J Am Soc Nephrol 14: 2908–2918, 2003

Hepatitis C and Renal Transplantation in the Era of

Modern Immunosuppression
KEVIN C. ABBOTT,* JAY R. BUCCI,* CAL S. MATSUMOTO,† S. JOHN SWANSON,†
LAWRENCE Y.C. AGODOA,‡ KENT C. HOLTZMULLER,储 DAVID F. CRUESS,# and
THOMAS G. PETERS†¶
*Nephrology Service, Walter Reed Army Medical Center (WRAMC), Washington, DC, and Uniformed Services
University School of the Health Sciences, Bethesda, Maryland; †Organ Transplant Service, WRAMC, Washington,
DC, and National Institutes of Health, Bethesda, Maryland; ‡National Institute of Diabetes and Digestive and
Kidney Diseases, National Institutes of Health, Bethesda, Maryland; 储Gastroenterology Service, WRAMC,
Washington, DC; Department of Preventive Medicine and Biometrics, Uniformed Services University of the Health
Sciences, Bethesda, Maryland; and ¶The Jacksonville Transplant Center at Shands, Jacksonville, Florida

Abstract. Kidneys from donors who are positive for hepatitis C
virus (DHCV⫹) have recently been identified as an indepen-
dent risk factor for mortality after renal transplantation. How-
ever, it has not been determined whether risk persists after
adjustment for baseline cardiac comorbidity or applies in the
era of modern immunosuppression. Therefore, a historical co-
hort study was conducted of US adult cadaveric renal trans-
plant recipients from January 1, 1996, to May 31, 2001; fol-
lowed until October 31, 2001. A total of 36,956 patients had
valid donor and recipient HCV serology. Cox regression anal-
ysis was used to model adjusted hazard ratios for mortality and
graft loss, respectively, adjusted for other factors, including
comorbid conditions from Center for Medicare and Medicaid
Studies Form 2728 and previous dialysis access-related com-
plications. It was found that DHCV⫹ was independently as-
sociated with an increased risk of mortality (adjusted hazard
ratio, 2.12, 95% confidence interval, 1.72 to 2.87; P ⬍ 0.001),
primarily as a result of infection. Mycophenolate mofetil was
associated with improved survival in DHCV⫹ patients, pri-
marily related to fewer infectious deaths. Adjusted analyses
limited to recipients who were HCV⫹, HCV negative, or age
65 and over, or by use of mycophenolate mofetil confirmed
that DHCV⫹ was independently associated with mortality in
each subgroup. It is concluded that DHCV⫹ is independently
associated with an increased risk of mortality after renal trans-
plantation adjusted for baseline comorbid conditions in all
subgroups. Recipients of DHCV⫹ organs should be consid-
ered at high risk for excessive immunosuppression.

