Donor Hepatitis C Seropositivity: Clinical Correlates and Effect on Early Graft and Patient Survival in Adult Cadaveric Kidney Transplantation
Jay R. Bucci*,
Cal S. Matsumoto,
S. John Swanson,
Lawrence Y. C. Agodoa,
Kent C. Holtzmuller,
Thomas G. Peters¶ and
Kevin C. Abbott*
*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 Disease, National Institutes of Health, Bethesda, MD; Gastroenterology Service, WRAMC, Washington, DC’ and ¶The Jacksonville Transplant Center at Shands, Jacksonville, Florida.
Correspondence to Dr. Kevin C. Abbott, LTC, MC, Director, 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{at}na.amedd.army.mil
ABSTRACT. The impact of hepatitis C virus–positive donorkidneys on patient survival has not been analyzed in a nationalstudy. This study analyzed 20,111 adult (age, 16 yr) recipientshaving solitary cadaveric kidney transplants from adult donorswith valid donor hepatitis C serologies from July 1, 1994, toJune 30, 1998, in an historical cohort study (the 2000 UnitedStates Kidney Data System) of patient survival. Analysis wasby the Cox proportional hazards models, which corrected forcharacteristics thought to affect outcomes. Of 484 kidneys positivefor hepatitis C virus serology, 165 (34%) were given to recipientswith confirmed negative hepatitis C serologies. Unadjusted 3-yrpatient survival was 93% in all recipients of donor hepatitisC–negative kidneys versus 85% in all recipients of donorhepatitis C–positive kidneys (P = 0.01). Among hepatitisC–positive recipients, those who received hepatitis C–positivekidneys had worse survival than recipients of hepatitis C–negativekidneys. Among elderly hepatitis C–negative recipients,those who received hepatitis C–positive kidneys also hadworse survival; in fact, all recipients of donor hepatitis C–positivekidneys had increased risk of mortality (P = 0.028). There wereno significant interactions between donor hepatitis C positivityand either recipient hepatitis C positivity or older recipientage. The use of hepatitis C–positive kidneys in recipientswho were hepatitis C–negative was fairly common and contraryto some current recommendations. Recipients of donor hepatitisC–positive kidneys were at independently increased riskof mortality, with no evidence that any subgroups were lessaffected.
Infection with hepatitis C virus (HCV) is a major cause of morbidityand mortality in the United States kidney transplant populationand in patients with end-stage renal disease (ESRD) (1,2). Testingfor HCV is required in all cases of cadaveric organ donation,but no firm consensus prevails regarding the allocation of hepatitisC–positive organs (3). Of particular concern is the highprevalence of HCV among kidney donors: nationwide, 4.2% of cadavericorgan donors demonstrated antibodies to HCV (4–6) comparedwith 1.8% in the general population (7).
Although many studies show that HCV acquired before kidney transplantationresults in increased morbidity and mortality (8–12), theimpact of HCV acquired at the time of transplantation is lesswell defined (13). It is, however, generally accepted that arecipient who was HCV-negative before organ transplantationmay acquire HCV from an HCV-positive donor organ (14), a circumstanceassociated with increased incidence of posttransplant liverdisease (14–19). As yet, no difference in post–kidneytransplant patient or graft survival regarding either donoror recipient hepatitis C status has been demonstrated. Absentdefinitive data, opinions regarding the proper use of hepatitisC–positive kidneys have varied widely (4,13,16,20–25).
Better characterization of the clinical course of patients receivinghepatitis C–positive kidneys is essential to developinga rational allocation strategy that maximizes safe usage andminimizes discard of otherwise suitable donor organs. To determineif donor hepatitis C serology had any significant relationshipwith graft and patient survival adjusted for other factors,we conducted an historical cohort study analyzing the 2000 UnitedStates Renal Data System (USRDS) data to assess factors associatedwith hepatitis C–positive kidneys, controlling for variablespreviously established to affect graft and patient survival.
