HBsAg as predictor of outcome in renal transplant patients
Ezequiel Ridruejo1, María del Rosario Brunet2, Ana Cusumano2, Carlos Díaz2, Mario Davalos Michel2, Luis Jost2, Luis Jost (h.)2, Oscar G. Mando1, Antonio Vilches2
1Sección Hepatología, 2Sección Nefrología, Departamento de Medicina; Centro de Educación Médica e Investigaciones Clínicas Norberto Quirno, (CEMIC), Buenos Aires
Postal address: Dr. Ezequiel Ridruejo, Azcuénaga 1057, 1115 Buenos Aires, Argentina. Fax: (54-11) 4809-1993. E-mail: eridruejo@cemic.edu.ar
Abstract
Chronic liver infections related to
hepatitis B and C viruses are a common problem in renal transplant patients
with a prevalence of 1.5 to 50% in different countries. There is no uniform
agreement regarding their influence on the incidence of acute rejection, graft
outcome and survival of renal transplant patients. We retrospectively evaluated
the influence of antiHBc, antiHCV and HBsAg positive status; gender; age over
50 years of age at the time of transplantation; pre and postransplantation
alaninaminotransferase (ALT) elevation; acute rejection; type of graft; number
of transplants; and maintenance and induction immunosuppression treatment on
the incidence of acute rejection and both graft and patient survival in the
population transplanted in our center between 1991 and 1998. The univariate
analysis showed that antiHCV, HBsAg and antiHBc status, more than one renal
transplant and one or more episodes of acute rejection were associated with
diminished graft survival; and being over the age of 50 at the time of transplantation
was also associated with diminished patient survival. In the multivariate
analysis HBsAg positive and one or more episodes of rejection were associated
with a diminished graft survival, and none of the variables studied was
associated with diminished patient survival. In conclusion antiHCV and HBsAg
positive status was associated with an increased risk of losing the
transplanted kidney, and HBsAg positivity was associated with an increased risk
of death, but this was not a statistically significant association.
Key words: Chronic viral hepatitis; Outcome; Renal transplantation.
Resumen
HBsAg como predictor de evolución en
trasplantados renales. Las hepatitis virales crónicas causadas
por los virus B y C son un problema común en los pacientes trasplantados
renales. No hay un consenso en cuanto a su influencia en la evolución del
injerto y la sobrevida de los pacientes trasplantados renales. Evaluamos
en forma retrospectiva la influencia de la positividad de antiHBc, antiHCV y
HBsAg; sexo; edad mayor de 50 años al momento del trasplante; elevación de la
alaninaminotransferasa en el período pre y postrasplante; rechazo agudo; tipo
de injerto; número de trasplantes; y tratamiento inmunosupresor en la sobrevida
del injerto renal y del paciente en los pacientes trasplantados en nuestro
centro entre 1991 y 1998. El análisis univariado mostró que la presencia de
antiHBc, antiHCV y HBsAg, más de un trasplante renal y uno o más episodios de
rechazo agudo se asociaron con una disminución en la sobrevida del injerto; y
la edad mayor de 50 años al momento del trasplante se asoció con una
disminución en la sobrevida de los pacientes. El análisis multivariado mostró
que la presencia de positividad para HBsAg y uno o más episodios de rechazo
agudo se asociaron con una disminución en la sobrevida del injerto, y ninguna
de las variables se asoció con una disminución en la sobrevida de los
pacientes. En conclusión: la presencia de antiHCV y HBsAg se asoció con
un mayor riesgo de perder el riñón trasplantado, y la positividad para HBsAg se
asoció con un mayor riesgo de muerte, aunque esto no fue estadísticamente
significativo.
Palabras clave: Hepatitis virales; Evolución; Trasplante renal.
Chronic liver diseases related to hepatitis B and C viruses are
a frequent problem in renal transplant recipients, and there is no agreement
regarding their impact upon both patient and allograft survival. Viral
hepatitis prevalence in dialysis patients on the transplant waiting list varies
between 1.5 to 50% according to different series1-5. The most relevant risk factors for these infections in
the dialysis population are the number of transfusions, the time on dialysis
and the dialysis modality, as they are much more frequent in hemodialysis than
in peritoneal dialysis.