The expected clinical course of hepatitis C infection as it affects
organ transplant recipients, as well as the use and effect of kidneys
from donors who are positive for hepatitis C, remain controversial
topics in renal transplantation. Recently published data confirmed
that kidneys from donors who were hepatitis C positive (HCV⫹)
were associated with an independently increased risk of death in
renal transplant recipients regardless of recipient HCV status (1).
However, donor hepatitis C seropositivity (DHCV⫹) was not
independently associated with mortality when limited to patients
with valid information (Centers for Medicare and Medicaid Stud-
ies [CMS] Form 2728) on comorbid conditions at the time of
dialysis initiation. This may have been because of the relatively
Received March 12, 2003. Accepted July 27, 2003.
Correspondence to Kevin C. Abbott, LTC, MC, Dialysis, Nephrology Service,
Walter Reed Army Medical Center, Washington, DC 20307-5001. Phone:
202-782-6462/6463/6288; Fax: 202-782-0185; E-mail: kevin.abbott@
na.amedd.army.mil
The opinions are solely those of the authors and do not represent an endorse-
ment by the Department of Defense or the National Institutes of Health. This
is a government work. There are no restrictions on its use.
1046-6673/1411-2908
Journal of the American Society of Nephrology
Copyright © 2003 by the American Society of Nephrology
DOI: 10.1097/01.ASN.0000090743.43034.72
small numbers of transplant recipients for whom complete data
were available during the study period or because cardiovascular
comorbidity was actually lower in patients who received DHCV⫹
kidneys, yet the mortality risk for recipients of DHCV⫹ kidneys
was still greater than for patients who received DHCV⫺ kidneys.
Possibly, recipients of DHCV⫹ kidneys were sicker to start with
and thus had a higher risk of death unrelated to receiving a
DHCV⫹ kidney. Since that study, there have been substantial
changes in maintenance immunosuppression practices in the
United States. In particular, recent reports have confirmed that
mycophenolate, in comparison with azathioprine, is associated
with a reduced risk of both death-censored graft loss (2) and death
with graft function (3). For better determining whether donor and
recipient hepatitis C serologic status remains important in graft
and patient survival in modern clinical transplantation, a historical
cohort study analyzing the 2002 United States Renal Data System
(USRDS) data assessed those factors associated with HCV⫹
kidneys while controlling for variables previously established to
have an impact on outcomes.
Materials and Methods
Data Sources and Study Sample
The data set and analytical techniques have previously been de-
scribed (4). In summary, the USRDS standard analysis file (SAF)
J Am Soc Nephrol 14: 2908–2918, 2003
provided the primary file including information at the time of trans-
plantation. Follow-up information included dates and causes of graft
loss, dates and causes of death, approximate dates of allograft rejec-
tion, and follow-up serum creatinine levels. Files were merged with
the main file using unique patient identifying codes to obtain fol-
low-up data. The file was also merged with SAF.PATIENTS to obtain
dates and causes of death. Fewer than 0.5% of living donor kidneys
were seropositive for HCV, and therefore analysis was limited to
recipients of cadaver kidneys. Sirolimus and tacrolimus were not
widely used in clinical practice until 1996. Therefore, analysis was
limited to adult patients who underwent cadaveric kidney transplan-
tation from January 1, 1996, to May 31, 2001. Information on med-
ications was limited to immunosuppressive medications. Only one
transplantation for a given patient during the study period (which
could have been a repeat kidney transplantation or a multiorgan
kidney transplantation) was included in analysis. Only cases with
specified HCV data for both donor and recipient were included. HCV
serology (presumably ELISA, although the variable “HCSRN” legend
indicated only “hepatitis C antibody screen,” and transplant question-
naires did not specify generation of ELISA) was not independently
confirmed. Similarly, the cause of ESRD could not be confirmed
independently. Additional variables in analysis included previous
hospitalizations for vascular or peritoneal dialysis access complica-
tions (infections, thrombosis, or other dysfunction) that occurred after
the first date of dialysis but before the date of transplantation. Co-
morbidity data, including selected laboratory data, from the time
patients presented to dialysis was also available from the CMS Form
2728. Because these data were not available for all patients, these
variables were used in separate models. Patients were followed
through October 31, 2001.
Analytic Variables and Outcome Measures
Factors Associated with Use of HCVⴙ Kidneys Given to
HCVⴚ Recipients. Because some American transplant centers al-
low the use of HCV⫹ kidneys in certain recipients who are HCV⫺,
we conducted a logistic regression analysis of factors independently
associated with a HCV⫺ patient receiving an HCV⫹ kidney. This
analysis used stepwise logistic regression (forward likelihood ratio
method) of factors thought to be clinically significant, such as previ-
Table 1. Characteristics of study population (continuous variables)a
Factor
Donor Age (yr; mean [SD])
Recipient age (yr; mean [SD])
Recipient body mass index (kg/m2; mean [SD])
Cold ischemic time (hr; mean [SD])b
Peak PRA (%; mean [SD])c
HLA mismatches (0–6)
Most recent serum creatinine at 1 yr posttransplantation
Years of dialysis before transplantation
Values from medical evidence form 2728d
hematocrit (%)
albumin (g/dl)
a
Analysis limited to patients with valid recipient and donor hepatitis C serologies. PRA, panel reactive antibodies.
b
P ⬍ 0.05 by t test versus patients who did not die or experience graft loss, respectively.
c
P ⬍ 0.05 by Mann-Whitney U test versus patients who did not die or experience graft loss, respectively.
d
Limited to patients who presented to dialysis on or after April 1, 1995 (thus limited to 63.3% of the study population).
Hepatitis C and Renal Transplantation 2909
ous history of access complications, as well as demographic and other
factors related to patient survival, including donor and recipient age,
gender, race, recipient HCV serology, duration of dialysis before
transplantation, body mass index, previous transplantation, recipient
sensitization, cold ischemic time, HLA mismatch, and use of immu-
nosuppressive medications. This analysis was performed for the entire
study population to construct propensity scores for the probability of
receiving a DHCV⫹ kidney (1 if positive, 0 if negative). Nagelkerke
r2 and the c-statistic (with 0.5 indicating a probability equivalent to
random chance and 1.0 indicating 100% prediction) were used to
assess model fit and predictive power.
Patient and Graft Survival. Survival time was defined as the
time between the date of transplantation and death, the most recent
follow-up date, or the end of the study period. Graft failure was
defined as return to dialysis after transplantation and did not include
death with a functioning graft. Variables entered into the model were
those previously associated with patient and graft survival after trans-
plantation (5) or significant in univariate analysis in Tables 1 and 2
and included transplant center. Medication use was determined as
induction therapy (at discharge from the initial transplant hospitaliza-
tion, primarily for antibody induction therapy) and maintenance ther-
apy. Maintenance therapy was determined at follow-up visits at 6, 12,
and 24 mo. For allowing for changes in medication use, any use of
medication at the specified visits was considerer maintenance therapy.
This resulted in overlap of medications. Therefore, models were also
performed excluding medication overlap. Graft loss was analyzed as
a time-dependent variable using previously described methods (6)
because it has recently been recognized as an independent predictor of
patient mortality in kidney transplant recipients (7). Stratified Cox
models were performed for each of the following subgroups of par-
ticular clinical interest: recipients who were HCV⫺, recipients who
were HCV⫹, and recipients who were age 65 yr or older. Analyses
were also performed excluding patients who received multiple organ
transplants. Covariates whose Kaplan Meier plots violated the as-
sumption of proportional hazards over time were assessed using
yearly intervals after transplantation, as described in other, similar
studies (8). Files were converted from SAS to SPSS using DBMS
Copy 7.0 (Conceptual Software, Houston, TX). SPSS version 11.5.0
(Chicago, IL) was used for primary analysis.
Study cohort Patients who died Patients with graft loss
35.4 ⫾ 17.1 39.53 ⫾ 17.92b 39.0 ⫾ 18.5b
47.0 ⫾ 12.5 52.46 ⫾ 12.08b 46.3 ⫾ 13.2b
26.2 ⫾ 21.5 26.3 ⫾ 6.1 26.6 ⫾ 6.1b
19.6 ⫾ 8.4 20.5 ⫾ 8.5 20.8 ⫾ 8.6b
13.9 ⫾ 25.9 14.9 ⫾ 26.7 20.3 ⫾ 30.7c
3.33 ⫾ 1.80 3.43 ⫾ 1.78b 3.65 ⫾ 1.68b
1.66 ⫾ 0.96 2.05 ⫾ 1.77c 2.09 ⫾ 2.74c
3.84 ⫾ 3.91 3.9 ⫾ 3.8c 4.5 ⫾ 4.4c
28.7 ⫾ 5.8 28.6 ⫾ 5.5 28.2 ⫾ 5.9
3.46 ⫾ 0.68 3.34 ⫾ 0.66b 3.38 ⫾ 0.69b
2910 Journal of the American Society of Nephrology J Am Soc Nephrol 14: 2908–2918, 2003

