Correspondence
Hepatitis C Virus and Organ Transplantation
N Engl J Med 1993; 328:511-513February 18, 1993
- Article
To the Editor:
Pereira et al. (Sept. 24 issue)1 recommended that organs from donors with antibodies to hepatitis C virus (HCV) not be used, even in anti-HCV-positive recipients, because of the heterogeneity of HCV and because the safety of these transplants has not been established1,2.
In Spain, although the number of renal transplantations is increasing,3 more than 6000 patients who are receiving dialysis are awaiting kidney transplantation. Hence, the policy in our hospitals is to allow the transplantation of anti-HCV-positive kidneys into seropositive recipients if there is good HLA-DR matching and if informed consent has been obtained4,5.
To evaluate the safety of this policy, we prospectively compared the clinical course of 22 anti-HCV-positive recipients (15 male and 7 female patients; mean age, 45 ±14 years) who received kidneys from seropositive donors with that of 27 seropositive patients (16 male and 11 female patients; mean age, 44 ±11 years) who received kidneys from seronegative donors during the same period.
The presence of HCV antibodies was determined by a second-generation enzyme-linked immunosorbent assay (Ortho Diagnostic Systems, Raritan, N.J.), and positive results were confirmed by a recombinant immunoblot assay (Ortho). Twenty-seven patients were receiving steroids and cyclosporine, and the others were receiving cyclosporine alone. In 28 patients, liver biopsies were performed before transplantation or in the first month after transplantation. Data obtained before and after transplantation are summarized in Table 1Table 1
Clinical and Biopsy Findings before and after Transplantation in Anti-HCV-Positive Recipients, According to the Presence or Absence of Liver Disease..During follow-up the most notable finding was the smooth course of the seropositive patients who received organs from seropositive donors. Only seven patients (32 percent) had evidence of liver disease, and only two had alanine aminotransferase levels that were more than 2.5 times the normal value; one had chronic persistent hepatitis five months after transplantation, and the other had had OKT3 rescue therapy during the second month after transplantation. The other five patients had only mild abnormalities. Interestingly, in 15 patients (68 percent) liver-function tests remained within normal limits during a median follow-up of one year. There was no difference between this group and the control group in the prevalence of liver disease. Finally, all patients remained seropositive for HCV.
In summary, our preliminary results suggest that anti-HCV-positive kidneys can be transplanted safely into anti-HCV-positive recipients without a major risk of severe liver disease. A long-term follow-up study of these patients is under way in Spain.
5 ReferencesJose M. Morales, M.D.
Amado Andres, M.D.
Hospital 12 de Octubre, 28041 Madrid, SpainJose M. Campistol, M.D.
Hospital Clinic Barcelona, 08036 Barcelona, Spain1
Pereira BJG ,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;327:910-915
Full Text | Web of Science | Medline2
Pereira BJG ,Milford EL ,Kirkman RL ,Levey AS . Transmission of hepatitis C virus by organ transplantation. N Engl J Med 1991;325:454-460
Full Text | Web of Science | Medline3
Matesanz R. Organizacion Nacional de Trasplantes. Memoria 1991.
4
Mizrahi S ,Hussey JL ,Hayes DH ,Boudreaux JP . Organ transplantation and hepatitis C virus infection. Lancet 1991;337:1100-1100
CrossRef | Web of Science | Medline5
Pirsch JD ,Belzer FO . Transmission of HCV by organ transplantation. N Engl J Med 1992;326:412-412
Web of Science | Medline
To the Editor:
Several important questions remain unanswered by the study of Pereira et al.,1 with critical data not provided. It appears clear from the studies of Pereira et al.1,2 and from our own work3 that HCV can be transmitted by solid-organ transplantation. However, their inclusion of four liver recipients is not relevant to the issue of transmission by kidney and heart donors. Other centers are now reporting little evidence of liver disease in recipients of organs from either donors positive for HCV RNA or true antibody-positive donors3,4. Perhaps pulsatile perfusion, which was not used by Pereira et al., or other center-specific regimens partly explain the different rates of disease transmission reported1,3. Again, as in their initial report,2 the perioperative blood-transfusion history was not provided, and there was the possibility of exposure to HCV-infected blood products from 1986 through 1989.
