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Saudi Journal of Kidney Diseases and Transplantation
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ORIGINAL ARTICLE Table of Contents   
Year : 1995  |  Volume : 6  |  Issue : 2  |  Page : 183-189
Impact of Hepatitis C Virus Infection on Kidney Transplant Outcome

1 Department of Medicine, King Faisal Specialist Hospital and Research Center, Riyadh, Saudi Arabia
2 Department of Pathology, King Faisal Specialist Hospital and Research Center, Riyadh, Saudi Arabia

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One hundred and forty kidney transplant recipients were evaluated to study the impact of hepatitis C virus (HCV) infection on patient and graft outcome. There .were 98 males arid 42 females with a mean age of 32.1 ± 13 years. The duration of follow-up ranged from 6-60 months with a mean period of 27.8 ± 18.2 months. Seventy-four (53%) patients had received cadaveric kidneys while 66 (47%) received living donor grafts. Anti-HCV reactivity was tested using second generation enzyme-linked immunosorbent assay and positivity was confirmed by recombinant immunoblot assay. HCV infection was diagnosed in 29 cases (20.7%) while HBsAg was found in nine (6.4%) and concomitant anti-HCV and HBsAg positivity was observed in two patients (1.4%). Seventeen of 29 (58.6%) patients with anti-HCV reactivity showed elevated ALT levels as against 17 of 111 (17.3%) anti-HCV non-reactive patients (P<0.001). There was no association between the sex of the patient, source of the graft, and anti-HCV reactivity. Serum creatinine values were higher in the anti-HCV positive group, but this did not rank to statistical significance. We observed a significantly higher graft loss among the anti-HCV reactive group (27.6% versus 1.8%, P< 0.003). Thirteen anti-HCV reactive patients were subjected to 18 liver biopsies; the commonest lesion observed was chronic active hepatitis, which was progressive in two patients subjected to re-biopsy. We conclude that HCV infection is a serious health problem among kidney transplant recipients and it significantly affects the graft outcome.

Keywords: Hepatitis C virus, Kidney transplantation.

How to cite this article:
Alfurayh OI, Sobh MA, Chaudry TS, Qunibi WY, Al Meshari K, Ellis M, Ali MA, Taher S. Impact of Hepatitis C Virus Infection on Kidney Transplant Outcome. Saudi J Kidney Dis Transpl 1995;6:183-9

How to cite this URL:
Alfurayh OI, Sobh MA, Chaudry TS, Qunibi WY, Al Meshari K, Ellis M, Ali MA, Taher S. Impact of Hepatitis C Virus Infection on Kidney Transplant Outcome. Saudi J Kidney Dis Transpl [serial online] 1995 [cited 2020 Jul 6];6:183-9. Available from: http://www.sjkdt.org/text.asp?1995/6/2/183/40864

   Introduction Top

The importance of liver disease and itsimpact on the long-term outcome of kidney transplants has been recognized with increasing frequency during recent years. This is mainly due to the following reasons:

The improved patient and graft survival rates with the consequent greater chance for appearance of chronic diseases such as liver cirrhosis.

More popular use of triple immuno­suppression, including azathioprin (AZA) and cyclosporin-A (CyA), both known to be hepatotoxic [1],[2],[3] ; also, this regimen is known to induce more potent immunosuppression with consequent greater difficulty in the clearance of the virus by the host immune system.

Increased awareness of the higher incidence of viral hepatitis, (particularly hepatitis C) among dialysis population.

We recently reported hepatitis C virus (HCV) infection in 40.4% of our patients on maintenance hemodialysis [4] . With the introduction of the second generation enzyme linked immunosorbent assay (ELISA 2) [5] and the second generation recombinant immunoblot assay (RIBA 2) [6] , an even higher incidence of HCV infection is expected to be detected. Di Maggio, et al [7] reported a two times higher incidence of anti-HCV positivity among their dialysis patients when screened by ELISA 2 than found when screened by ELISA 1.

The information available regarding the impact of HCV infection on kidney transplantation is scanty and the results are inconclusive and conflicting. The objective of this work was to study the prevalence of HCV infection among our kidney transplant recipients and to evaluate its effect on patient and graft outcome.