Data Sources and Study Sample
The present analysis used a data set and analytical techniquesthat have been previously described (26). In summary, the USRDSstandard analysis file (SAF) SAF.TXUNOS was the primary fileincluding baseline information. Information on medications waslimited to immunosuppressive medications. This file was mergedwith SAF.TXFUUNOS by using unique patient identifying codesto obtain follow-up data. The file was also merged with SAF.PATIENTSto obtain dates and causes of death. Donor HCV serology wasnot collected by UNOS before April 1, 1994 (27). In addition,less than 0.5% of living donor kidneys were seropositive forHCV. Therefore, analysis was limited to adult patients who underwentcadaveric kidney transplantation from July 1, 1994, to June30, 1998. Only the first transplant for a given patient duringthe study period (which could have been a repeat transplant)was included in analysis. Cases with unknown recipient HCV statuswere not excluded from univariate analysis to allow completeanalysis of associations of other factors related to donor HCVstatus. However, in outcome comparisons relating recipient anddonor HCV status, only cases with specified HCV data for bothdonor and recipient were included. HCV serology was not independentlyconfirmed. Similarly, the cause of ESRD was also not independentlyconfirmed. Patients were followed through April 2000.
Analytic Variables and Outcome Measures Associations with Donor Hepatitis C Status.
Singular donor and recipient factors used are listed in Tables 1 and 2and were entered into multivariable with stepwise LogisticRegression analysis for strength of association with donor hepatitisC status (1 if positive, 0 if negative) if P < 0.10 in univariateanalysis (2 for categorical variables; t test for continuousvariables). Because hepatitis C–negative recipients transplantedwith hepatitis C–positive kidneys might represent a differentpopulation, separate logistic regression analysis was performedwith all hepatitis C–negative recipients who receivedhepatitis C–positive kidneys as 1, and all other transplantrecipients with valid hepatitis C serologies as 0.
Table 2. Characteristics of study population (continuous variables)a
Patient and Graft Survival.
Survival time was defined as the time between the date of transplantand death, the most recent follow-up date, or the end of thestudy period. Logistic regression analysis was used to modelassociations with donor hepatitis C status, using techniquesand variables similar to Cox regression mentioned above. Graftfailure was defined as return to dialysis after transplant anddid not include death with a functioning graft. Variables enteredinto the model were those previously associated with patientand graft survival after transplantation (26,28). Graft losswas analyzed as a time-dependent variable using previously describedmethods (29), because it has recently been recognized as anindependent predictor of patient mortality in kidney transplantrecipients (30). Stratified Cox models were performed for eachof the following subgroups of particular clinical interest:recipients who were hepatitis C–negative, recipients whowere hepatitis C–positive, and recipients who were aged65 yr or older. Covariates whose Kaplan Meier plots violatedthe assumption of proportional hazards over time were assessedusing yearly intervals after transplantation, as described byprevious investigators (31).
Comorbidity data from Center for Medicare and Medicaid Studies(CMS) Form 2728 was only available for a minority of recipients.Therefore, hospitalizations for cardiovascular disease (32)and for liver disease (8,33,34), because of their possible relationshipwith later all-cause or liver-related morbidity and mortalityin ESRD patients, were extracted from the USRDS database (anyappearance of these diagnoses in the final five discharge diagnoses),merged with the patient files, and used as covariates in subsequentanalyses.
There were 24,262 adult recipients of solitary cadaveric kidneytransplants meeting study criteria in the United States fromJuly 1, 1994, to June 30, 1998. Of these, 3953 were missingfollow-up data, leaving 20,309 recipients for whom data couldbe assessed by univariate analysis. Only 198 (1%) of recipientshad no data regarding their donor hepatitis C status; they andan additional 2414 (12%) lacking data for recipient HCV statuswere excluded, leaving 17,697 patients for study in multivariableanalysis. Notably, the 13% of recipients with missing HCV data(their own or their donor) did not differ statistically frompatients for whom these data were known. Mean follow-up was1.85 ± 1.12 yr.
Associations with Donor Hepatitis C Seropositivity
The allocation of kidneys by donor and recipient hepatitis Cserology is detailed in Table 1. As shown, 165 (34%) of donorkidneys positive for hepatitis C were given to recipients whowere negative for hepatitis C. The proportion of kidneys fromhepatitis C–positive donors transplanted into hepatitisC–positive recipients was stable over the years of thestudy (Figure 1).
Figure 1. The proportion (Y axis) of patients transplanted in the years of the study (X axis) who received donor hepatitis C virus (DHCV)–positive kidneys (left column, unhatched) and those who were HCV-positive at the time of transplant (right column, hatched) is shown. There was no significant trend for either patients who were themselves HCV-positive or who received HCV-positive kidneys or over time.
