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Saudi Journal of Kidney Diseases and Transplantation
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Table of Contents   
ORIGINAL ARTICLE  
Year : 2013  |  Volume : 24  |  Issue : 4  |  Page : 682-687
Outcomes following renal transplantation in patients with chronic hepatitis C based on severity of fibrosis on pre-transplant liver biopsy


1 Methodist Transplant Institute, The University of Tennessee Health Sciences Center, Memphis, TN, USA
2 Division of Digestive Diseases, Section of Hepatology, Emory University School of Medicine, Atlanta, GA, USA

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Date of Web Publication24-Jun-2013
 

   Abstract 

Data regarding long-term outcomes following renal transplantation in patients with hepatitis C virus (HCV) infection have been controversial. Our aim was to determine whether there is a difference in outcomes between patients with HCV and more advanced fibrosis on pretransplant biopsy and those with minimal or no fibrosis. Patients were divided according to the severity of fibrosis and their outcomes (including acute rejection, chronic rejection, re-initiation of dialysis, progression of liver disease and mortality) were compared. Thirty-one patients with minimal or no fibrosis (Scheuer stages 0 and 1: Group-A) and 10 patients with more advanced fibrosis (Scheuer stages 2 and 3: Group-B) were included in the final data analysis. Acute rejection occurred in 29% (9/31) of the patients with minimal and 30% (3/10) of the patients with advanced fibrosis (P = 0.95), while chronic allograft nephropathy occurred in 6.5% (2/31) of the patients without and 50% (5/10) of the patients with fibrosis (P = 0.006). None of the patients without fibrosis required re-initiation of dialysis compared with 50% (5/10) of the patients with fibrosis (P <0.05). Median graft survival was 46 months and 18 months for patients with minimal and advanced fibrosis, respectively. There were four deaths among patients with advanced and three deaths among patients with minimal fibrosis (P = 0.04). Our data suggests that patients with chronic HCV and more advanced fibrosis on liver biopsy who undergo a renal transplant have a higher incidence of chronic rejection, graft failure and mortality following renal transplant compared with those with minimal fibrosis.

How to cite this article:
Dbouk N, Parekh S. Outcomes following renal transplantation in patients with chronic hepatitis C based on severity of fibrosis on pre-transplant liver biopsy. Saudi J Kidney Dis Transpl 2013;24:682-7

How to cite this URL:
Dbouk N, Parekh S. Outcomes following renal transplantation in patients with chronic hepatitis C based on severity of fibrosis on pre-transplant liver biopsy. Saudi J Kidney Dis Transpl [serial online] 2013 [cited 2014 Nov 24];24:682-7. Available from: http://www.sjkdt.org/text.asp?2013/24/4/682/113847