Table 2. Analysis of associations with donor hepatitis C seropositivity by variable, adult cadaveric kidney transplant
recipients, January 1, 1996, to May 31, 2001a
All cadaveric kidney
Univariate RR Episodes of graft Univariate RR
transplant recipients Deaths (N [%])
(95% CI) loss (N [%]) (95% CI)
(N [%])

N 36,956 4552 (12.3) 2448 (6.6)

Mean follow-up (yr) 2.77 ⫾ 1.66
Variable (N)
recipient hepatitis C positive 2525 (6.8) 403 (15.8) 1.38 (1.24 to 1.55) 227 (8.9) 1.43 (1.24 to 1.64)
donor hepatitis C positive 873 (2.4) 174 (19.6) 1.80 (1.52 to 2.14) 68 (7.7) 1.20 (0.93 to 1.54)
Categories of donor and recipient
HCV (compared with D⫺/R⫺)
D⫹/R⫺ 280 (0.8) 72 (25.4) 2.49 (1.90 to 3.26) 18 (6.4)b 0.97 (0.60 to 1.56)
D⫹/R⫹ 593 (1.6) 102 (16.9) 1.49 (1.20 to 1.85) 50 (8.3)b 1.30 (0.97 to 1.75)
D⫺/R⫹ 1932 (5.2) 301 (15.5) 1.38 (1.24 to 1.55) 77 (9.1) 1.45 (1.23 to 1.70)
D⫺/R⫺ 34,431 (92.4) 4088 (11.8) 1 (reference) 2214 (6.4) 1 (reference)
Recipient male (versus female) 22,608 (60.4) 2821 (12.5) 1.07 (1.004 to 1.14) 1439 (6.4) 0.93 (0.85 to 1.008)
Recipient black (versus all other 9725 (26.0) 1252 (12.9) 1.09 (1.01 to 1.17) 830 (8.5) 1.49 (1.37 to 1.63)
races)
Donor black (versus all other 4116 (11.0) 560 (12.3) 1.15 (1.04 to 1.26) 349 (8.5) 1.36 (1.21 to 1.53)
races)
Dialysis in the first week 8810 (23.7) 1610 (18.3) 1.95 (1.82 to 2.08) 1320 (15.0) 4.28 (3.94 to 4.66)
posttransplantation (Y/N)
Body mass index ⱖ30 kg/m2 6586 (20.1) 819 (12.4) 1.11 (1.02 to 1.21) 494 (7.5) 1.27 (1.15 to 1.42)
(versus all others)
Donor CMV⫹ 22,806 (61.3) 2928 (12.8) 1.17 (1.09 to 1.25) 1563 (6.9) 1.12 (1.03 to 1.22)
Rejection in the first year 6642 (17.8) 996 (15.0) 1.34 (1.24 to 1.44) 678 (10.2) 1.82 (1.66 to 1.99)
posttransplantation, diagnosis
and treatment (Y/N)
Graft loss 2448 (6.6) 924 (37.7) 5.16 (4.72 to 5.64) NA NA
Repeat transplantation (versus 4083 (11.0) 496 (12.3)b 1.00 (0.91 to 1.11) 365 (8.9) 1.48 (1.32 to 1.66)
primary)
NS
Cause of ESRD
diabetes (Y/N) 10,693 (32.8) 1737 (16.2) 1.69 (1.58 to 1.81) 566 (5.3) 0.75 (0.68 to 0.82)
Maintenance medicationsc
cyclosporine 22,724 (67.8) 2537 (11.2) 1.23 (1.14 to 1.32) 982 (4.3) 0.63 (0.57 to 0.69)
tacrolimus 14,235 (42.5) 1249 (8.8) 0.71 (0.62 to 0.77) 767 (5.4) 1.12 (1.01 to 1.23)
azathioprine 7985 (23.8) 1015 (12.7) 1.33 (1.23 to 1.44) 468 (5.9) 1.23 (1.10 to 1.37)
mycophenolate 26,433 (78.9) 2442 (9.2) 0.55 (0.51 to 0.60) 1104 (4.2) 0.47 (0.43 to 0.52)
sirolimus 2317 (6.9) 177 (7.6) 0.69 (0.59 to 0.80) 142 (6.1) 1.24 (1.04 to 1.48)
Induction antibody use 17,676 (47.8) 2037 (11.5) 0.87 (0.82 to 0.92) 1243 (7.0) 1.13 (1.04 to 1.23)
Previous hospitalizations for 6207 (16.8) 869 (14.0) 1.20 (1.11 to 1.30) 553 (8.9) 1.49 (1.35 to 1.64)
access complicationsd
Comorbidities from medical
evidence Form 2728e
chronic obstructive pulmonary 358 (1.5) 74 (20.7) 2.43 (1.87 to 3.15) NS NS
disease
ischemic heart disease 1758 (7.4) 308 (17.5) 2.04 (1.79 to 2.33) NS NS
congestive heart failure 2493 (10.5) 426 (17.1) 2.05 (1.83 to 2.30) NS NS
peripheral vascular disease 1108 (4.5) 192 (17.3) 2.03 (1.72 to 2.38) NS NS
smoking 1249 (5.3) 156 (12.5) 1.32 (1.11 to 1.57) NS NS
alcohol use 201 (0.8) 33 (16.4) 1.79 (1.23 to 2.60) NS NS
a
Results given as % (N) or mean ⫾ SD. CMV, cytomegalovirus. NA, not-included in model; NS, not significant.
b
Only factors that were significantly associated with death or graft loss are shown in the tables, with the exception of hepatitis C
categories indicated, and repeat transplant with death as indicated.
c
Percentages do not total to 100 because of missing values and overlap.
d
Codes for access complications were 996.1x, 996.56x, and 996.6x.
e
This information from this form was available only for patients who started dialysis on or after April 1, 1995, or for 23,405 (63.3%)
of the study population.