The way in which samples are handled and preserved can also affect the subsequent detection of HCV RNA by the polymerase chain reaction (PCR)5. Thawed and refrozen serum samples drawn from recipients before transplantation cannot be fairly compared with fresh serum samples; Pereira et al. found a striking change in the rate of HCV RNA detection from the pretransplantation period (7 of 26 samples positive) to the post-transplantation period (23 of 24 samples positive). In contrast, in two centers for which we have data, only 5 of 10 and 8 of 22 kidney recipients who were negative for HCV RNA on PCR and who received an organ from a donor who was positive on PCR or recombinant immunoblot assay (or both) were positive after transplantation on PCR with freshly obtained serum samples. Several received transfusions perioperatively.
On the basis of currently available figures for the seroprevalence of anti-HCV among cadaveric organ donors, a complete moratorium on their use could translate into the loss of 8 percent of organs. Pereira et al. even suggest that the transplantation of organs from HCV-positive donors to HCV-positive recipients may be unsafe. Farci et al.6 have recently demonstrated in chimpanzees that persistent infection with one strain of HCV appears to cause “viral interference” against infection with other strains. This issue could be studied in humans.
We feel fully justified in continuing to use HCV-positive organ donors because of the low incidence of disease in recipients after a mean follow-up of five years.
This letter reflects the opinions of the workers involved in a number of transplantation programs7,8.
8 ReferencesJoshua Miller, M.D.
David Roth, M.D.
Eugene R. Schiff, M.D.
University of Miami, Miami, FL 331011
Pereira BJG ,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;327:910-915
Full Text | Web of Science | Medline2
Pereira BJG ,Milford EL ,Kirkman RL ,Levey AS . Transmission of hepatitis C virus by organ transplantation. N Engl J Med 1991;325:454-460
Full Text | Web of Science | Medline3
Roth D ,Fernandez JA ,Babischkin S , et al. Detection of hepatitis C virus infection among cadaver organ donors: evidence for low transmission of disease. Ann Intern Med 1992;117:470-475
Web of Science | Medline4
Tessi R, Henry M, Elkhammas E, Ferguson R. Prospective study of low risk HCV positive donors for kidney transplantation. Transplantation (in press).
5
Wang J-T ,Wang T-H ,Sheu J-C ,Lin S-M ,Lin J-T ,Chen D-S . Effects of anticoagulants and storage of blood samples on efficacy of the polymerase chain reaction assay for hepatitis C virus. J Clin Microbiol 1992;30:750-753
Web of Science | Medline6
Farci P ,Alter HJ ,Govindarajan S , et al. Lack of protective immunity against reinfection with hepatitis C virus. Science 1992;258:135-140
CrossRef | Web of Science | Medline7
Diethelm AG ,Roth D ,Ferguson RM , et al. Transmission of HCV by organ transplantation. N Engl J Med 1992;326:410-411
Full Text | Web of Science | Medline8
Pirsch JD ,Belzer FO . Transmission of HCV by organ transplantation. N Engl J Med 1992;326:412-412
Web of Science | Medline
To the Editor:
Pereira et al. suggest restricting the use of organs from anti-HCV-positive donors to lifesaving procedures1,2. There is strong evidence that HCV infection can be transmitted by organ transplantation, but the dynamics of transmission remain unclear because of the lack of a prospective follow-up of the recipients at risk. The authors analyzed the prevalence of anti-HCV among donors but did not indicate the prevalence of HCV RNA.