   Patients and Methods Top

One hundred and forty kidney transplant recipients at King Faisal Specialist Hospital and Research Center were subjected to this study. Fifty five patients were evaluated retrospectively, while 85 were studied in a prospective manner. Ninety eight (70%) patients were male, and 42 (30%) were female. Their age ranged between 6-61 years with a mean of 32.1 ± 13.1 years. Seventy four patients (53%) received cadaveric kidneys, while 66 (47%) received living related donor kidneys. The patients received either double [Prednisone (Pred) + CyA] or triple (Pred + CyA + AZA) immuno-therapy. Prednisone was given in an initial dose of 1.5 mg/kg/day, decreased gradually to 0.15 mg/kg/day by the second post-operative month, 0.125 mg/kg/day by the sixth month, and 0.10 mg/kg/day by the end of the first year post­transplantation.

Azathioprin was given in a dose of 2 mg/ kg/day, which was adjusted according to the white blood cell count and liver function tests. Cyclosporin-A was given in a dose of 5-8 mg/kg/day in divided doses, and the dose was adjusted to maintain whole blood trough levels of 400-800 ng/ml, as measured by cyclosporin non-specific kits, during the first post­operative month, 300-700 ng/ml till the end of the sixth month, and 150-400 ng/ml thereafter. Sera of patients was examined for anti-HCV reactivity using ELISA (Ortho Diagnostic System); positive reactions were confirmed by RIBA (Ortho Diagnostic System).

All the patients were subjected to the following assessment:

a)Virology screening including Hepatitis B Virus (HBV), Cytomegalovirus (CMV), Epstein-Barr virus (EBV), Varicella Zoster virus (VZV) and Herpes Simplex virus (HSV) prior to transplantation.

b)Regular biochemical assessment including liver function tests including serumbilirubin, alanine transaminase (ALT), aspartate transaminase (AST), kidney function tests (serum creatinine, creatinine clearance, and urine analysis), fasting blood sugar, serum sodium, potassium, calcium and phosphate. These tests were performed for all patients monthly during the first year post­transplantation, then at least every third month indefinitely.

c) Drug (AZA and CyA) dosages were evaluated periodically.

d) Thirteen patients with anti-HCV reactivity gave consent for liver biopsies; two of them were biopsied more than once. Liver tissue was obtained using Menghi ni needle, fixed in 10% formalin and paraffin sections 4-5 fxm. thick were prepared and stained by H & E, reticulin silver stain, Van Giesson Stain (for collagen fibers) and Prussian blue (for hemosiderin deposits). Periodic acid schiff reagent with or without diastase digestion was used. In addition, sections were stained for hepatitis B surface antigen (HBsAg) and hepatitis B core antigen (HBcAg) by immunoperoxidase technique.

   Statistical Analysis of Data Top

Patients were divided into HCV positive (those with anti-HCV reactivity by ELISA and confirmed by RIBA) and HCV negative (having no anti-HCV reactivity). The following statistical analyses were done:

a) The relationship between HCV infection and the ALT values, CyA and AZA doses, and the graft function at different time intervals after kidney transplantation (3, 12, 24,36,48 and 60 months) were analyzed using analysis of variance (ANOVA) tests.

b) Correlation between ALT levels and CyA and AZA doses using Spearman rank order correlation test was performed.

c) * Student t-test was used to study the effect of patients' sex and source of the graft on ALT values and HCV infection.

d) Graft function over a period of time in HCV positive and HCV negative groups (ANOVA) was compared.

e) Meier Log-Rank Test was used to compare the actuarial graft survival rates in the two groups.

   Results Top

One hundred and forty kidney transplant recipients were evaluated for HCV infection and it's impact on patient and graft outcome. The duration of follow-up after transplantation ranged between 6 to 60 months with a mean of 27.8 ± 18.2 months.

Anti-HCV antibody was positive in 29 patients (20.7%), HBsAg was detected in nine (6.4%) and concomitant anti-HCV and HBsAg positivity was observed in two cases (1.4%). We found no significant association between anti-HCV positivity and the sex of the patient (P = 0.408), and among those with HCV infection, there was no significant effect of patients' age or sex on serum ALT values (P = 0.412). Also, no significant difference was observed between the graft source and prevalence of HCV infection (P = 0.43).

Serial follow-up showed a higher prevalence of elevated liver enzymes (>1.5 of high normal values) in anti-HCV positive patients. [Figure - 1]. shows the one way ANOVA for ALT values at different time intervals after transplantation in anti-HCV positive and negative patients. Seventeen of 29 (58.6%) anti-HCV positive patients showed high ALT values during follow-up as against 17 of 111 (15.3%) of anti-HCV negative patients (P=< 0.001). In the HCV positive cases, the abnormal ALT values were persistent in 10 (58.8%), fluctuating in four (23.5%) and occurred in a single episode in three patients (17.7%). In the HCV negative cases the high ALT values were persistent in four (23.5%), fluctuating in one (5.9%), and occurred in a single episode in 12 (70.6%) cases.