   Introduction Top


The prevalence of chronic hepatitis C virus (HCV) among patients with end-stage renal disease (ESRD) on hemodialysis (HD) ranges between 10% and 30%, which is more than five times in the general population. [1],[2] Studies have shown that patients with HCV on HD who receive a kidney transplant have better survival than those who are not transplanted. [3] On the other hand, data on the long-term outcomes of HCV patients following kidney transplantation have been controversial, with some studies showing no difference in graft and patient survival between HCV-positive and HCV-negative patients, [4],[5] while others showing that patients with HCV had worse outcomes following a renal transplant. In a study by Legendre et al, mortality was significantly higher among patients with HCV compared with those without HCV (13.4% vs. 4.9%) after a mean follow-up of approximately 80 months following kidney transplantation (OR: 2.8 for mortality among patients with HCV). [6] Similarly, Hanafusa et al found that patients with HCV who underwent a kidney transplant had a worse 10- and 20-year survival compared with patients who were HCV-negative (83.7% vs. 88.9% and 63.9% vs. 87.9%, respectively). [7] Not all studies are in agreement with these findings. In a large study of 73,707 kidney transplant recipients including 535 patients with HCV, Ulf Meier-Kriesche et al found no difference in patient and graft survival at eight-years following transplant between patients with and without HCV. [4] Controversy also exists regarding the long-term course of HCV infection following a kidney transplant. Kliem et al found that progression to end-stage liver disease occurred in only 4.3% of the HCV pa­tients following transplant and that liver disease did not impact the overall patient and graft survival after a mean follow-up period of 7.4 years. [5] In another study by Alric et al, the rate of progression of liver fibrosis was similar between patients with HCV who underwent a renal transplant and those with HCV without kidney disease. [8] On the contrary, Legendre et al and Hanafusa et al found that chronic liver disease was responsible for an increase in mortality among patients with HCV compared with those without HCV following kidney transplantation. [6],[7] Furthermore, it remains unclear whether or not the severity of underlying liver disease in patients with HCV has an impact on outcomes after renal transplantation. Currently, there are no reliable serum laboratory markers that correlate with liver histology in patients with ESRD, [9] underscoring the need for a liver biopsy as the most accurate assessment of underlying liver disease before renal transplantation. To the best of our knowledge, there is only one study published that has examined the effects of liver fibrosis by pre-transplant liver biopsy on patient survival following kidney transplant among patients with chronic HCV. [10] After a median follow-up period of 52 months post-transplant, the investigators found no difference in mortality between patients with advanced fibrosis (stages 3 and 4) and those with less-advanced fibrosis (stages 0, 1 and 2). This study did not examine whether or not the severity of liver disease based on pre-transplant liver biopsy had any impact on graft survival following kidney transplantation.


   Methods Top


This was a retrospectively designed study evaluating the outcomes following renal transplantation among patients with chronic HCV, comparing them based on the degree of hepatic fibrosis by pre-transplant liver biopsy. Data were collected from our electronic transplantation database, the Organ Transplant Tracking Record (OTTR). The OTTR is a prospectively maintained repository of all clinical patient information at The Emory Transplant Center. All patients with chronic HCV who underwent renal transplantation at The Emory University Hospital between 1 January 1998 and 1 January 2008, and who underwent a liver biopsy prior to transplantation, were included in the study. Patients were divided into two groups based on the degree of hepatic fibrosis by pretransplant biopsy; Group-A included patients with stage 0 or 1 fibrosis and Group-B included patients with stage 2 or 3 fibrosis. Staging was according to the Scheuer classification system. None of the patients with stage 4 fibrosis (cirrhosis) underwent single organ renal transplantation; these patients were referred for combined liver and kidney transplantation and were excluded from the data analysis. Patients were also excluded if they tested positive for hepatitis B, if they had any other cause(s) of chronic liver disease or if they had any evidence of decompensated liver disease including ascitis, encephalopathy, variceal bleeding, jaundice or hepatocellular carcinoma. Serum levels of creatinine, liver enzymes and bilirubin, prothrombin time, platelet count and viral load were recorded at baseline and then at 1, 3 and 5 years post-renal transplant. We also obtained data on patient ethnicity, gender, age at transplant, genotype, pre-transplant HCV treatment with interferon and the presence of co-morbid illnesses, including diabetes and cardiovascular disease, as well as data on immunosuppressant regimens received following transplantation. The outcomes evaluated were acute rejection, chronic allograft nephropathy (CAN), need for re-initiation of HD, progression of liver disease and mortality from all causes in both study groups. A diagnosis of acute rejection or CAN was made based on histological examination of allograft biopsy samples. Progression of liver disease was assessed based on laboratory parameters of liver function, clinical evidence of decompensated liver disease and follow-up liver biopsies obtained following renal transplantation. Statistical analysis was performed using the SPSS 16 for windows software. The Fisher exact test was used for qualitative data and the Wilcoxon test for quantitative data. A P-value less than 0.05 was considered significant.


