephropathy was 20.4% for group A versus 18.4% for group B. Hepatitis C virus-related death was observed in 7 patients (21.9%). Infection was the main cause of death, with 40.6% of patients in group A versus 53% of patients in group B. On multivariate analyses, better patient survival was associated with greater interval of acquiring HCV after transplant (P = .038).
Conclusions: HCV infection acquired after renal transplant is not associated with increased HCV-related mortality, and prognosis is related to the time interval of acquiring infection after transplant.
Key words : Hemodialysis, HCV, Mortality, Prognosis, Renal transplantation
The survival rate of hepatitis C virus (HCV)-infected renal transplant recipients is excellent compared with HCV-infected hemodialysis patients. Therefore, HCV infection is not considered a contraindication to renal transplant.1 When HCV infection is acquired before renal transplant, the negative effects on graft survival mostly occur between 10 and 20 years after transplant.2 For renal transplant recipients who are infected with HCV shortly before or after renal transplant, little information is available on the course and progression of HCV-related liver disease and renal graft-related mortality and morbidity.
Here, our main objective was to determine the HCV-related morbidity and mortality in renal transplant recipients who acquired infection after renal transplant.
Materials and Methods
Study population and design
Our study included 81 renal transplant recipients who died between January 2011 and January 2015 at Sindh Institute of Urology and Transplantation (Karachi, Pakistan). Transplant procedures for these patients were carried out between 1989 and 2014 at our center. Before renal transplant, as per protocol, all patients and donors were routinely screened for hepatitis B surface antigen and HCV antibody (anti-HCV). All 81 patients were negative for both viral markers before renal transplant, both by serology and by molecular tests (polymerase chain reaction; PCR). These latter tests were done to rule out the possibility of aberrant HCV infection in dialysis patients.3 Study patients were thoroughly investigated before transplant as per standard protocols, including liver function tests to detect occult HCV infection.4
Patients were divided into 2 groups according to the presence or absence of de novo HCV infection, with group A being HCV positive by PCR and group B being HCV negative by PCR. Data were collected from patients’ records. Induction treatments with cyclosporine and methylprednisolone were given at 2 and 15 mg/kg at the time of transplant. Primary immunosuppressive regimen consisted of prednisone, cyclosporine, and azathioprine. In recipients with poor antigen match, antithymocyte globulin (ATG) was used as induction immunosuppressant, whereas tacrolimus was used as primary immunosuppressive agent along with azathioprine and prednisone. Starting doses of cyclosporine, azathioprine, and tacrolimus were 6, 1.5, and 0.15 mg/kg/day.
Statistical analyses were performed with SPSS software (SPSS: An IBM Company, version 20.0, Chicago, IL, USA). All continuous variables are shown as means ± standard deviation and categorical variables as frequencies and percentages. Groups were compared by using chi-squared, Fisher exact, and Mann-Whitney U tests, as appropriate. P values < .05 were considered to indicate statistical significance. Binary logistic regression analysis was used for determining independent risk factors for patient death.
Clinical characteristics and demographics of the 81 renal transplant recipients are shown in Table 1. All donors were negative for anti-HCV and hepatitis B surface antigen (by both serologic and molecular tests) at the time of transplant. Most recipients were male patients (75.3%). The mean duration of survival of all recipients was 61.85 ± 62.48 months (range, 1-305 mo; median of 39 mo). Group A included 32 transplant recipients with positive HCV PCR after renal transplant, and group B included 49 renal transplant recipients negative for HCV PCR. Duration of dialysis before transplant was longer in recipients in group B. In group A, HCV infection was acquired at a mean of 60.25 ± 65.4 months after transplant.
Mean survival was 67.59 ± 67.14 months in group A and 58.1 ± 59.6 months in group B (P = .41). Ascites developed in 20 patients in group A with spontaneous bacterial peritonitis in 3 patients (9.4%). Varices were found in 1 patient only. Cytomegalovirus (CMV) infection and new-onset diabetes mellitus were more often observed in group A than in group B.
Graft and patient survival
The rates of acute and chronic rejection were higher in group A than in group B. Ten patients (31.3%) in group A had graft failure versus 18.4% in group B. Of 32 patients in group A, HCV-related deaths were observed in only 7 patients (21.9%) versus 25 patients (78.1%) with other than HCV-related deaths. In both groups, infection was the most common cause of death (40.6% vs 53.1% in group A vs B). Death due to liver involvement was observed more in group A than in group B. To assess factors that predicted better patient survival, the duration of survival was calibrated as a median value of 39 months. Age (P = .032) and interval between transplant and acquisition of HCV infection (P = .013) were found to be statistically significant on univariate analysis (Table 2). On binary logistic regression analysis, interval from renal transplant and the acquisition of infection was the only independent risk factor for patient survival (P = .038; Table 3).
To our knowledge, the present study is the first to assess the clinical impact of de novo HCV infection acquired after renal transplant. Our study demonstrated that HCV-related deaths are less common than other non-HCV-related causes of death in renal transplant recipients.
