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Saudi Journal of Kidney Diseases and Transplantation
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ORIGINAL ARTICLE Table of Contents   
Year : 1999  |  Volume : 10  |  Issue : 4  |  Page : 487-492
Impact of Hepatitis C on Renal Transplantation: A Long-Term Study

1 Nephrology Department, University Hospital of Zagazig, Egypt
2 Nephrology Dialysis & Transplantation Department, CHU Saint Etienne, France

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Viral hepatitis, especially "C" type (HCV), is an important cause of morbidity and mortality among recipients of renal transplants. In a retrospective long-term study, we reviewed 399 renal transplant patients (133F, 266M) who received 415 kidneys during the past eight-years. We evaluated their HCV infection and liver status. Stored sera (frozen at 80 C) as well as fresh sera collected at the time of transplant and/or at the last observation were used. The donors were cadavers in 386 and living related in 29 renal transplants. The mean follow-up period was 74 months (range 24-124 months). At the time of transplantation 105 recipients (26%) were HCV positive. A the last follow-up 105 (26%) recipients remained positive, 12 (2.8%) seroconverted from negative to positive due to graft and/or blood transfusion and 277 remained negative. Liver biopsy was obtained from 71 to 117 (60.6%) HCV +ve patients. Liver biopsy showed normal histology in 57 (80%) patients, chronic active hepatitis in 42 (59%) patients according to scoring of Knodle's classification. Recurrence of glomerulonephritis in renal allografts occurred in 21 patients. Membrano proliferative glomerulonephritis (< PGN) occurred in nine patients; seven (78%) of them were HCV +ve compared to 29% HCV +ve in the whole group (117/399) (P<0.001). The actuarial patient and graft survival was similar in HCV-ve and HCV +ve patients. We conclude that HCV is an important cause of liver disease in renal allograft recipients, it might be the cause of recurrence of MPGN, however, it affects neither patients nor graft survival.

Keywords: Hepatitis C, Cyclosporine A, Renal transplantation.

How to cite this article:
Hassan A A, Berthoux P, El deeb S, Bonnevial L, Cecillon S, Berthoux F. Impact of Hepatitis C on Renal Transplantation: A Long-Term Study. Saudi J Kidney Dis Transpl 1999;10:487-92

How to cite this URL:
Hassan A A, Berthoux P, El deeb S, Bonnevial L, Cecillon S, Berthoux F. Impact of Hepatitis C on Renal Transplantation: A Long-Term Study. Saudi J Kidney Dis Transpl [serial online] 1999 [cited 2019 Dec 6];10:487-92. Available from: http://www.sjkdt.org/text.asp?1999/10/4/487/37206

   Introduction Top

Liver disease is an important cause of morbidity and mortality among recipients of renal transplants. Abnormal liver function tests are seen in 7 to 24% of transplant recipient and liver failure in the cause of death in 8 to 28% of long term survivors after renal transplantation[1],[2]

Previously, approximately one-half of the cause of liver disease among transplanted patients were attributed to a variety of etiologies. These include viral infection such as hepatitis B virus (HBV), Epstein­Barr virus, or cytomegalovirus, and alcohol and drugs such as Azathioprine or cyclosporine A, or hemosidrosis. The remaining one-half were attributed to non­A non-B hepatitis. [3],[4] The cloning and characterization of hepatitis C virus (HCV) has permitted the development and refinement of tests to detect antibodies to multiple HCV antigens, and the presence and titer of HCV RNA. These modalities have opened the way to study the prevalence, transmission, and natural course of HCV infection in transplant recipients.

In this report, we studied retrospectively the incidence of HCV infection among renal transplant recipients and its consequences upon patients and graft survival in both short-and long-terms.

   Subjects and Methods Top

This is a joint study between Nephrology, dialysis and transplantation Center University of Saint Etienne-France and Nephrology, dialysis and transplantation centers in University Hospital in Zagazig­Egypt, and Nile International Kidney Center.

We evaluated 399 renal transplantation of 41.7 yeas (8-65 years). These patients underwent 415 renal transplants during a period of eight years 91990-1998), The donors were cadavers in 386 and living related in 29 transplants. The mean follow-up period was 75 months (range 48-124 months) and the minimum follow-up period was two years.

All patients received cyclosporine a as main immunosuppressive (10-15 mg/kg as starting dose followed by 4-5 mg/kg as a maintenance dose) and prednisolone (30 mg on discharge), 15 mg at three months and 10 mg at one year).

All patients were subjected to routine medical and biochemical investigation during follow-up. Serum alanine amino­transferase activity was considered elevated if values are 1.5 of normal or higher.

