The Impact of Hepatitis C Virus Infection on the Clinical Course, Short Term and Long–Term Outcome in Renal Transplant Recipients–A Prospective and Retrospective Study

Viral hepatitis is prevalent in patients with end stage renal disease (ESRD) on renal replacement therapy (RRT) because the patients are exposed to the transmission risk factors such as blood transfusion and nosocomial factors, etc. Nevertheless, there has been a decrease in the prevalence of hepatitis B infection after the application of vaccination program, isolation of infected patients and common use of erythropoiesis stimulating agents.


Introduction
Viral hepatitis is prevalent in patients with end stage renal disease (ESRD) on renal replacement therapy (RRT) because the patients are exposed to the transmission risk factors such as blood transfusion and nosocomial factors, etc. Nevertheless, there has been a decrease in the prevalence of hepatitis B infection after the application of vaccination program, isolation of infected patients and common use of erythropoiesis stimulating agents.

Abstract
Background: Hepatitis C (HCV) Infection is not uncommon in patients on maintenance hemodialysis (around 10% in our dialysis population). It is also known to increase morbidity and mortality in Renal Allograft Recipients more so in post-transplant period with various studies quoting mixed results.
Aim: To fi nd the impact of HCV infection on graft and patient survival and to compare the incidence of rejection, infections, liver dysfunction, NODAT(New Onset Diabetes after Transplantation) in HCV infected and negative patients.

Setting and Design:
Retrospective and prospective institutional based study.
Method: HCV RNA positive patients without portal hypertension/abnormal liver scan were included in the study. Patients were divided into three groups on the basis of whether or not they received anti HCV treatment and how they responded to it.

Results and Conclusion:
Patients who are anti-HCV positive before transplantation have a signifi cantly increased risk of post-transplant liver disease. Most of the literature quotes a relative risk of 5 and an incidence of 19%-64% for post-transplant liver disease.(Vs. 1%-30% for general population) In our study 15% of patients had deranged liver function post-transplant however none of these patients showed any sign of decompensation. Confl icting results surround the question as to whether post-transplant liver disease is associated with decreased survival. As an example, three studies failed to detect signifi cant differences in patient survival between recipients with and without anti-HCV prior to renal transplantation. The same fact is also highlighted in our study where in there were no graft loss and the patient survival were comparable to our regular cohort at 1 and 5 year post transplant. Rejection rate were higher compared to regular cohort particularly in modern era. As such renal transplant is a safe and viable option in HCV + patients with or without anti HCV treatment pretransplant medically, fi nancially, socially and physically. chronic hepatitis in patients with end-stage renal disease.
The effect of HCV infection on patient survival after kidney transplantation has been a subject of debate, with some but not all studies fi nding an increased risk of death among patients with a positive anti-HCV antibody before transplantation [1,2].
Even though there has been signifi cant amount of research worldwide, to the best of our knowledge, there has been limited information on the prognosis of HCV-infected patients who have had received kidney transplantation in India [3][4][5][6]. The prevalence of HCV infection among patients undergoing haemodialysis in our country is at around 10% which is considered to be high. Renal transplantation (RTx) is considered as the treatment of choice in HCVinfected ESRD patients compared to dialysis treatment [5,6].
However, the impact of HCV infection on graft and patient survival after RTx remains controversial. Several studies suggest that HCV infection could worsen both graft and patient survival rates [7] and increase the risk of post-transplant infections, sepsis and diabetes mellitus [8,9]. On the other hand, some studies have documented that HCV infection did not infl uence patient or graft survival signifi cantly [10][11][12].
The purpose of this study is to determine the effect of HCV infection on patient-graft survival and liver function in renal allograft recipients.

Study area
The study was conducted in the Department of Nephrology

Sample size and sample technique
The medical reports of the patients were evaluated retrospectively as well as prospectively.
HCV infected prospective transplant patients were offered HCV treatment with GFR appropriate doses of Pegylated Interferon -2a (once weekly) and oral Ribavarin (once daily). However, refusal to take HCV treatment on part of the patient or, inadequate response to the therapy was not a criterion for refusal of transplantation. Patients were grouped into three groups as under ( Figure 1). 3. Those who refused HCV related treatment.