A comparison of continuous variables between recipients of donor-positiveversus donor-negative kidneys is detailed in Table 2. In parallelwith single-center experience showing reduced time on the transplantwaiting list for HCV-positive transplant recipients who receivedHCV-positive donor kidneys (35), the duration of time on dialysisbefore transplant for recipients who were hepatitis C-positivewas significantly shorter if they received a hepatitis C-positivekidney than if they received a hepatitis C-negative kidney.Categorical variables for the study population are shown inTable 3, with results of univariate analysis and logistic regressionfor their association with donor hepatitis C-positive kidneysand also with recipients who were negative for hepatitis C whoreceived hepatitis C-positive kidneys. The contrast betweenthe two groups is noteworthy: those recipients who were negativefor hepatitis C who received hepatitis C-positive kidneys weremore likely to be African American, older, recipients of kidneysfrom cytomegalovirus-positive donors, as well as being recipientsof repeat transplants. Significant associations between immunosuppressivemedications and donor hepatitis C–positive status wereseen in univariate, but not multivariate, analysis, primarilyconfounded by African American race.
Table 3. Analysis of associations with donor hepatitis C seropositivity by variable: adult solitary cadaveric kidney transplant recipients, July 1, 1994, to June30, 1998 (n = 20,111)
Patients who received hepatitis C–positive kidneys weremore likely to receive kidneys from African American donors,were at the extremes of age, and had higher levels of HLA mismatch,longer cold ischemic time, and some element of geographic variation.However, such patients were much less likely to have cardiovascularcomorbidity at presentation to ESRD. Chronic lung disease anddrug use were more often noted in these recipients, but bothconditions were relatively infrequent compared with cardiovasculardisease.
Among hepatitis C–negative recipients who were transplantedwith hepatitis C–positive kidneys, however, recipient(not donor) African American race and male gender were morecommon, as were receipt of kidneys positive for cytomegalovirusand repeat transplantation; HLA mismatching and cold ischemictime were similar, whereas geographic variation was less marked,and there was no significant association with comorbidity incomparison with all recipients of hepatitis C–positivekidneys. A stratified model limited only to all patients withvalid HCV data who received hepatitis C positive kidneys wasalso performed. In this analysis, hepatitis C–negativerecipients who received hepatitis C–positive kidneys wereolder, experienced greater HLA mismatching with the donor, andreceived kidneys with a longer cold ischemic time when thesefactors were compared in recipients who were hepatitis C–positive.
Patient and Graft Survival
Kaplan-Meier plots are shown comparing survival of recipientstransplanted with hepatitis C–positive kidneys versusrecipients transplanted with hepatitis C–negative kidneys,stratified for hepatitis C–negative recipients only (Figure 2),hepatitis C–positive recipients only (Figure 3), recipientsaged 65 yr (Figure 4), and recipients of hepatitis C–positivekidneys comparing the effect of recipient hepatitis C status(Figure 5). Survival was worse for recipients of hepatitis C–positivekidneys in all subgroups. However, in analysis limited to recipientswho were hepatitis C–positive (Figure 3), differencesin survival were not seen until 1 yr after transplant. Becausethis violated the assumption of proportional hazards over time,separate analysis was performed limited to patients who survivedat least 2 yr after transplantation. In this group, differencesin survival were statistically significant in both unadjustedanalysis and in multivariable analysis (Figure 3). Among patientswho received hepatitis C–positive kidneys, recipientswho were hepatitis C–negative had trends toward increasedmortality, although this was not statistically significant (Figure 5).
Figure 2. Patient survival by DHCV status (July 1, 1994 to June 30, 1998). Adult cadaveric renal transplant recipients who were HCV-negative. For HCV-negative recipients, DHCV-negative total deaths = 2215. DHCV-positive total deaths = 50. P < 0.01 by log rank test and Cox regression; covariates listed in Materials and Methods section.
Figure 3. Patient survival by DHCV status (July 1, 1994, to June 30, 1998). Adult cadaveric renal transplant recipients who were HCV-positive. For HCV-positive recipients, DHCV-negative total deaths = 150. DHCV-positive total deaths = 63. P = 0.01 by log rank test, and P = 0.02 by Cox regression; covariates listed in the Materials and Methods section.
Figure 4. Survival of renal transplant recipients (July 1, 1994, to June 30, 1998) aged 65 yr by DHVC status. DHCV total deaths = 170. DHCV total deaths = 12. P < 0.01 by log rank test and Cox regression; covariates listed in the Materials and Methods section.
Figure 5. Kaplan-Meier analysis limited to patients with valid hepatitis C serologies who received hepatitis C–positive kidneys, n = 484. As shown, recipients who were hepatitis C–positive had a lower rate of mortality then hepatitis C–negative recipients over the study period, although this was not significant by log rank test (P = 0.17).