Since January 1991, cadaveric organ donors at our institution have been screened for antibody to HCV, but in some cases the test results were not available quickly enough, and transplantation was nevertheless performed. Ten months ago we transplanted the kidneys from an anti-HCV- and HCV RNA-positive cadaveric donor who had no detectable liver disease to two recipients who had no evidence of liver disease and who were negative for anti-HCV and HCV RNA. Between day 10 and day 20 after transplantation, one recipient had an isolated increase in alanine aminotransferase levels, reaching a maximum of 290 units per liter. Except for this one incident, both recipients had no evidence of post-transplantation liver disease. Both were tested repeatedly, at least 10 times, for HCV. Two and 12 days after transplantation, HCV RNA was detectable by PCR3 and persisted in subsequent samples. Anti-HCV seroconversion took place eight and nine months after transplantation. Our observations confirm that HCV infection can be transmitted by kidney transplantation and show that HCV RNA is detectable within a few days after transplantation, whereas seroconversion occurs several months later without association with clinical symptoms.
To assess the prevalence of anti-HCV and HCV RNA among our cadaveric organ donors, we retrospectively analyzed serum samples from 207 consecutive donors whose organs were obtained from 1986 to 1991. A second-generation enzyme-linked immunosorbent assay was used to detect anti-HCV antibody (HCV ELISA 2.0 Test System, Ortho), and positive test results were confirmed by a second-generation strip immunoblot assay (RIBA HCV Test System, Chiron, Emeryville, Calif.). Four of the 207 donors (1.9 percent) were anti-HCV-positive, and 3 of the 207 donors (1.4 percent) were positive for HCV RNA. These results show that the prevalence of anti-HCV among European donors is comparable to that reported by Pereira et al. No test results were found in which the serum sample was positive for HCV RNA but negative for anti-HCV, suggesting that second-generation anti-HCV tests provide an adequate estimate of the prevalence of HCV RNA.
3 ReferencesDaniel Candinas, M.D.
Helen I. Joller-Jemelka, M.D.
Felix Largiader, M.D.
University of Zurich Hospital, 8091 Zurich, Switzerland1
Pereira BJG ,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;327:910-915
Full Text | Web of Science | Medline2
Pereira BJG ,Milford EL ,Kirkman RL ,Levey AS . Transmission of hepatitis C virus by organ transplantation. N Engl J Med 1991;325:454-460
Full Text | Web of Science | Medline3
Garson JA ,Ring C ,Tuke P ,Tedder RS . Enhanced detection by PCR of hepatitis C virus RNA. Lancet 1990;336:878-879
CrossRef | Web of Science | Medline
Author/Editor Response
The authors reply:
To the Editor: The data provided by Candinas and colleagues and the results published by several other groups,1,2 including those of Miller and his coworkers, corroborate our data on the transmission of HCV by organ donors positive for HCV RNA. We agree with Miller et al. that differences in organ-preservation protocols could contribute to the variation in the rates of transmission of HCV by organ transplantation. Our ongoing analysis from a U.S. collaborative study3,4 shows that 1.9 percent of cadaveric organs would be wasted if a moratorium on the use of donors with anti-HCV were implemented nationwide. We are therefore developing strategies based on clinical, biochemical, and serologic characteristics that would more accurately identify anti-HCV-positive donors with ongoing HCV infection.
The safety of transplantation of kidneys from organ donors with anti-HCV into recipients with anti-HCV has been a subject of considerable debate5. Although the study by Morales and colleagues is a step in the right direction, the number of recipients studied was small, the duration of follow-up was short, and hence the power of the study to detect an adverse effect may have been limited. Furthermore, the donors and recipients were not tested for HCV RNA. Our study and those by others2,6,7 reveal a wide variation in the positive predictive value of the anti-HCV tests in identifying ongoing HCV infection in both organ donors and potential recipients. Finally, the anti-HCV antibodies detected by the currently available tests are non-neutralizing and do not confer immunity8. In contrast to the assertion by Miller and colleagues, a recent study in a chimpanzee model indicated that prevous infection with HCV did not protect against reinfection with a different or even the same strain of the virus8. In fact, reexposure did not protect against the reappearance of viremia or biochemical or histologic evidence of liver disease8.