Results
From January 1, 1996, to May 31, 2001, 46,078 adult
recipients of cadaveric kidney transplants met study criteria
in the United States. Of these, 2914 (6.3%) recipients had no
data regarding their donor hepatitis C status; an additional
6387 (13.9%) who lacked data for recipient HCV status
were excluded (with some overlap between the two groups),
leaving 36,956 patients for study in multivariable analysis.
Notably, recipients with missing HCV data (their own or
their donor) did not differ statistically from patients for
whom these data were known. Among study patients, only
7121 (19.3%) recipients had valid data for HCV recombi-
J Am Soc Nephrol 14: 2908–2918, 2003
nant immunoblot (RIBA), 9.3% of whom were positive, and
only 1534 (4.2%) had valid data for HCV RNA, 10.2% of
whom were positive. There was no information on donor
HCV RIBA or HCV RNA.
Factors Associated with Receipt of HCV⫹ Kidneys and
of HCV⫹ Kidneys Given to HCV⫺ Recipients
In logistic regression analysis of factors associated with
receipt of a HCV⫹ donor kidney, the following factors were
independently significant: HCV⫹ recipient, recipient age ⱖ65
yr, black recipient race, older donor age, lower prevalence of
diabetes, increased HLA mismatch, longer cold ischemic time,
and lower recipient sensitization. Notably, neither transplant
center nor any comorbid conditions in CMS Form 2728 were
significantly associated with receipt of a DHCV⫹ kidney. In
this model, which was used to generate propensity scores, the
Nagelkerke r2 was 0.54, and the c-statistic was 0.955 (95%
confidence interval [CI], 0.946 to 0.964). In logistic regression
analysis, the following factors were independently associated
with use of a HCV⫹ kidney in a recipient who was HCV⫺:
recipient age ⱖ65 yr (adjusted odds ratio [AOR], 4.98; 95%
CI, 3.34 to 7.41, P ⬍ 0.001), black recipient (AOR, 2.82; 95%
CI, 1.97 to 4.05), older donor age (AOR, 1.011; 95% CI, 1.001
to 1.021; P ⫽ 0.045), longer cold ischemic time and higher
HLA mismatch, and lower use of tacrolimus (AOR, 0.57; 95%
CI, 0.39 to 0.85; P ⫽ 0.005). Neither a history of hospitaliza-
tion for access complications, transplant center, duration of
dialysis before transplantation nor any comorbid conditions
from CMS Form 2728 were independently associated with use
of a HCV⫹ kidney in a recipient who was HCV⫺.
Patient and Graft Survival
A cross-tabulation of the study population by donor and
recipient HCV status (Table 3) disclosed that 280 (32%) of 873
of HCV⫹ donor kidneys were given to HCV⫺ recipients, and
593 (23%) of HCV⫹ recipients received an HCV⫹ kidney.
Table 1 shows continuous variables and their unadjusted asso-
ciation with death and graft loss, respectively. Factors that
were significantly associated with both death and graft loss
included older donor and recipient age, HLA mismatch, ele-
vated creatinine level by the end of the first year posttrans-
plantation, and longer duration of dialysis before transplanta-
Table 3. Adult cadaveric renal transplant recipients, January
1, 1996, to May 31, 2001a
Donor HCV⫺ Donor HCV⫹ Total
Recipient HCV⫺ 34,151 280 34,431
Recipient HCV⫹ 1932 593 2525
Totals 36,083 873
a stratified by receipt of a kidney positive for hepatitis C (DHCV⫹) or
Cross-tabulation of Hepatitis C seropositivity by donor and
recipient, among patients with valid donor and recipient hepatitis C
serologies. HCV⫹, hepatitis C positive; HCV⫺, hepatitis C
negative. As shown, 32% of HCV⫹ donor kidneys were given to
recipients who were HCV⫺. Other percentages are given in the
text of the Results section.
Hepatitis C and Renal Transplantation 2911
tion. Factors associated only with graft loss included elevated
body mass index, longer cold ischemic time, and higher patient
sensitization.
Table 2 shows results of categorical variables and their
respective unadjusted associations with death and graft loss.
Categories of donor and recipient HCV status were compared
with D⫺/R⫺ (donor and recipient both negative). D⫹/R⫺ had
the highest comparative mortality, and every other category
had a significantly higher risk of death in comparison with
D⫺/R⫺. However, there was no significant relationship seen
for graft loss.
Figures 1 to 6 show Kaplan-Meier plots of patient survival
stratified by recipient and donor HCV status, age, and use of
mycophenolate. Figure 1 shows HCV⫹ recipients only, com-
paring survival for those who received DHCV⫹ and those who
received DHCV⫺. Survival curves crossed at 2 yr, violating
the proportional hazards assumption. In analysis limited to
patients who survived at least 2 yr, DHCV⫹ was significantly
associated with greater mortality compared with DHCV⫺ in
recipients who were HCV⫹ (P ⬍ 0.001 by log rank test).
Figure 2 shows results only of patients who received DHCV⫹,
in which HCV⫹ patients had significantly lower mortality than
HCV⫺ patients in unadjusted analysis (P ⫽ 0.01 by log rank
test). However, these results did not persist in Cox regression
analysis. Figure 3 shows that DHCV⫹ was significantly asso-
ciated with increased mortality in recipients age 65 and older
(P ⬍ 0.001 by log rank test). Figure 4 shows that mycophe-
nolate use (versus all other medications, but primarily versus
azathioprine) was significantly associated with reduced mor-
tality in patients who received DHCV⫹ (P ⬍ 0.01 by log rank
test). The significant association between DHCV⫹ and mor-
Figure 1. Kaplan-Meier plot of patient survival after renal transplan-
tation, hepatitis C–positive (HCV⫹) recipients only (n ⫽ 2525),
negative for hepatitis C (HCV⫺). In the first 1 to 2 yr after trans-
plantation, survival was equivalent; however, after 2 yr after trans-
plantation, survival for DHCV⫹ was significantly lower than for
DHCV⫺ (P ⬍ 0.001 by log rank test). This association remained
significant in adjusted Cox regression analysis (see Table 4).
2912 Journal of the American Society of Nephrology
Figure 2. Kaplan-Meier plot of patient survival after renal transplan-
tation, limited to patients who received a kidney positive for hepatitis
C (DHCV⫹; n ⫽ 873) stratified by recipients who were HCV⫹ and
HCV⫺. In unadjusted analysis, HCV⫺ patients had significantly
lower survival than HCV⫹ patients (P ⬍ 0.01 by log rank test).
However, in adjusted Cox regression analysis, this difference was NS
(P ⫽ 0.37).
Figure 3. Kaplan-Meier plot of patient survival limited to patients
who were aged 65 and older (n ⫽ 732). Recipients of hepatitis C
positive kidneys (DHCV⫹) had lower survival than those who re-
ceived HCV⫺ kidneys (P ⫽ ⬍0.001 by log rank test). Survival was
comparable until approximately halfway through the first posttrans-
plantation year. Analysis was limited to 3 yr because of insufficient
numbers of DHCV⫹ past that point. Furthermore, among recipients
aged 65 and older who received DHCV⫹, 19 of 20 specified causes
of death were due to either infection or liver disease/hepatitis.
tality persisted regardless of the use of mycophenolate use,
however (Figures 5 and 6).
The independent association of DHCV⫹ with patient sur-
vival for the entire study cohort is shown in Table 4. Table 4
shows results of analysis excluding (left columns) and includ-
J Am Soc Nephrol 14: 2908–2918, 2003
Figure 4. Kaplan-Meier plot of patient survival after renal transplan-
tation, limited to patients who received a kidney positive for hepatitis