We used in this study scored sera (frozen at -80° C) as well as fresh area taken at the time of transplantation, at the time of liver biopsy, and/or at the last follow-up visit. HCV antibodies was detected using the second-generation test (ELISA 1), [5] and positive test was confirmed by RIBA 2 test. The test should demonstrate at least two bands in order to be considered positive, one band is considered undetermined and zero band as negative. [6] The virus RNA was detected in the serum by revere­transcription polymerase chain reaction. [7],[8]

Liver biopsy was obtained from 71 of 117 (60.6%) HCV positive patients. We excluded patients who returned to dialysis, had polycystic liver or refused lifer biopsy. The biopsy was examined by light microscopy and was classified as normal, portal lesions (inflammation and/or fibrosis), acute hepatitis, chronic active hepatitis (CAH) and scored according to Knodle classification.

   Statistical Analysis Top

Statistical analysis was performed using the SPSS program. We used the chi-square with the Fisher exact test, the Kaplan-Meier analysis of actuarial patient and graft survival, and the Student "I" test. Results are expressed as mean + standard deviation (SD). Statistical significance is set at p <0.05.

   Results Top

At the time of transplantation, 105 (26%) patients were HCV antibody positive whereas 294 were negative. Twelve patients seroconverted from negative to positive during the course of transplantation, due to transmission from confirmed HCV-positive organ donors. Patients geographical region an modality o dialysis significantly affected the incidence of positively [Table - 1],[Table - 2].

Nine patients of 117 positive HCV recipients were coinfected with HBV and 18 patients were positive for HBV and negative for HCV, HCV positively has a statistically significant correlation with duration of hemodialysis (66 months for HCV +ve vs 45 months for HCV - ve, P <0.001).

Correlation between HCV antibody positivity, structural antigen (C22.3 antibody of the virus) and viremiare presented by presence of RNA in blood of the study patients is shown in [Table - 3].

Serum alanine aminotransferase activity (ALT) was high in 23 out of 117 919.7%) HCV +ve recipients compared to 29 to 253 (11.4%) HCV-ve recipient, (P<0.01). Only one out of 117 HCV +ve recipients had over cirrhosis.

Seventy-one (66%) HCV +ve renal transplant recipients were biopsied. The mean time of liver biopsy was 58 months post transplant (range 3-109 month). [Table - 4], shows results of liverbiopsy. Patietns with CAH were classified according Knodle score [Table - 5]. HCV detection in liver biopsy was done in 39 specimens, and was positive in 37 (95%). All patients with normal liver pathology had repeatedly normal liver enzymes.

We received all the renal graft biopsies performed in our study group. Twelve of 399 93%) patients had membranous GN (MGN) either do novo recurrence and nine cases (2.2%) had membranoproliferative glomerulonephritis (MPGN) type 1.

HCV infection was present I three out of 12 MGN patients (25%) and seven out of nine MPGN (78%) compared to 29% in the whole group 9117/399). The difference was highly significant for the MPGN group (P<0.001). On the contrary, the incidence of MPGN was 2.3% in the whole study group, 0.7% (2/282) in the HCV -ve and 6.0% (7/117) in the HCV +ve subgroups.

Among the nine cases with MPGN, two cases were recurrent (all HCV +ve) and seven were de novo GN (with 5 HCV +ve).

In most patients with MPGN in HCV +ve patients had hypocomplementemia (low CH 50, acquired C2 deficiency, however, normal C3), positive rheumatoid factor (RF), and intermittent cryoglobulinemia. In most patients, the disease progressed rapidly to end­stage renal disease (ESRD).

The actuarial patients and graft survival was not statistically different in both HCV -ve and HCV +ve patients. Seven out of 117 (6.0%) in the HCV +ve group died vs 12/282 (4.3%) in HCV -ve group. Graft losses were 24/117 (20.5%) in HCV +ve group vs 61/282 (21.6%) in HCV -ve group.

In patients with elevated liver enzymes and/or biopsy proven CAH, we slowly tapered and then discontinued azathioprine. In most patients, we tried to discontinue steroids by the end of 18 months post transplant. Most patients were kept on cyclosporine A as monotherapy after 18 months.

   Discussion Top

In recent years, HCV has been identified as the primary cause of non-A, non-B hepatitis and became a clinical problem of growing significance. This applies not only to the population at large, but also specifically to the end-stage renal disease patients on dialysis, and immunosuppressed renal allograft recipients.