The aim of this study was to retrospectively determine the
incidence of acute rejection, graft outcome and overall survival of renal
transplant patients with a positive serology for hepatitis C (antiHCV positive)
and B (HBsAg positive) when compared with our seronegative population.
Materials and Methods
The clinical records of the 254 renal
transplants (252 adult patients) performed at CEMIC between January 1st 1991 and December 31st 1998 were systematically reviewed. All
the information gathered up to July 31st 1999 was included in the analysis and the variables considered were the
following: graft survival was the period (in days) elapsed between renal
transplantation up to the return to dialysis or to the end of the evaluation;
rejection: an episode of acute renal dysfunction treated with antirejection
drugs, regardless of whether or not a biopsy was performed to establish the
diagnosis; patient survival: the time (in days) elapsed between renal
transplantation up to the patient's death with a functioning graft, or up to
the end of the evaluation.
We also analyzed the influence of the following variables
(dependent) upon the previously mentioned (independent) variables: gender; age
over 50 years at the time of transplantation; pretransplantation antiHCV
(hepatitis C virus antibody), HBsAg (hepatitis B surface antigen) and antiHBc
(hepatitis B core antibody) positivity; pre and postransplantation
alaninaminotransferase (ALT) elevation; rejection; type of graft; number of
transplantations; and induction and maintenance immunosuppression treatment .
All these variables were subjected to a univariate and
multivariate data analysis, using the Cox proportional hazard model and the
hazard ratio (HR) associated with patient survival, graft survival and
incidence of acute rejection with their corresponding 95% confidence intervals
(CI) and p values. P values < 0.05 were
considered statistically significant. Cumulative patient and graft survival
rates were calculated using the Kaplan Meier method and the comparisons were
performed using the log rank method. For statistical analysis STATA® software, statistics
data analysis version 7.0 (Stata Corporation, Tx., USA), was used.
Results
We evaluated all 252 adult recipients transplanted during the study period. All were Caucasian, 61% were men, 92% were on hemodialysis before renal transplantation, 62% were cadaveric transplantations, and the average age at the time of the evaluation was 38 years (Table 1). Twenty one patients (9%) were excluded because of insufficient data (moved to another country, transferred to another center, or lost to follow up for other reasons). Of the 231 remaining patients, 106 were antiHCV positive and 17 HBsAg positive. The number of HBsAg positive patients receiving a transplant each year, remained stable during the study period. The median time of follow up was 1199 days (range 1-3125). The median time on hemodialysis before transplantation was 67.26 months (SD 47.69 months) for antiHCV positive patients and 25.4 months (SD 23.04 months) for antiHCV negative patients (p < 0.001). In HBsAg positive patients the time on dialysis was 57.18 months (SD 61.63 months) and in the HBsAg negative group the time was 43.42 months (SD 39.95 months) (p= 0.10).
TABLE 1.- Population demographic characteristics and other
variables (231 patients)
Univariate analysis showed positive testing for antiHCV, HBsAg and antiHBc, being the first renal transplant and one or more episodes of rejection were associated with diminished graft survival and a greater risk of returning to dialysis. None of the other variables studied showed statistically significant correlations (Table 2). In the multivariate analysis only being HBsAg positive and having sustained one or more episodes of rejection were associated with a diminished graft survival. AntiHCV positivity and more than one renal transplant were associated with a greater risk of returning to dialysis, but these were not statistically significant (Table 3). In antiHCV positive patients the risk of returning to dialysis was 5.51/100 patients year, and in antiHCV negative this risk was 1.87. HBsAg positive patients had a risk of 12.53/100 patients year, whilst in the HBsAg negative the risk was 2.83.
TABLE 2.- Univariate analysis evaluating the risk of
returning to dialysis for each variable studied
TABLE 3.- Multivariate analysis evaluating the risk of
returning to dialysis for each variable studied
Cumulative graft survival rate at 7 years was 86% in HBsAg negative patients and 54% in positive patients (p=0.0147) (Fig. 1). In antiHCV positive patients cumulative graft survival rate was 74% versus 91% in those who tested negative (p= 0.0347) (Fig. 2).