   Results Top


Forty-one patients with chronic HCV and ESRD underwent a renal transplant during the specified time period of our study and had a liver biopsy prior to their transplantation. Liver biopsies were obtained at a median of 19 months prior to transplantation. Thirty-one patients had no or minimal fibrosis (Scheuer stage 0 or 1) and constituted Group-A, while the remaining 10 patients had more advanced fibrosis (Scheuer stage 2 or 3) and constituted Group-B. Thirty-two patients (78%) were male, nine (22%) were female; 27 patients were African-American (66%), 12 were Caucasian (29%) and two were Hispanic (5%). Genotype data was available for 30 patients, with the most common genotype being 1 (24/30: 80%). The most common etiology of ESRD was hypertensive kidney disease (22/41: 54%). Other common etiologies included diabetic nephropathy (8/41: 20%) and glomerulonephritis (8/41: 20%). The majority of patients (38/41: 93%) received deceased donor kidney grafts. There was no difference in baseline amino-transferase levels, prothrombin time, platelet count, genotype, viral load and age at transplant between the two groups [Table 1]. Immunosuppressant regimens were identical between the two groups, with the majority of patients receiving a combination of tacrolimus (36/41: 88%), mycophenolate (31/41: 76%) and low-dose prednisone not exceeding 10 mg (41/41: 100%). Acute rejection occurred in 29% (9/31) of the patients in Group-A and 30% (3/10) of the patients in Group-B (P = 0.95), while CAN occurred in 6.5% (2/31) of the patients in Group-A and 50% (5/10) of the patients in Group-B (P = 0.006). Diagnosis of acute rejection and CAN was based on histological examination of renal biopsy samples obtained from patients with evidence of impaired renal function following transplantation. None of the patients in Group-A required re-initiation of dialysis compared with 50% (5/10) of the patients in Group-B (P < 0.05). The median graft survival was 46 and 18 months (P = 0.15) and the mean graft survival was 51.4 ± 34.3 and 35.9 ± 36.9 months (P = 0.23), respectively, for patients in Group-A and Group-B [Table 2]. There were three deaths among patients in Group-A and four deaths among patients in Group-B (P = 0.04). The main causes of death were sepsis and cardiovascular disease. None of the patients had any symptoms consistent with decompensated liver disease, such as ascitis, hepatic encephalopathy, jaundice or variceal bleeding during follow-up, and none of the deaths were due to complications of liver disease. There was no significant difference in the mean amino-transferase levels, platelet counts and prothrombin time at 1, 3 and 5 years post-transplant between the two groups. Viral load measurements were available for both groups at 1 and 3 years; additionally, for Group-A patients, the values were available at 5 years post-transplant. The serum creatinine levels were similar in both groups at one-year post-transplant (Group-A: 1.55 ± 0.55 and Group-B: 1.63 ± 0.32 mg/dL, P = 0.74); however, the creatinine levels at three and five years were significantly higher among patients in Group-B (2.08 ± 0.36 and 2.80 ± 1.31 mg/dL) compared with that in Group-A (1.53 ± 0.45 and 1.39 ± 0.38 mg/dL), with P-values of 0.035 and 0.016, respectively. The odds ratio for mortality and graft failure among Group-B patients were 6.2 (P = 0.047) and 14.5 (P = 0.006), respectively.
Table 1: Baseline characteristics of patients in the two study groups.

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Table 2: Comparison of primary outcomes between Group-A and Group-B.

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Follow-up liver biopsies were available for ten patients (25%), and these showed evidence of histological progression in three patients (all three patients had minimal fibrosis pre-transplant and progressed to bridging fibrosis post-transplant). Three patients with advanced fibrosis on pre-transplant biopsy had stable disease or regression to a lower stage. The median interval between pre- and post-transplant liver biopsies was 81 months, with the main indication being abnormal liver enzymes.