C (DHCV⫹; n ⫽ 873) stratified by recipients who received myco-
phenolate mofetil (MMF) or those who did not (no MMF). In unad-
justed analysis, patients who received MMF had significantly reduced
mortality compared with those who did not (P ⬍ 0.01 by log rank
test). This significance persisted in adjusted analysis (see Tables 1 to
5). The only major cause of death that was lower in users of MMF was
death as a result of infection.
Figure 5. Kaplan-Meier plot of patient survival after renal transplan-
tation, limited to patients who used MMF stratified by recipients who
received a kidney positive for hepatitis C (DHCV⫹) or negative
hepatitis C (DHCV⫺). In unadjusted analysis, patients who received
DHCV⫹ had significantly increased mortality compared with those
who did not (P ⬍ 0.01 by log rank test). This significance persisted in
adjusted analysis (see the Results section).
ing (right columns) comorbid information at the time of dial-
ysis initiation. Data on comorbid conditions were available
only for patients who started dialysis on or after April 1, 1995,
or for 23,405 (63.3%) of the study population. Patients with
prolonged waiting times before dialysis would have been less
likely to have this information. As shown, DHCV⫹ was con-
sistently associated with increased risk of mortality in both
models. In Table 4, HCV⫹ recipients had a favorable interac-
tion with DHCV⫹, but this association did not persist after
J Am Soc Nephrol 14: 2908–2918, 2003
Figure 6. Kaplan-Meier plot of patient survival after renal transplan-
tation, limited to patients who did not use MMF stratified by recipi-
ents who received a kidney positive for hepatitis C (DHCV⫹) or
negative hepatitis C (DHCV⫺). In unadjusted analysis, patients who
received DHCV⫹ had significantly increased mortality compared
with those who did not (P ⬍ 0.01 by log rank test). This significance
persisted in adjusted analysis (see the Results section).
adjustment for baseline comorbid conditions. Also in Table 4,
use of mycophenolate had a favorable interaction with HCV⫹
that did persist in analysis including comorbid conditions. In
recipients age 65 and older, in whom it is often assumed that
the contribution of DHCV⫹ to mortality would be minimal,
DHCV⫹ had a significantly adverse interaction. This interac-
tion did not persist in the smaller model accounting for comor-
bid conditions. Mycophenolate use had a significantly benefi-
cial interaction with DHCV⫹ only in the model accounting for
baseline comorbid conditions. Results of analyses excluding
patients who received multiple organ transplants were not
substantially different.
Stratified analyses were also performed limited to recipients
who were HCV⫹, HCV⫺, and age 65 and older, respectively.
In HCV⫹ recipients, analysis was limited to patients who had
survived for at least 2 yr after transplantation because of the
violations of the proportional hazards assumption shown in
Figure 1. The association of DHCV⫹ with mortality was
actually stronger in the model accounting for comorbid condi-
tions (AHR, 2.04; 95% CI, 1.20 to 3.45) than in the larger
model that did not account for comorbid conditions (AHR,
1.43; 95% CI, 1.02 to 2.02). In HCV⫺ recipients, DHCV⫹
was significantly associated with mortality in models without
(AHR, 2.30; 95% CI, 1.75 to 3.26; P ⫽ 0.025) and with (AHR,
2.25; 95% CI, 1.56 to 3.24; P ⬍ 0.001) comorbid conditions.
Among recipients age 65 and older (Figure 3), the association
of DHCV⫹ with mortality was the strongest of any subgroup
(AHR, 3.48; 95% CI, 2.35 to 5.17; P ⬍ 0.001 in the model
without comorbid conditions, and AHR, 3.99; 95% CI, 2.46 to
6.49; P ⬍ 0.001 in the model with comorbid conditions.
Associations of DHCV⫹ with survival by use of mycopheno-
late are shown in Figures 4 to 6. Mycophenolate use had a
significantly beneficial interaction with DHCV⫹ in this age
group, accounting for comorbid conditions (AHR, 0.49; 95%
CI, 0.27 to 0.90; P ⫽ 0.03). Among recipients age 65 and older
Hepatitis C and Renal Transplantation 2913
who received DHCV⫹, unadjusted 4-yr survival was 49% for
mycophenolate users versus 27% for non-mycophenolate users
(P ⬍ 0.01 by log rank test). In comparison, among recipients
age 65 and older who did not receive DHCV⫹, unadjusted 4-yr
survival was 71% for users of mycophenolate versus 57% for
non-mycophenolate users (P ⬍ 0.01 by log rank test). Results
of analysis did not differ in models excluding overlapping
medications.
Causes of death were listed as known in ⬎44% of all cases.
Among the 873 recipients of donor HCV⫹ kidneys, the cause
of death was known in 36% of cases. Therefore, results were
not compared statistically. Infection was the leading specified
cause of death for recipients of DHCV⫹ kidneys, similar to the
incidence of infectious deaths of those who received DHCV⫺
kidneys. In contrast, cardiac death was less common in recip-
ients of donor HCV⫹ kidneys (13.2%) than in donor HCV⫺
(22.8%) recipients. Deaths as a result of any liver disease were
more common for recipients of donor HCV⫹ kidneys (6.9%)
than for recipients of donor HCV⫺ kidneys (1.5%).
Neither HCV⫹ nor DHCV⫹, separately or as an interaction
term, was significantly associated with graft survival in ad-
justed analysis of factors including serum creatinine at 1 yr
posttransplantation (Table 5). However, HCV⫹ recipients
were at increased risk of graft loss in a model that included
only baseline factors at the time of renal transplantation (and
thus not including allograft rejection, delayed graft function, or
posttransplantation serum creatinine levels).
Discussion
The present study confirms that patients who receive kid-
neys from HCV⫹ donors are independently at increased risk of
mortality. Increased risk persisted in adjusted analysis of every
subgroup assessed. Furthermore, the leading cause of death in
patients who received DHCV⫹ kidneys was infection, in con-
trast to the leading cause of death for all other renal transplant
recipients, namely, cardiovascular disease. These findings sug-
gest a direct adverse effect of DHCV⫹ kidneys on survival in
renal transplant recipients, rather than greater severity of pre-
existing illness in patients who are given DHCV⫹ kidneys.
Recent recommendations include restricting the use of
DHCV⫹ kidneys to patients who are HCV RNA positive, not
just ELISA positive (9). However, it is not clear that such
patients would be protected from infection by all strains of
HCV.
A possible adverse effect of DHCV⫹ kidneys, at least in
HCV⫹ or elderly recipients, has often been discounted be-
cause of the long duration between inoculation/viral transmis-
sion and development of cirrhosis in patients who contract
HCV in the general population (10). This long incubation
period has been presumed also to occur in transplant patients,
possibly disregarding the impact of maintenance immunosup-
pression in this population. However, very rapid progression of
clinical hepatitis has been documented after renal transplanta-
tion as well as in other immunosuppressed conditions, namely
HCV and HIV coinfection (11–14) In addition, HCV positivity
in the general population is associated with a significantly
increased risk of opportunistic infections even in the absence of
2914 Journal of the American Society of Nephrology J Am Soc Nephrol 14: 2908–2918, 2003