Fig. 1.- Cumulative graft survival rate according to HBsAg
status.
Fig. 2.- Cumulative graft survival rate according to antiHCV
status.
We found that only being over the age of 50 at the time of
transplantation was associated with an increase in the risk of acute rejection
(HR 2.39, p=0.001 CI 95% 1.45-3.93). In the multivariate analysis none of the
variables studied were associated with an increased risk of rejection.
Being older than 50 at the time of transplantation was also
associated with an increased risk of death (HR: 4.64, p >0.001, CI 95% 2.07-10.75),
whilst transplantation using a living donor was associated with a lower
mortality (HR: 0.308, p=0.031, CI 95% 0.109-0.89). HBsAg positive patients
showed a higher mortality, but this was not statistically significant (HR:
2.02, p= 0.258, CI 95%: 0.597-6.838). AntiHCV positive status (HR: 1.11, p=
0.805, CI 95%: 0.481-2.564) and all the other variables studied did not have an
impact upon the risk of death. In the multivariate analysis none of the
variables studied was associated with an increased risk of death. In HBsAg
positive patients cumulative survival rate was 76% and in the HBsAg negative
population it was 88% (p= 0.24). In antiHCV positive patients this rate was 86%
versus 87% in the negative group (p= 0.80).
Discussion
In this study antiHCV and HBsAg positive status was associated
with an increased risk of losing the transplanted kidney, although the
correlation attained significance only in the case of the B virus infection.
HBsAg was also associated with an increased risk of death, but this was not
statistically significant. Since chronic viral infections of the liver are
diseases with a long term course, with a longer follow up period positive
serologies might show a statistically significant association with patient
death.
The present study has various limitations. It is a retrospective
study and data from a small number of patients is missing. We did not have HCV
viremia confirmation by the detection of HCV RNA by PCR in the antiHCV positive
patients; given that other studies found a concordance of 75 and 98% between
antiHCV and PCR positivity4-6,
we believe that our population would show similar results. Although it has been
shown that alterations in liver function tests do not predict patient outcome6, 7, considering that less than 10% of
our patients had liver biopsies performed, it is not possible to be certain if
the group of patients with more severe liver disease had a different outcome
from the group of patients with milder disease, as various publications suggest5, 6, 8.
The results of the many studies dealing with these issues are
controversial. Some indicate that antiHCV/HBsAg positive renal transplant
patients have a lower survival and/or a higher risk of graft failure than
negative patients8-13, 20, but
other studies found contradicting results14-20
on the other hand data from third world countries, especially from
Latin America are virtually non-existent.
Based in series demonstrating a greater long term survival in
chronic renal failure patients receiving a renal transplantation when compared
with patients remaining on dialysis21,
two studies showed that even though mortality of antiHCV positive renal
transplant patients is higher than in negative ones, the positive group's
mortality is still lower than that of patients remaining on dialysis22, 23.
There are multiple explanations for the difference in the
results of the published studies: a short time of follow up, usually less than
10 years, for a disease which evolves over decades; most series have included a
small number of patients from a single center; and the greatest difficulty in
the interpretation of the data is that patients have usually not been
adequately studied in relation to the severity of their liver disease. Also,
some groups do not include patients with viral hepatitis in their transplant
list and patients with severe comorbidities are generally not transplanted,
thus generating a selection of patients which makes comparisons virtually
impossible.
The results in our population suggest that antiHCV and HBsAg
positive renal transplant patients have a worse outcome than negative ones. In
spite of these results, and considering the diversity of the conclusions of the
published studies, it is difficult to make general recommendations about the
inclusion or exclusion of these patients in the renal transplantation list.
Such recommendations, based upon uniform evaluation criteria, must be
individualized4, 5, in order to
avoid transplanting a patient with severe liver disease and allowing
transplantation of patients with mild chronic viral hepatitis, who are unlikely
to have complications in the long term.
Acknowledgements: We are indebted to Dr. Andrés Pichón Riviere for his help with the statistical analysis.
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Received: 27-02-2004
Accepted:
30-06-2004