Donor hepatitis C positivity was independently significant inCox regression analysis of patient survival (Table 3). Otherfactors significantly associated with decreased patient survival(increased hazard ratio) were consistent with prior studies(26,28). Interactions between donor hepatitis C status and recipienthepatitis C status, as well as donor hepatitis C status andrecipient age 65 yr, were not statistically significant.
In stratified analysis limited to patients who received hepatitisC–positive kidneys, recipient hepatitis C status was notsignificantly associated with mortality, whether the model includedcomorbidities from Form 2728 or not. Donor hepatitis C positivitywas not independently significant in Cox regression analysisof graft survival (P = 0.37), compared with recipient hepatitisC positivity (P = 0.0048). Causes of graft failure for hepatitisC–positive recipients were not different from hepatitisC–negative recipients.
Causes of death were listed as blank or unknown in more than45% of cases. Among recipients of donor hepatitis C–positivekidneys, the cause of death was missing or unknown in 44.8%of cases. Overall, cardiovascular causes of death were the mostfrequent cause of death for recipients of either donor hepatitisC–positive (56%) or donor hepatitis C–negative (49%)kidneys, followed by infection for donor hepatitis C–positive(28%) or donor hepatitis C–negative (32%) recipients.Deaths due to liver disease were more common for recipientsof donor hepatitis C–positive kidneys (6.6%) than forrecipients of donor hepatitis C–negative kidneys (0.5%).Deaths due to malignancy were not different between donor hepatitisC–positive (2.2%) and donor hepatitis C–negativerecipients (4.4%).
Transplantation of donor hepatitis C–positive kidneyswas independently associated with poorer patient survival. Thiswas true even among subgroups such as the elderly and recipientswith pretransplant HCV positivity. Patient survival curves weredistinct soon after transplant for hepatitis C–negativerecipients who received hepatitis C–positive kidneys (Figure 2),whereas differences in survival took longer to manifestfor hepatitis C–positive recipients who received hepatitisC–positive kidneys (Figure 3). The additional mortalityincurred by donor hepatitis C–positive kidney recipientswas not fully accounted for by death from liver disease, graftfailure, or educational status. Also, in contrast with currentrecommendations (3), more than one third of donor hepatitisC–positive kidneys in the United States were given tohepatitis C–negative recipients.
Although many studies have noted an increased incidence of liverdisease among recipients of donor hepatitis C–positivekidneys (14–17), none have shown an increase in mortalityfrom all causes until the present study. Because of the longduration between inoculation/viral transmission and developmentof cirrhosis in patients contracting HCV in the general population(36), it has been suggested that elderly recipients and thosewith serious comorbidities are less likely than other recipientsto be adversely affected by donor hepatitis C–positivekidneys (37). The present study indicates that these subgroupswere similarly affected, although a survival difference appearedlater in recipients who were hepatitis C–positive beforetransplantation. Interestingly, no recipient group was at greaterrisk of liver-related mortality, a finding that we cannot fullyexplain.
Of the 484 donor hepatitis C–positive kidneys among patientswith valid HCV serologies in this study, 165 (34.1%) were givento hepatitis C–negative recipients. In comparison withall other recipients, these recipients of hepatitis C–positivekidneys were more likely to be African American and male; inseparate comparisons against all other recipients and hepatitisC–positive recipients, respectively, these recipientswere older, with a higher HLA mismatch, longer cold ischemictime, and repeat transplant status. Many of these factors arewidely considered risks for poorer graft or patient survival,so it is possible that high-risk situations may attend use ofdonor hepatitis C–positive kidneys, particularly in hepatitisC–negative recipients. Despite this, recipient hepatitisC status was not associated with mortality among recipientsof hepatitis C–positive kidneys (Figure 5). The presentstudy could not determine whether the poorer survival of HCV-negativepatients who received donor hepatitis C–positive kidneyswas better or worse than the survival of such patients had theyremained on dialysis. The possibility remains, however, thatthis patient group could be deemed a somewhat more urgent transplantpriority because of access failure, poor dialysis tolerance,or other problems indeterminable in the database.