Table 4. Multivariable associations (by Cox regression) with patient mortality in adult cadaveric kidney recipientsa
Without comorbidities With comorbidities
Variable
P value AHR 95% CI P value AHR 95% CI

Donor HCV⫹ ⬍0.001 2.12 1.72 to 2.87 0.003 2.66 1.38 to 5.13
Recipient HCV⫹ 0.026 1.34 1.04 to 1.74 NS
Liver-kidney transplant 0.013 2.76 1.24 to 6.17 0.008 3.26 1.35 to 7.86
Most recent serum creatinine level at 1 yr ⬍0.001 1.21 1.18 to 1.24 ⬍0.001 1.18 1.15 to 1.22
posttransplantation (per mg/dl)b
Diabetes as cause of ESRD ⬍0.001 1.84 1.70 to 1.99 ⬍0.001 1.81 1.62 to 2.02
Years of dialysis before transplantation ⬍0.001 1.04 1.03 to 1.05 ⬍0.001 1.04 1.02 to 1.05
(per year)
Recipient age ⱖ65 yr ⬍0.001 2.45 2.21 to 2.74 ⬍0.001 2.36 2.02 to 2.74
Delayed graft function ⬍0.001 1.29 1.18 to 1.41 0.001 1.23 1.09 to 1.38
Donor CMV⫹ 0.001 1.16 1.07 to 1.27 0.035 1.13 1.01 to 1.26
Donor age (per year) ⬍0.001 1.007 1.005 to 1.01 ⬍0.001 1.008 1.005 to 1.011
Mycophenolate usec ⬍0.001 0.68 0.63 to 0.74 ⬍0.001 0.69 0.61 to 0.77
Previous hospitalization for access 0.016 1.15 1.03 to 1.30 0.040 1.21 1.01 to 1.46
complications
Propensity score for receiving DHCV⫹ 0.027 1.033 1.004 to 1.063 0.77 0.99 0.93 to 1.05
kidney (per higher quartile)
Transplant Center ⬍0.001 NG ⬍0.001 NG
Comorbid conditions from CMS Form
2728d
ischemic heart disease NA 0.007 1.24 1.06 to 1.45
congestive heart failure NA ⬍0.001 1.59 1.40 to 1.82
peripheral vascular disease NA ⬍0.001 1.56 1.30 to 1.87
smoking NA 0.011 1.28 1.06 to 1.56
Interaction terms
HCV⫹*DHCV⫹ ⬍0.001 0.51 0.36 to 0.73 NS
recipient age ⱖ65 years*DHCV⫹ 0.002 1.91 1.26 to 2.91 NS
mycophenolate use*DHCV⫹ NS 0.043 0.55 0.30 to 0.98
N in final sample 21,465 15,454
a
All variables significant in univariate Kaplan Meier analysis in Table 1 were entered into stepwise Cox regression analysis (see
Methods section for covariates used). Only variables significant in final analysis are shown. For variables in quartiles, the hazard ratio is
for higher quartiles above the mean.
b
Results shown for patients who survived at least 1 yr after transplantation.
c
Compared with patients taking azathioprine or sirolimus, and limited to patients on calcineurin inhibition (either cyclosporine or
tacrolimus).
d
This information from this form was available only for patients who started dialysis on or after April 1, 1995, or for 23,405 (63.3%)
of the study population.
NG, not given due to the large number of transplant centers analyzed.