[Figure - 2] shows the doses of CyA at different time intervals after transplantation in HCV positive and negative groups. Sig nificantly lower doses were given to patients with HCV infection (P= < 0.001).Among patients with HCV infection, doses of CyA administered were significantly lower in those with high ALT values (P=<0.001, <0.004, and <0.05 at two, three and four years, respectively). Overall, there was a significant negative correlation between CyA dose and level of ALT (r = 0.401, P= <0.001 at 1 year; r = 0.277, P=<0.0064 at two years; r= - 0.262, P=<0.23 at three years; r = 0.296, P=<0.034 at four years; and r= -0.433, P= < 0.031 at five years). The dose of AZA administered was also significantly lower in the HCV infected group (P=< 0.0466, ANOVA). Also, a negative correlation was observed between dose of AZA and level of ALT (r= - 0.585, P= < 0.0017 at five years).

Serum creatinine values were higher in anti­HCV positive cases with persistently high ALT values than those noted in anti-HCV negative patients with normal ALT values, but this difference was not statistically significant. During the follow-up period, eight (27.6%) of the anti-HCV positive patients lost their grafts, while this was seen in only two (1.8%) of those without HCV infection. This difference was found to be statistically significant (P= < 0.003). Graft loss in the HCV positive group was due to chronic rejection in six and infection in two patients. In the HCV negative group, graft loss was due to chronic rejection in both cases.

Thirteen patients with anti-HCV reactivity gave consent for liver biopsy and among these, four had normal, and nine had persistently high, ALT values. Biopsies were performed 8 to 60 months after transplantation with the mean period being 34 months. The biopsy findings in their relation to serum ALT values are given in [Table - 1]. Of the patients with CAH, five showed mild CAH, while three others showed moderate severity, with distortion of architecture, portal and periportal fibrosis, interportal bridge formation and piece-meal necrosis. Two patients with persistently high liver enzymes were subjected to re-biopsies; definite histopatho-logic progression of the disease was documented in both of them. In the four cases with anti-HCV reactivity and persistently normal liver enzymes, biopsies showed mild lesions, either of nonspecific nature or of unresolved viral hepatitis with mild steatosis, mild portal and periportal fibrosis, focally prominent Kupffer cells, very little pericellu-lar fibrosis, and scanty parenchymal lympho-cytic infiltration.

In none of our cases, whether with high or normal liver enzymes, HBsAG or HB core antigen were detected by immunoperoxidase technique. Hemosiderosis was documented in one case with normal liver enzymes and in three cases with high liver enzymes. Iron pigments were seen in clusters of macrophages, most prominent around the central veins.

   Discussion Top

Chronic liver disease after renal transplantation is an important cause of death in patients with long-functioning renal allografts [8],[9] . Infection with non-A, non-B virus accounts for much of this serious, often fatal, complication [10] . Recently, using the second generation ELISA and RIBA, it has been proven that HCV is responsible for more than 90% of the cases labelled as non-A, non-B hepatitis [11] .

Out of 140 kidney transplant recipients screened at our institution for anti-HCV antibody, reactivity was detected in 29 patients (20.7%). HCV infection was diagnosed using ELISA and positive reactions were confirmed by RIBA. This combination is reported to be highly sensitive and specific for the diagnosis of HCV infection [6] . Polymerase chain reaction (PCR) for detecting HCV RNA is still far from being a routine practice and needs sophisticated equipment and experience.

Alivanis, et al [12] reported HCV reactivity in 16.6% of their kidney transplant recipients. This reported lower prevalence could be due to the lower prevalence of anti-HCV among their dialysis population (9%) in contrast to 40.4% in our dialysis population [4] and/or due to the first generation ELISA they used. Higher prevalence rates of HCV infection in transplant recipients have been reported by several other groups. Roth, et al [13] reported a prevalence of 30% among 621 retrospectively evaluated kidney transplant recipients. Ponz, et al [14] reported a prevalence of 34% among their patients and Pol, et al [15] and Morales, et al [16] reported prevalence rates of 24.3% and 25% respectively.