Certain limitations of the current analysis must be considered.Because the study was retrospective, the reason behind the decisionto offer a hepatitis C–positive kidney to a given transplantcandidate could not be determined. Furthermore, not all donorkidneys positive for hepatitis C antibody are infective. Thisis relevant because Pereira et al. (38) and Natov et al. (39)also reported that only donors with HCV antigen in the peripheralblood circulation are likely to transmit HCV to the kidney.Fortunately, hepatitis C infection before seroconversion inpotential donors (specifically, blood donors) is rare (40).The specific HCV used to establish hepatitis C status was unknown,as were HCV genotypes, although ELISA testing (41) is almostuniversally performed for donor cadaver kidneys due to timeconstraints. However, Natov et al. (42) reported that HCV RNAwas detected in 81% of patients positive by ELISA-3, which wasavailable in 1993 (43) but may not have been in wide use untila few years later. The present study showed the percentage ofHCV-positive donors was constant over the time of the study,arguing against a significant increase in sensitivity of HCVserology in the study population. Liver biopsy results, whichmay have been useful in risk-stratifying patients for posttransplantliver disease, were unavailable as well. De novo GN, an importantcause of graft loss in transplant recipients with HCV, was notlisted as a cause of graft loss in the USRDS. There was incompleteinformation on comorbidities, although transplant patients areconsistently screened for serious diseases before placementon the cadaveric waiting list. Longenecker et al. (44), foundthat the specificity of CMS Form 2728 was >90% for cardiovasculardisease. Similarly, causes of death were incomplete in nearly50% of patients, precluding firm conclusions on this matter.Nonetheless, the analysis includes nearly the entire transplantpopulation and thus minimizes the likelihood of sampling errorand referral bias.
Because of study limitations, firm recommendations regardingthe use of donor hepatitis C–positive kidneys should notbe proffered. Specifically, we cannot yet recommend avoidingdonor hepatitis C–positive kidneys in all circumstances.However, this study does appear to refute the assumption thatdonor hepatitis C–positive kidneys may be entirely safefor hepatitis C–positive recipients and the elderly. Untilthe link between donor hepatitis C–positive kidneys andpatient mortality is better established, patient counselingpractices may need to be altered, especially for hepatitis C–positiverecipients who are offered donor hepatitis C–positivekidneys.
Footnotes
The opinions are solely those of the authors and do not representan endorsement by the Department of Defense or the NationalInstitutes of Health. This is a government work. There are norestrictions on its use.
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Received for publication June 25, 2002.
Accepted for publication August 1, 2002.
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Abstract
Introduction
16 yr) recipients having solitary cadaveric kidney transplants from adult donors with valid donor hepatitis C serologies from July 1, 1994, to June 30, 1998, in an historical cohort study (the 2000 United States Kidney Data System) of patient survival. Analysis was by the Cox proportional hazards models, which corrected for characteristics thought to affect outcomes. Of 484 kidneys positive for hepatitis C virus serology, 165 (34%) were given to recipients with confirmed negative hepatitis C serologies. Unadjusted 3-yr patient survival was 93% in all recipients of donor hepatitis C–negative kidneys versus 85% in all recipients of donor hepatitis C–positive kidneys (P = 0.01). Among hepatitis C–positive recipients, those who received hepatitis C–positive kidneys had worse survival than recipients of hepatitis C–negative kidneys. Among elderly hepatitis C–negative recipients, those who received hepatitis C–positive kidneys also had worse survival; in fact, all recipients of donor hepatitis C–positive kidneys had increased risk of mortality (P = 0.028). There were no significant interactions between donor hepatitis C positivity and either recipient hepatitis C positivity or older recipient age. The use of hepatitis C–positive kidneys in recipients who were hepatitis C–negative was fairly common and contrary to some current recommendations. Recipients of donor hepatitis C–positive kidneys were at independently increased risk of mortality, with no evidence that any subgroups were less affected. 
2 for categorical variables; t test for continuous variables). Because hepatitis C–negative recipients transplanted with hepatitis C–positive kidneys might represent a different population, separate logistic regression analysis was performed with all hepatitis C–negative recipients who received hepatitis C–positive kidneys as 1, and all other transplant recipients with valid hepatitis C serologies as 0. 
with results of univariate analysis and logistic regression for their association with donor hepatitis C-positive kidneys and also with recipients who were negative for hepatitis C who received hepatitis C-positive kidneys. The contrast between the two groups is noteworthy: those recipients who were negative for hepatitis C who received hepatitis C-positive kidneys were more likely to be African American, older, recipients of kidneys from cytomegalovirus-positive donors, as well as being recipients of repeat transplants. Significant associations between immunosuppressive medications and donor hepatitis C–positive status were seen in univariate, but not multivariate, analysis, primarily confounded by African American race. 