Several investigators have reported the prevalence of anti-HCV among kidney transplant recipients. [9],[10],[11] Using a second­ generation anti-HCV assay, 26% of our serum samples collected from the transplanted patients were anti-HCV positive. This is consistent with other reports in which 10% to 49% of transplanted patients were anti-HCV positive. [9],[11],[12],[13],[14],[15] These findings are not unexpected considering the prevalence of anti­HCV among hemodialysis patients.[16],[17]

Positivity to anti-HCV was strongly affected by the geographical origin of the patients. It was more prevalent among Italian than French patient. We observed 12 cases with seroconversion (HCV -ve to HCV +ve) during the course of transplantation. The source of infection is either blood transfusion or the solid grafts.

This problem has been studied by Pereira et al. [18] Out of 716 donors, they found 13 (1.8%) positive for anti-HCV by ELISA-1 test. Twenty-nine recipients received different organs from these donors, and 14 (48%) developed acute hepatitisafter a mean period of 3.8 months. In addition, if the donors were serum HCV-RNA positive, the transmission of HCV-RNA was 100% and 70% had seroconverted later on. Harvesting organs from anti-HCV positive donors is still debatable. Roth et al [14] tested retrospectively sea from 484 cadaver organ donors, 89 were reactive by ELISA; 33 donors were RIBA seropositive. Hepatitis C viral R NA sequences were detected in 50% of the RIBA A-positive serum samples tested. Liver tissue was available from 24 of the 33 RIBA-positive donors and showed CAH in 16, chronic persistent hepatitis in two and no abnormality in six. Among the 46 recipients of a kidney from a RIBA-positive donor, 13 developed post-transplant liver disease, of which only four cases were highly suggestive of viral transmission from the donor. The author's conclusion was HCV transmission by organ transplantation was low and that the consequenes of infection were small.

Morales et al [12] experience indicated little harm in recipients receiving organs HCV genotypes, there is a possibility of transmission of different HCV variant, which could be responsible for reinfection.

Periera et al [18] detected HCV-RNA in seven of 24 (29%) recipients preoperatively and 23 of 24 (96%) following transplantation of an organ from HCV carrier donor. Their conclusion that transmission of HCV by solid organ transplantation occurs frequently when using an organ from an HCV-positive donor was suggested by their data; undoubtedly, viral transmission can and does occur in a certain number of cases. The authors did not state whether these patients received any blood products in the preoperative period.

The association between duration of dialysis and an increased prevalence of anti-HCV has been suggested by our study. These results were in accordance with those reported by others.[17],[19],[20]

Seventy one (66%) of HCV positive patients were subjected to liver biopsy. Forty-two (59%) patients had findings compatible with chronic active hepatitis; none had severe lesion according to Knodle's Score. Serum transminases were positively correlated with the degree of hepatic affection.

Rollino et al [21] were the first to associate HCV infection with immune complex type of glomerulonephritis. Johnson et al [22] described eight patients with membranoproliferative glomerulonephritis pattern associated with active HCV infection. All patients had circulating HCV RNA, elevated transaminases, and hypocomplementemia. Five of eight had circulating cryoglobulines. Our results were in accordance with these observations. Seven out of nine MPGN patients had hyocomplementemia and circulating cryoglobulins.

HCV was less correlated with other types of immune complex diseases, and membranous GN as on the top of the list. It interesting to speculate that immunosuppression might alter the circulating viral load in such a way to disturb the balance of antigen-antibody complexes. These data might show the importance of investigating patients with chronic liver disease and evidence of HCV infection for cryoglobulins, rheumatoid factor and complement concentrations. Renal graft biopsy is mandatory to confirm the diagnosis. In our findings, HCV affected neither patient nor graft survivals. Data of others [23] showed no adverse effect on patient or graft survival, however, recipients or organs from anti-HCV positive donors had a higher risk of developing liver disease.

We conclude that HCV is an important cause of liver disease in renal allograft recipients, it might be the cause of recurrence of MPGN, however, it affects neither patient nor graft survival.