Chronic liver disease (CLD) as diagnosed by high liver enzymes for six months'or more was observed in 17 of 29 (58.6%) cases with anti­HCV reactivity. Similar observation was reported by other workers as well [12],[13],[14] . High liver enzymes were also observed in 17 (15.3%) of the patients who were anti-HCV negative of whom, two were positive for HBsAg. The cause of high liver enzymes in the remaining 15 cases could be due to false negative HCV reactivity, or due to AZA and/ or CyA hepatotoxicity. Tests for the diagnosis of recent infection with HBV, CMV, EBV, HSV and VZV in these cases remained negative. Ponz, et al [14] reported high liver enzymes in 28% of their HCV negative cases. We did not find a relationship between ICV infection and the patient's sex, or the source of the graft (cadaveric or living donor). Alivanis, et al [12] reported similar findings in their group of patients. We observed a significantly higher graft loss in HCV positive patients (27.6% versus 1.8%). The commonest cause of graft loss was chronic rejection. This observation is in contradiction with those reported by Ran-jan, et al [17] , Roth, et al [13] and LaQuaglia, et al [10] . Ranjan, et al [17] reported comparable patient and graft survival in patients with and without anti-HCV positivity. In contrast, LaQuaglia, et al [10] reported a significantly better graft survival among patients with chronic hepatitis claiming that this could be due to a marked immunosuppressive effect imposed by the chronic viral infection and liver disease.

The discrepancy between our results and those reported by other authors [10],[13],[17] could be explained by racial differences that exist in response to HCV infection. Interestingly, Fritsche, et al [18] examining their kidney transplant recipients for impact of HCV infection on graft outcome, reported that black anti-HCV positive patients had a 5-year graft survival of 28 + 11 % compared to black anti-HCV negative patients in whom the 5­year graft survival was 67 ± 7% (P=< 0.003). On the other hand, black anti-HCV negative, white anti-HCV negative, and white anti-HCV positive patients all had similar graft survival. This finding clearly supports our hypothesis. Possibly, if the results of studies performed on mixed population [13] are re-evaluated after splitting them according to race, statistical analysis may show similar data to ours and to those of Fritsche, et al [18] . The higher graft loss observed in our patients with HCV infection could be explained by the significantly lower doses of azathioprin and cyclosporin given.

Information regarding hepatic histopathologic changes in anti-HCV positive patients after kidney transplantation is sparse. In our study, CAH was diagnosed in all but one HCV positive case with persistently high liver enzymes. In the two cases subjected to repeat biopsy, definite histologic progression was observed. Interestingly, biopsies from patients with persistently normal liver enzymes showed nonspecific changes.

In a recent study, Morales, et al [16] described liver biopsy findings in HCV positive kidney transplant recipients. Severe disease (chronic active hepatitis with or without cirrhosis) was reported in 14 out of 27 patients examined, while mild disease (chronic persistent hepatitis, siderosis, or others) were reported in the remaining 13 patients. Moreover, in cases subjected to re-biopsy, a definite deterioration was observed in 11 out of 14 cases. Our data and those of Morales, et al [16] when compared to those from patients having the same disease but on a maintenance hemodialysis [4],[16] , clearly demonstrate the serious course the disease takes after kidney transplantation. The absence of serious lesions in biopsies of HCV positive patients with persistently normal liver enzymes is interesting, but a larger number of cases with longer duration of follow-up is needed before a definite conclusion is made. The significance of anti-HCV reactivity in patients with persistently normal liver enzymes is not yet known. Studies of the HCV RNA polymerase chain reaction (PCR) might be of help in detecting such patients at risk to develop active liver disease after renal transplantation.

During follow-up, three patients died, one was HCV reactive, and two were HCV non­reactive. Two of the three deaths were due to liver cell failure. The demonstration of a significantly higher incidence of chronic liver disease with histologically proven CAH in the HCV positive cases may foretell a bad prognosis on longer term follow-up in this group of patients.

In conclusion, this study demonstrates the serious impact of HCV infection on kidney transplant outcome; 20.7% of patients were anti-HCV positive and 58.6% of them had CLD. Graft survival was significantly reduced in this group of patients when compared with those who were anti-HCV negative. Facing this high prevalence of HCV infection among kidney transplant recipients with its serious impact on patient and graft outcome, we believe that finding an anti-HCV vaccine and optimization of anti-viral drugs should be a target for future researches.

   Acknowledgment Top

The authors would like to thank Mr. Sir El-Khatim A. Rahim Toto, Hospital Assis­tant I and Ann Selfe, Hospital Assistant II, for their secretarial assistance, Mr. Ismail H, Wais, Renal Transplant Nurse, and Mr. Fathi A. Al-Mamoon for their help.