We suggest that a large clinical study is needed to compare the long-term outcome in HCV RNA-positive recipients of organs from HCV RNA-positive donors with that in HCV RNA-positive recipients of organs from HCV RNA-negative donors. This study could be further refined by sequence analysis of donor and recipient HCV RNA before and after transplantation to determine whether infection after transplantation is caused by the same or a different strain of the virus. Until such data and better tests to identify HCV infection are available, the safety of transplantation of organs from anti-HCV-positive donors into anti-HCV-positive recipients remains to be established.
8 ReferencesBrian J.G. Pereira, M.D.
Andrew S. Levey, M.D.
New England Organ Bank, Newton, MA 021581
Aeder MI, Shield CF, Tegtmeier GE, et al. The incidence and clinical impact of hepatitis C virus (HCV) positive donors in cadaveric transplantation. Transplant Proc (in press).
2
Roth D ,Fernandez JA ,Babischkin S , et al. Detection of hepatitis C virus infection among cadaver organ donors: evidence for low transmission of disease. Ann Intern Med 1992;117:470-475
Web of Science | Medline3
Pereira BJG, Kirkman RL, Bryan CF, et al. National collaborative study of the prevalence of hepatitis C antibody (anti-HCV) in cadaver organ donors. XI Annual Meeting of the American Society of Transplant Physicians, Chicago, May 26-27, 1992:322. abstract.
4
Pereira BJG ,Kirkman RL ,Bryan CF , et al. National collaborative study of anti-HCV in cadaver donors: reduced organ wastage using a second generation anti-HCV test. J Am Soc Nephrol 1992;3:875-875 abstract.5
Pirsch JD ,Belzer FO . Transmission of HCV by organ transplantation. N Engl J Med 1992;326:412-412
Web of Science | Medline6
Berland Y ,Dussol B ,Chicheportiche C ,Cantaloube J-F ,Berthezene P . Detection of hepatitis C virus by polymerase chain reaction among hemodialysis patients. J Am Soc Nephrol 1992;3:354-354 abstract.7
Chung RT ,Karkov WN ,Dienstag JL ,Kaplan LM . Chronic renal failure is frequently associated with false-negative anti-C100 in patients with hepatitis C viremia. Gastroenterology 1991;100:A729-A729 abstract.8
Farci P ,Alter HJ ,Govindarajan S , et al. Lack of protective immunity against reinfection with hepatitis C virus. Science 1992;258:135-140
CrossRef | Web of Science | Medline
- Citing Articles (6)
Citing Articles
1
J. M. Morales, J. M. Campistol, B. Domínguez-Gil, A. Andrés, N. Esforzado, F. Oppenheimer, G. Castellano, A. Fuertes, M. Bruguera, M. Praga. (2010) Long-Term Experience With Kidney Transplantation From Hepatitis C-Positive Donors Into Hepatitis C-Positive Recipients. American Journal of Transplantation 10:11, 2453-2462
CrossRef2
Beatriz Domínguez-Gil, Jose M. Morales. (2009) Transplantation in the patient with hepatitis C. Transplant International 22:12, 1117-1131
CrossRef3
Beatriz Domínguez-Gil, Nuria Esforzado, Jose M. Campistol, Amado Andres, Jose M. Morales. (2007) Use of hepatitis C–positive donors for kidney transplantation. Transplantation Reviews 21:4, 195-203
CrossRef4
José M. Morales, Josep M. Campistol, Amado Andrés, José L. Rodicio. (1998) Hepatitis C virus and renal transplantation. Current Opinion in Nephrology and Hypertension 7:2, 177-184
CrossRef5
A.F. Santos, F. Busetto, R. Franco, E. Keitel, A.E. Bittar, V.D. Garcia. (1997) Renal transplantation using hepatitis B or C serology-positive donors. Transplantation Proceedings 29:8, 3320
CrossRef6
A. Rodrigues, T. Morgado, A. Castro Henriques, A. Morais Sarmento, M. Pereira, S. Guimarãcs. (1996) Outcome of renal graft recipients with hepatitis C virus infection. Transplant International 9:s1, S28-S31
CrossRef