Multiple factors have been implicated in liver disease after renal transplant,2 among which HCV is the main cause.5 The prevalence of anti-HCV antibodies among hemodialysis patients ranges from 1% to 83%, depending on generation of anti-HCV tests and the geographic location.6,7 This widely variable prevalence has also been reported in different centers of Pakistan ranging from 16.4% to 68%.8 The frequency of HCV infection in renal transplant recipients ranges from 10% to 65%.9-12 Acquiring HCV infection in this population not only depends on dialysis before renal transplant but also transmission through graft or blood.2,9-12 Hepatis C virus infection acquired before renal transplant has been reported to have variable effects on patient and graft survival.1 Some studies have shown detrimental effects,10,11 whereas others have disagreed.5,12 It has been previously reported that transplant recipients with positive anti-HCV have been on dialysis for longer periods of time than noninfected recipients.12 This has also been reported in a study of 30 patients who acquired HCV infection after renal transplant.2 However, and similar to the study by Toz and associates,5 our patients did not have longer duration of hemodialysis before transplant, with duration of 8.18 ± 11.17 months in HCV-positive and 12.86 ± 13.31 months in HCV-negative patients.
Although new immunosuppressive agents have reduced the incidence of acute cellular rejection in renal transplant recipients, the risk of graft failure from other causes have increased.13 Transplant patients with HCV infection have been reported to have controversial association with acute cellular rejection.2,14 However, studies on patients with HCV infection after renal transplant have reported a higher rate of acute cellular rejection,2 as observed in our study results (25% vs 20.8%). Mahmoud and associates15 first reported the higher prevalence of chronic allograft nephropathy in renal transplant recipients who are anti-HCV positive in 2005. This was further affirmed by the Spanish Chronic Allograft Nephropathy Study Group16 and in Australia and New Zealand Dialysis and Transplant Registry analyses.17 The prevalence of chronic allograft nephropathy in renal transplant recipients who acquire HCV infection after transplant has not been reported. Our study reports for the first time the prevalence of chronic allograft nephropathy in posttransplant HCV-positive patients. In our study, there was a higher frequency of chronic allograft nephropathy in renal transplant recipients with de novo HCV infection versus in patients who were HCV negative (25% vs 18.4%).
In a meta-analyses, Fabrizi and associates18 reported no differences in the rate of bacterial infection between anti-HCV negative and anti-HCV positive groups. However, a multicenter study19 reported anti-HCV as a risk factor for bloodstream infection. In our study, septicemia was the main cause of death in both groups, but the rate of infection was more in patients who were HCV negative than in those who were HCV positive.
Cytomegalovirus infection causes symptoms in 20% to 60% of renal transplant recipients and is an important cause of mortality and morbidity in this population.20 Death rate is increased by CMV-mediated reactivation of HCV infection,11 possible due to enhanced production of tumor necrosis factor α.21 In our study, higher rate of CMV infection was noted in patients with HCV infection; however, whether it affected patient survival or viral load of HCV could not be investigated.
We did not analyze the mode of acquisition of HCV infection in our patients. However, HCV infection is highly prevalent in our country, ranking second in the world22 and accounting for 4.9% rate in the general population.23 The possibility of transmission of HCV infection from the graft is less likely as all donors and recipients were anti-HCV and HCV PCR negative at the time of transplant. It takes around 1 to 3 weeks for HCV PCR to become positive after infection.1 In our study, the mean duration of acquisition of HCV infection after transplant was much longer at 60.25 ± 65.4 months. This excludes the possibility of peritransplant transmission of infection.
Various case reports, encompassing both renal and nonrenal transplant patients, have shown progressive fatal liver failure in HCV-infected recipients.24-26 Lim and associates27 and Pereira and associates28 described increased liver-related mortality with organ-transmitted infection. Toz and associates5 and Ok and associates29 also reported an aggressive course in patients infected shortly before and after renal transplant. Our results contradict the above findings. Although in our study the rate of ascites was high (62.5%) depicting impaired liver function, liver-related deaths occurred in 28.1% of recipients. This discrepancy can be attributed to HCV infection acquired late after transplant, a longer period than in previously reported studies. The other possible factor may be that, in both previous studies, the possibility of HCV-infected donors could not be ruled out due to unavailability of anti-HCV tests at that time, whereas in our study, as per protocol, anti-HCV donors were not accepted for transplant donation.
Toz and associates5 identified recipient age as an independent risk factor for survival in patients with HCV infection after renal transplant. On univariate analysis, age was also found to be a significant factor; however, on multivariate analysis, the time interval between transplant and acquisition of HCV infection was found to be statistically significant. The importance of this interval has also been noted in previous studies,2,5 where patients had worse survival if they were infected during the early posttransplant period. In our study, patients had better survival, as HCV infection was acquired quite late after transplant.
Our study possesses some limitations. Its retrospective nature confers unavoidable biases. Tests for HCV viral load were not performed in our study, and no treatment was given to HCV-positive patients. Despite these limitations, to our best knowledge, this is the first study to demonstrate the clinical effects of HCV infection acquired after renal transplant.
Hepatitis C virus infection acquired after renal transplant is associated with increased renal graft-related pathology but not with increased HCV-related mortality. The prognosis of patients with de novo HCV infection posttransplant is related to the time interval of acquiring infection after transplant.
Volume : 15
Issue : 1
Pages : 56 - 60
DOI : 10.6002/ect.2016.0034
From the 1Department of Hepatogastroenterology, the 2Department
of Nephrology, and the 3Department of Pathology, Sindh Institute of
Urology and Transplantation, Karachi, Pakistan
Acknowledgements: The authors declare that they have no sources of funding for this study, and they have no conflicts of interest to declare.
Corresponding author: Farina M. Hanif, Department of Hepatogastroenterology, Sindh Institute of Urology and Transplantation, Karachi-74200, Pakistan
Phone: +922 199 215 752
Table 1. Demographics and Clinical Features of Renal Transplant Recipients
Table 2. Comparing Patient Survival of Renal Transplant Recipients
Table 3. Multivariate Analysis