   References Top

1.Pirson Y, van Ypersele de Strihou C, Noel H, Alexandre GP, Trouoh R Liver disease in transplanted patients. Proc Eur Dial Transplant Assoc 1973;10:434-45.  Back to cited text no. 1    
2.Sparberg M, Simon N, del-Greco F. Intrahepatic oholestiasis due to azathioprine. Gastroenterology 1969;57:439-41.  Back to cited text no. 2    
3.A randomized clinical trial of cyclosporine in cadaveric renal transplantation. N Engl J Med 1983;309:809-15.  Back to cited text no. 3    
4.Alfurayh O, Sobh. M, Buali A, et al. Hepatitis C virus infection in chronic haemodialysis patients: a clinicopathologic study. Nephrol Dial Transplant 1992;7:327-32.  Back to cited text no. 4    
5.Alter HJ, Purcell RH, Shib. JW, et al. Detection of antibody to hepatitis C virus in prospectively followedtransfusion recipients with acute and chronic non-A, non-B hepatitis. N Engl J Med 1989;321:1494-500.  Back to cited text no. 5    
6.Van der Poel CL, Cuypers HT, Reesink HW, et al. Confirmation of hepatitis C virus infection by new four-antigen recombinant immunoblot assay. Lancet 1991;337:317-9.  Back to cited text no. 6  [PUBMED]  
7.Di Maggio A, Annicchiarico R, De Siati M, et al. Confirmation of high prevalence of hepatitis C antibodies in hemodialysis patients by second generation immunoblot assay. Nephron 1992;61:347-9.  Back to cited text no. 7  [PUBMED]  
8.Rubin RH Wolfson JS, Cosimi AB, Tolkoff- Rubin NE. Infection in the renal transplant recipient. Am J Med 1981;70:405-ll.  Back to cited text no. 8    
9.Ware AJ, Luby JP, Hollinger B, et al. Etiology of liver disease in renal­transplant patients. Ann Intern Med 1979;91:364-71.  Back to cited text no. 9  [PUBMED]  
10.LaQuaglia MP, Tolkoff-Rubin NE, Dienstag JL, et al. Impact of hepatitis on renal transplantation. Transplantation 1981;32(6):504-7.  Back to cited text no. 10    
11.Genesca J, Esteban JI, Alter HJ. Blood­borne non-A, Non-B hepatitis: Hepatitis C. Semin Liver Dis 1991;ll(2):147-64.  Back to cited text no. 11    
12.Alivanis P, Derveniotis V, Dioudis C, et al. Hepatitis C virus antibodies in hemodialysed and in renal transplant patients: Correlation with chronic liver disease. Transplant Proc 1991;23(5):2662-3.  Back to cited text no. 12    
13.Roth D, Fernandez JA, Burke GW, Esquenazi V, Miller J. Detection of antibody to hepatitis C virus in renal transplant recipients. Transplantation 1991;51(2):396-400.  Back to cited text no. 13    
14.Ponz E, Campistol JM, Barrera JM, et al. Hepatitis C virus antibodies in patients on hemodialysis and after kidney transplantation. Transplant Proc 1991;23(1 Pt 2):1371-2.  Back to cited text no. 14    
15.Pol S, Legendre C, Saltiel C. Hepatitis C virus in kidney recipients:Epidemiology impact on renal transplantation. In Hollinger FB, Lemon SM, Margolis HS, (eds). Viral hepatitis and liver disease. Baltimore, Williams & Wilkins, 1991.  Back to cited text no. 15    
16.Morales J, Compo C, Castellano G. The impact of hepatitis C in long­functioning renal transplants. A clinicopathological follow-up. XIV International Congress of Transplant Society, Paris, 1992:A 203.  Back to cited text no. 16    
17.Ranjan D, Burke G, Esquenazi V, et al. Factors affecting the ten-year outcome of human renal allografts. The effect of viral infections. Transplantation 1991;51(l):113-7.  Back to cited text no. 17    
18.Fritsche C, Brandes JC, Delaney SR, et al. Hepatitis C is a poor prognostic indicator in black kidney transplant recipients. Transplantation 1993;55(6):1283-7.  Back to cited text no. 18    

Correspondence Address:
Osman I Alfurayh
Department of Medicine, King Faisal Specialist Hospital and Research Center, P.O. Box 3354, Riyadh 11211
Saudi Arabia
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