Data collection technique and tools
The period of data collection was from January 2008 to February 2014. As both prospective and retrospective data was collected; duration of follow up was atleast 12 months post transplantation in the prospective arm and in the retrospective arm the mean duration of follow up was 18±7 months was done. These three groups mentioned above were then compared to the historical HCV negative transplant recipients of the centre. The control group was selected from recipients who were HCV-negative and matched for age, sex, donor type, pretransplantation dialysis duration, cytotoxic antibody status, and immunosuppressive regimen.
Physical examination and biochemical tests including liver function tests and renal function test were performed at the The Fisher exact test, chi-square test, Mann Whitney U test, and Student t test were used to make univariate comparisons. The Kaplan-Meier method and log rank test were used for patient and graft survival analyses. Continuous variables were demonstrated as mean ± standard deviation or median, where appropriate. The criterion for statistical signifi cance was a P value less than 0.05.

Results
Among 51 patients in our study group who were HCV +ve there were 40 males (78.43%) and 11 females (21.56%). Likewise the maximum numbers of patients were in the age group of 30-60 years which comprised about 71% .The highest average aged patient belonged to group 1 followed by 2 and 3 respectively. The most common cause of renal failure across the three groups was chronic glomerulonephritis (CGN) followed by diabetes and hypertension. Among 51 patients we had only one patient of ADPKD who was also HCV+ve.
The minimum and maximum period for which the patient was on hemodialysis prior to transplant was 3 and 48 months respectively and the mean duration was 25±22 months.
The duration for which patients took anti HCV treatment ranged from 1 to 24 months with a mean of 12.5±10 months.
The most common genotype encountered was 3 followed by 1 and 2.
Highest number of deaths was observed in patients not receiving any induction therapy; however infections were more common in the induction group. A total of 5 patients died of sepsis (9.8%). 3 out of 5 deaths occurred in group 2 and 2 deaths in group 3 who received no anti HCV treatment.
Interestingly the maximum number of rejection was observed in group 2 who received anti HCV treatment for some duration but did not respond to it. The incidence of NODAT was 17.6% and all cases were seen in patients taking tacrolimus. Further most of these cases occurred in Group 2 patients.
In our regular cohort incidence of NODAT was 14.92%.
Death rate in our study was 3.92%, 5.88% and 9.8% at 1, 3 and 5 years respectively. Consequently patient survival rates at 1, 3 and 5 years were 96.02%, 94.12% and 90.1% respectively. Number of death was equally distributed among Group 2 and 3 but was null in Group 1 which received adequate treatment and responded to it favourably.
We had one graft loss among 51 patients in our study (1.96%) and about 1.91% in our regular cohort.
On comparing the variables of patient survival, graft survival, infections, incidence of NODAT and effect of transplantation (liver enzymes, renal function tests, viral load) among the three groups it was not found to be statistically signifi cant.
However when comparing it to our regular cohort the incidence of infection was indeed higher as was the acute rejection rate (17.6% Vs. 7.62) and incidence of NODAT (17.6% vs. 14.2%) but which again was not statistically signifi cant.
These results have been tabulated as shown in tables 1-3.

Conclusions
Our data suggest that HCV infection per se has no adverse effect on short-term and long-term graft and patient survival.
Rate of acute rejection was comparable among HCV+ve patients receiving or not receiving anti HCV treatment, though rejection rate was higher when compared to HCV-ve cohort. Incidence of other complications like infection, NODAT, hospitalization and liver failure was not statistically signifi cant among the HCV+ve group. However it was higher when compared to the regular cohort. Since sepsis was slightly more frequent as the cause of death in HCVpositive patients, kidney transplant recipients with HCV infection should be monitored for severe systemic bacterial infections.
Renal transplantation is still plausible in patients not responding adequately or not undergoing anti HCV treatment prior to transplant since survival rates are better in patients undergoing transplantation then those who remain on hemodialysis. These conclusions were based on comparison of the three subgroups with the historical HCV-ve cohort.

Recommendations
The recommendations from our study are as under; Induction therapy decreases the incidence of acute rejections