clinically overt liver disease (15). Figure 1 shows that during
the first year after renal transplantation, mortality among
HCV⫹ recipients was similar whether they received DHCV⫹
or DHCV⫺ kidneys. It was only after 2 yr that those who
received DHCV⫹ kidneys manifested increased mortality.
Thus, recipient HCV⫹ serology pretransplantation does not
seem to be protective in the long term when a DHCV⫹ kidney
is transplanted.
Transplant clinicians have long appreciated that HCV⫹
transplant recipients are vulnerable to overimmunosuppression
(16,17) and have attempted lower doses of immunosuppression
or even steroid-free protocols with some success (18). Reports
now indicate that hepatitis C viral peptides may themselves
adversely affect T-cell function. These effects occur very early
after transmission in animal models, often before clinical ill-
ness (19), and may have implications for the development of
vaccines to hepatitis C (20,21). An abstract reported that such
effects on T-cell activity are additive to the effects of cal-
cineurin inhibitors (22). Thus, evidence is mounting that acute
transmission of hepatitis C through donor kidneys could result
in heightening of immunosuppression, even early after trans-
plantation. The apparent crossing of survival curves at 2 yr
seen in Figure 1 for HCV⫹ recipients of DHCV⫹ kidneys is
consistent with this hypothesis and also consistent with find-
ings that recipient antibodies to HCV do not necessarily pre-
vent new HCV infection (23).
J Am Soc Nephrol 14: 2908–2918, 2003 Hepatitis C and Renal Transplantation 2915

Table 5. Multivariable associations (by Cox regression) with graft loss (censored for death) in adult cadaveric
kidney recipientsa
Hazard ratio for
Variable P value 95% CI
graft loss

Model including most recent serum creatinine level at 1 yr

posttransplantation
donor HCV⫹ 0.66 0.77 0.25 to 2.42
recipient HCV⫹ 0.51 0.85 0.52 to 1.39
HCV⫹*DHCV⫹ 0.58 1.48 0.37 to 5.85
most recent serum creatinine level by 1 yr ⬍0.001 1.30 1.15 to 1.47
posttransplantation (per mg/dl)b
delayed graft function ⬍0.001 3.57 1.83 to 6.94
duration of dialysis before transplantation (yr; [per higher 0.049 2.88 1.01 to 8.23
quartile])
N in final sample 20,890
Model not including serum creatinine (baseline factors only)
recipient HCV⫹ 0.006 1.70 1.16 to 2.49
black recipient ⬍0.001 2.05 1.56 to 2.68
donor age (per year) ⬍0.001 1.02 1.01 to 1.03
donor black 0.03 1.50 1.04 to 2.16
a
All variables significant in univariate Kaplan Meier analysis in Table 1 were entered into stepwise Cox regression analysis (see the
Methods section for covariates used). Only variables significant in final analysis are shown. For variables in quartiles, the hazard ratio is
for higher quartiles above the mean.
b
Results shown for patients who survived at least 1 yr after transplantation.