   References Top

1.Pereira BT. Hepatitis c infection and post transplantation liver disease. Nephrol dial Transplant 1995;1:58-67.  Back to cited text no. 1    
2.Pereira BJ, Levey AS. Hepatitis C infection in dialysis and renal transplantation. Kidney Int 1997;51:981-99.  Back to cited text no. 2  [PUBMED]  
3.Weir MR, Kirkmana RL, Strom TB, Tilney NL. Liver disease in recipients of long­functioning renal allografts. Kidney Int 1985;28:839-44.  Back to cited text no. 3    
4.Rao KV, Anderson RW, 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. 4    
5.Aach RD, Stevens CE, Hollinger FB, et al. Hepatitis C virus infection in post­transfusion hepatitis. An analysis with first and second-generation assays. N Engl J Med 1991;325:1325-9.  Back to cited text no. 5    
6.Nakatsuji Y, Matsumoto A, Tanaka E, Ogata H, Klyosawa K. Detection of chronic hepatitis C virus infection by four diagnostic systems: first-generation and second-generation enzyme-linked immunosorbent assay, seond-generation recombinant immunoblot assay and nested polymerase chain reaction analysis. Hepatology 1992;16:300-5.  Back to cited text no. 6    
7.Tong CY, Codd AA. Riba-2 band intensity and PCR in HCV infection. Lancet 1992;340:117.  Back to cited text no. 7    
8.Weiner AJ, Kuo G, Bradley DW. Detection of hepatitis C viral sequences in non-A non-B hepatitis. Lancet 1990;335:1-3.  Back to cited text no. 8    
9.Roth D, Fernandez JA, Burke GW, Esquenazi V, Miller J. Detection of antibody to hepatitis C virus in renal transplant recipients. Transplantation 1991;51:396-400.  Back to cited text no. 9  [PUBMED]  
10.Ponz E, Campistol JM, Bruguera M, et al. Hepatitis C virus infection among kidney transplant recipients. Kidney Int 1991;40:748-51.  Back to cited text no. 10  [PUBMED]  
11.Pol S, Legendre C, Saltiel C, et al. Hepatitis C chez le transplante renale: Epidemiologie et impact sur la transplantation renale. Presse Med 1991;20:2025-7.  Back to cited text no. 11  [PUBMED]  
12.Morales M, Campo C, Castellano G, et al. Clinical implications of the presence of antibodies to hepatitis C after renal transplantation. Transplant Proc 1992;24:78-80.  Back to cited text no. 12    
13.Roth D, Zucker K, Cirocco R, et al. The impact of hepatitis c virus infection on renal allograft recipients. Kidney Int 1994:45:238-44.  Back to cited text no. 13    
14.Roth D, Fernandez JA, Babisckkin S, et al. Detection of hepatitis C virus infection among cadaver organ donors: evidence for low transmission of disease. Ann Intern Med 1992;117:470-5.  Back to cited text no. 14    
15.Huang CC, Liaw YF, Lai MK, et al. The clinical outcome of hepatitis C virus antibody positive renal allograft recipients. Transplantation 1992;53:763-5.  Back to cited text no. 15  [PUBMED]  
16.Chan TM, Lock AS, Cheng IL, Chan RT. A prospective study of hepatitis study of hepatitis C virus infection among renal transplant recipients. Gastroneterology 1993;104:862-8.  Back to cited text no. 16    
17.Oguchi H, Miyasaka M, Tokunaga S, et al. Hepatitis virus infection (HBV and HCV) in eleven Japanese hemodialysis units. Clin Nephrol 1992;38:36-43.  Back to cited text no. 17  [PUBMED]  
18.Pereira BJ, Milford EL, Kirkman RL, et al. Prevalence of hepatitis C virus RNA in organ donors positive for hepatitis C antibody and in the recipients of their organs. N Engl J Med 1992;327:910-5.  Back to cited text no. 18  [PUBMED]  
19.Chauveau P, Courouce AM, Lemarec N, et al. antibodies to hepatitis C virus by second generation test in hemodialyzed patients. Kidney Int Sippl 1993;41:S149-52.  Back to cited text no. 19    
20.Dussol B, Chickeportiche C, Cantaloube JF, et al. Detection of hepatitis c infection by polymerase chain reaction among hemodialysis patients. Am J Kidney Dis 1993;22:574-80.  Back to cited text no. 20    
21.Rollino c, Roccatello d, Giachino O, Basolo B, Piccoli G. Hepatitis c virus infection and membranous glomerulonephritis. Nephron 1991;59:319-20.  Back to cited text no. 21  [PUBMED]  
22.Johnson RJ, Gretch DR, Yamabe H, et al. Membranoproliferative glomerulonephritis associated with hepatitis C virus infection. N Eng J Med 1993;328:465-70.  Back to cited text no. 22    
23.Mendez R, El-Shahawy M, Obispo E, et al. Four years follow up of hepatitis C positive kidneys into hepatitis C negative recipients' prospective study. J am Soc Nephrol 1995;6:1105.  Back to cited text no. 23    

Correspondence Address:
A A Hassan
Nile International Kidney Center, 18 Khalifa El-Maamoun Street, Heliopolis, Cairo
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