   Discussion Top


Hepatitis C is very common among patients with ESRD, with an estimated prevalence ranging between 10% and 30%. Studies have shown that patients with HCV and ESRD who receive a kidney transplant have better outcomes compared with those who remain on long-term HD. There is still significant controversy regarding the long-term outcomes following kidney transplant between patients who have HCV and those who do not. Several studies have demonstrated worse graft and patient survival among HCV-positive patients following kidney transplant after ten and 20 years of follow-up, while other studies have found similar patient survival between patients with HCV and those without HCV. Data on the course of HCV infection following kidney transplantation has also been conflicting. While some studies have demonstrated no difference in the rates of progression of liver fibrosis or mortality from chronic liver disease, other studies have found that an increased mortality among patients with HCV who underwent kidney transplantation was in fact due to progressive liver disease. Furthermore, it remains unclear whether the severity of underlying liver disease pre-transplant has any impact on patient outcomes following kidney transplantation among HCV-positive patients. Only one study so far has tried to address this question. This study included 58 patients with HCV and ESRD, including 10 patients with advanced fibrosis (METAVIR stages 3 or 4) who underwent kidney transplantation. There was no difference in survival between patients with advanced fibrosis and those with less-advanced fibrosis (stages 0, 1 or 2) after a median follow-up of 52 months. It should be noted that patients in the advanced fibrosis group were younger and had a lower incidence of diabetes mellitus. This study did not report the main causes of mortality and also did not examine the effect of severity of pre-transplant liver disease on graft survival. To the best of our knowledge, our study is the first to evaluate renal graft survival among patients with HCV undergoing kidney transplantation, based on the severity of underlying liver disease determined by pre-transplant liver biopsy. In our study, patients with more advanced liver fibrosis (Scheuer stages 2 or 3) had similar rates of acute rejection compared with those with less-advanced fibrosis. However, they had higher rates of CAN, higher likelihood of requiring re-initiation of HD and higher mortality rates. The median and mean graft survival was shorter among Group-B patients compared with Group-A patients (18 vs. 46 months and 51 vs. 36 months, respectively). The main causes of mortality for patients in both groups were sepsis and cardiovascular disease, which is similar to the findings from other outcomes series of patients following kidney transplantation, where the major causes of death were cardiovascular disease, infections and malignancy. There have been several studies showing that HCV independently conferred an increased risk for cardiovascular disease, which can further explain the prevalence of cardiovascular disease among our patients. [11],[12],[13] None of the deaths in our study were attributed to complications of liver disease. In fact, there was no observed difference in amino-transferase levels, bilirubin and prothrombin times between patients in the two Groups at 1, 3 and 5 years following transplantation. The creatinine levels were significantly higher in Group-B patients at three and five years post-transplant, which is expected given a higher incidence of chronic rejection among these patients compared with patients in Group-A.

Our study had several limitations. The number of patients included in the data analysis was small, and only a small proportion of these patients had advanced fibrosis (stages 2 or 3). Patients with cirrhosis were not included because they were referred for combined liver and kidney transplantation. Follow-up liver biopsies after kidney transplantation were available in only ten patients. Histological progression to more advanced stages was noted in three of those patients, while the others had stable or improved histological findings. The median interval between pre- and post-transplant liver biopsies was 81 months, which is an adequate amount of time to allow for disease progression. Although we did show that patients in both groups had similar liver enzymes and similar parameters of liver function such as prothrombin time, bilirubin and platelet count, these are less accurate than a liver biopsy for defining hepatic fibrosis. Data on viral loads was incomplete at three and five years post-transplantation; however, none of the earlier studies have shown any association between viral loads and outcomes post-renal transplantation.

The main finding in our study was the higher incidence of CAN among patients with more advanced liver fibrosis. The underlying cause for this is unclear. Patients in both groups had similar immunosuppressant regimens consisting mainly of tacrolimus, mycophenolate and low-dose prednisone. Tacrolimus is mostly metabolized by the liver and mycophenolate is converted to its active metabolite through enterohepatic circulation. It is thus possible that patients with more advanced liver fibrosis have impairment in metabolic pathways involved in the activation and metabolism of immunosuppressant drugs. Our patients were carefully followed-up post-transplant and the drug levels were monitored periodically and adjusted as needed; however, this did not prevent the development of CAN in 50% of the patients with advanced liver fibrosis.