DHCV⫹ seemed to have particularly adverse consequences
for recipients aged 65 and older, a group in which it has been
assumed that the impact of DHCV⫹ might be minimal. Elderly
transplant recipients are at greatly increased risk of death as a
result of infection; minimization of immunosuppression has
been recommended in these patients (24,25). Low-dose immu-
nosuppression may be an even more important consideration
for elderly recipients of DHCV⫹ kidneys.
The present analysis shows a continued high percentage of
DHCV⫹ kidneys given to recipients who were HCV⫺ in the
United States, a practice that is proscribed in Europe (26).
Many American transplant centers note that use of DHCV⫹
kidneys for HCV⫺ recipients is limited to patients who are
elderly or have significant access problems limiting their abil-
ity to receive dialysis. Although our ability to ascertain access-
related problems was limited to those who had Medicare as
their primary payer while on dialysis, we did not find that
previous hospitalization for access complications or serious
comorbid illnesses were independently associated with this
practice; instead, older age and black race were the strongest
associated factors, independent of time on dialysis before
transplant, comorbid conditions, or access complications, all
factors that are often cited as reasons to consider renal trans-
plantation in patients who would otherwise not be transplant
candidates.
We did not find that any specific immunosuppressive med-
ications were harmful in patients who were HCV⫹ or
DHCV⫹. In fact, we found a beneficial interaction between
mycophenolate and patients who received DHCV⫹ kidneys
after adjustment for comorbid conditions. Recent trials have
yet to show a benefit of mycophenolate in either renal or liver
transplantation for recipients with HCV infection, albeit with
very short follow-up and lack of a direct comparison with
azathioprine (27–32). However, Fasola et al. (33) showed that
manifestations of hepatitis C disease recurrence after steroid-
resistant allograft rejection following orthotopic liver trans-
plantation seems to be less severe in patients who use myco-
phenolate. Mycophenolate has also been used as adjunctive
therapy in the treatment of HIV infection (34,35). However,
some of the benefit of mycophenolate use may also be due to
lowered rates of acute rejection after transplantation (36).
Certain limitations of the current analysis must be consid-
ered, and they are similar to those of our previous report (1).
The most important was an inability to assess the relative
survival of recipients of DHCV⫹ kidneys compared with their
potential survival if they remained on maintenance dialysis.
Although HCV⫹ recipients may have an increased risk of
mortality compared with all other renal transplant recipients
(37,38), Pereira et al. (39) showed that HCV⫹ recipients have
a net survival advantage after renal transplantation compared
with remaining on dialysis. However, information on HCV
status before transplantation is not available in the USRDS
database. We also could not assess the development of HCV
seropositivity after renal transplantation. There was incomplete
information on comorbidities, although transplant patients are
consistently screened for serious diseases before placement on
the cadaveric waiting list. Longenecker et al. (40) found that
the specificity of CMS Form 2728 was ⬎90% for cardiovas-
cular disease, although sensitivity was lower. Cardiovascular
disease may certainly present after initiation of dialysis, but it
2916 Journal of the American Society of Nephrology
is often occult and detected earlier by serial echocardiography
than by clinical manifestations. After 2 yr of dialysis, most
patients have discernible cardiovascular disease; therefore, the
duration of dialysis before transplantation may be a reasonable
surrogate for underlying comorbid conditions (41). In any case,
the best predictor of acute coronary events in the general
population is the combination of C-reactive protein and LDL
levels (42), which were not available in the database. Causes of
death were incomplete in nearly 50% of patients, precluding
firm conclusions about mortality. Nonetheless, the analysis
includes nearly the entire transplant population and thus min-
imizes the likelihood of sampling error and referral bias. Trans-
mission of HCV by antibody-negative donors has been re-
ported (43), but this issue is beyond the scope of the present
analysis. Also, not all donors who were HCV antibody positive
by ELISA were likely to be viremic. This depends on the
generation of HCV ELISA assay used, which, unfortunately,
the USRDS database did not indicate. The largest study that
has so far compared the sensitivity of HCV ELISA for HCV
RNA found that 1 in 134,000 donations were RNA positive
and ELISA 2.0 negative, compared with 1 in 540,000 dona-
tions that were RNA positive and ELISA 3.0 negative (P ⫽
0.001) (44). The specificity of HCV ELISA 3.0 in blood
donors is 99.7% (45), similar to ELISA 2.0. HCV ELISA 3.0
was introduced in 1993 and therefore before the start of the
current study (46,47). However, according to the Centers for
Disease Control and Prevention, in populations with a preva-
lence of hepatitis C infection of ⬍10%, such as the potential
kidney donor pool, the percentage of HCV ELISA assays that
are false positive ranges from 15 to 60% (48). The current
prevailing opinion is that only PCR-positive donors are likely
to transmit disease (49). The proportion of false-positive HCV
ELISA assays could not be determined in the present study.
However, according to the Centers for Disease Control and
Prevention, although HCV ELISA positivity does not always
indicate active infection, it does indicate past or present infec-
tion. The impact of immunosuppression on organs from donors
who were ELISA positive for HCV is not fully known at this
time.
This study clearly challenges the assumption that donor
HCV⫹ kidneys may be entirely safe for HCV⫹ and elderly
recipients. The persistence of these findings after adjusting for
comorbid conditions, as well as the high rate of infectious
death among DHCV⫹ recipients, argues against preexisting
cardiovascular disease as an explanation for the increased
mortality seen in this analysis. The use of HCV⫹ kidneys in
HCV⫺ recipients also seems problematic. After adjustment for
older recipient age and black race, the presence of underlying
serious medical conditions and waiting time before transplan-
tation were no longer significantly associated with this prac-
tice. Until the link between donor HCV⫹ kidneys and patient
mortality is better established, patient-counseling practices for
those who are offered donor HCV⫹ kidneys may require
disclosure of the stark facts that outcomes, possibly including
life itself, may be at risk when DHCV⫹ kidneys are trans-
planted, consistent with the recommendations for other “ex-
panded donor criteria kidneys” (50). At the very least, studies
J Am Soc Nephrol 14: 2908–2918, 2003
of the optimal types and levels of immunosuppression (partic-
ularly mycophenolate mofetil) in patients who receive
DHCV⫹ kidneys may be enlightening regarding diminishing
mortality risk and optimizing overall outcomes, and any pa-
tients who receive a DHCV⫹ organ should be monitored
vigilantly for infection. Finally, transplant professionals must
consider ways to increase safely and effectively cadaveric and
living organ donation in ways that best serve all who are in
need of a life-saving organ transplantation.
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