In conclusion, this single-center retrospective study was the first to evaluate renal transplant outcomes based on severity of liver fibrosis. Our study demonstrated that patients with HCV who had more advanced fibrosis at baseline had a higher incidence of graft failure, shorter graft survival and higher mortality rates compared with patients with minimal fibrosis on pre-transplant biopsy; however, advanced liver disease was not a cause of mortality in either group. Large prospective studies are still needed to determine the effects of baseline liver disease on outcomes post-renal transplantation in HCV-positive patients to help guide transplant practices.

 
   References Top

1.Mathurin P, Mouquet C, Poynard T, et al. Impact of Hepatitis B and C virus on Kidney Transplantation Outcome. Hepatology 1999;29: 257-63.  Back to cited text no. 1
    
2.Martin P, Carter D, Fabrizi F, et al. Histopathological features of hepatitis C in renal transplant candidates. Transplantation 2000;69: 1479-84.  Back to cited text no. 2
    
3.Pereira BJ, Natov SN, Bouthot BA, et al. Effect of hepatitis C infection and renal transplantation on survival in end-stage renal disease. Kidney Int 1998;53:1374-81.  Back to cited text no. 3
    
4.Ulf Meier-Kriesche H, Akinlolu O, Hanson JA, Kaplan B. Hepatitis C antibody status and outcomes in renal transplant recipients. Transplantation 2001;72:241-4.  Back to cited text no. 4
    
5.Kliem V, van den Hoff U, Brunkhorst R, et al. The long term course of Hepatitis C after kidney transplantation. Transplantation 1996;62:1417-21.  Back to cited text no. 5
    
6.Legendre Ch, Garrigue V, Le Bihan C, et al. Harmful Long-Term Impact of Hepatitis C Virus Infection in Kidney Transplant Recipients. Transplantation 1998;65:667-70.  Back to cited text no. 6
    
7.Hanafusa T, Ichikawa Y, Kishikawa H, et al. Retrospective study on the impact of Hepatitis C virus infection on kidney transplant patients over 20 years. Transplantation 1998;66:471-6.  Back to cited text no. 7
    
8.Alric L, Di-Martino V, Selves J, et al. Longterm impact of renal transplantation on liver fibrosis during hepatitis C virus infection. Gastroenterology 2002;123:1494-9.  Back to cited text no. 8
    
9.Rao KV, Anderson WR, Kasiske BL, Dahl DC. Value of liver biopsy in the evaluation and management of chronic liver disease in renal transplant recipients. Am J Med 1993;94:241-50.  Back to cited text no. 9
    
10.Campbell MS, Constantinescu S, Furth EE, Rajender Reddy K, Bloom RD. Effects of Hepatitis C-induced liver fibrosis on survival in kidney transplant candidates. Digest Dis Sci 2007;52:2501-7.  Back to cited text no. 10
    
11.Aytaman A, McFarlane SI. Hepatitis C and the risk of cardiovascular disease: An evolving epidemic? Expet Rev Cardiovasc Ther 2006;4: 439-42.  Back to cited text no. 11
    
12.Bahtiyar G, Shin JJ, Aytaman A, Sowers JR, McFarlane SI. Association of diabetes and hepatitis C infection: Epidemiologic evidence and pathophysiologic insights. Curr Diabetes Rep 2004;4:194-8.  Back to cited text no. 12
    
13.Ayung S, Reich D, Sapiro LE, Bernstein D, Begum N. Impaired IRS-1/PI3-Kinase signaling in patients with HCV: A mechanism for increased prevalence of Type 2 diabetes. Hepatology 2003;38:1384-92.  Back to cited text no. 13
    

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Correspondence Address:
Nader Dbouk
Methodist Transplant Institute, The University of Tennessee Health Sciences Center, 1211 Union Avenue, Memphis, TN 38104
USA
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DOI: 10.4103/1319-2442.113847

PMID: 23816714

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