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Whether transplantation of deceased donor kidney allografts from donors with antibodies against hepatitis C virus (HCV) confers a survival advantage compared with remaining on the kidney transplant waiting list is not yet known. We studied 38,270 USRDS Medicare beneficiaries awaiting kidney transplantation who presented with end-stage renal disease from April 1, 1995 to July 31, 2000. Cox regression was used to compare the adjusted hazard ratios for death among recipients of kidneys from deceased donors, and donors with antibodies against hepatitis C (DHCV+), controlling for demographics and comorbidities. In comparison to staying on the waiting list, transplantation from DHCV+ was associated with improved survival among all patients (adjusted hazard ratio for death 0.76, 95% CI 0.60, 0.96). Of patients receiving DHCV+ kidneys, 52% were themselves hepatitis C antibody positive (HCV+), so outcomes associated with use of these grafts may have particular implications for HCV+ transplant candidates. Recommendations for use of DHCV+ kidneys may require analysis of data not currently collected from either dialysis or transplant patients. However, transplantation of DHCV+ kidneys is associated with improved patient survival compared to remaining wait-listed and dialysis dependent.
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Transplantation of kidneys from deceased donors who are antibody positive for hepatitis C virus (DHCV+) is associated with greater recipient mortality than occurs with kidneys transplanted from deceased donors who are antibody negative for hepatitis C virus (DHCV−) (1,2). While use of DHCV+ kidneys for recipients who are themselves hepatitis C antibody positive (HCV+) is associated with an increased risk in late mortality compared to use of DHCV− kidneys (2,3), no previous analyses have compared survival after transplantation of DHCV+ kidneys with survival of wait-listed patients who remain on dialysis.
More than half of DHCV+ kidneys are transplanted in HCV+ recipients in the United States; risk factors associated with DHCV+ kidney transplantation include advanced donor and recipient age, African American race, and the possibility of a high rate of dialysis access complications (1,2,4). In addition, DHCV+ kidneys may be used with substantial variation between or within transplant centers depending on circumstances impossible to capture in reviewing single- or multi-center experiences. In order to determine any comparative trend in patient survival with DHCV+ kidney transplantation, we conducted a retrospective cohort study of the United States Renal Data System (USRDS). Our objective was to determine whether transplantation of DHCV+ kidneys was associated with a survival advantage or disadvantage for chronic dialysis patients receiving such a transplant compared to wait-listed patients remaining on dialysis.
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Of 454,447 patients in the USRDS database who initiated ESRD therapy from April 1, 1995 to July 31, 2000, 53,369 were subsequently entered on the kidney transplant waiting list on or after April 1, 1995 and before August 1, 2000. Of these, 38,360 had evidence of Medicare as primary payer as defined. An additional 90 patients did not have information on survival status, leaving 38,270 patients in the study group. The mean date of first ESRD service was June 16, 1997. The mean date of listing for transplant was June 13, 1998, and the mean date of transplant was March 24, 1999. Characteristics of the study cohort including patients not transplanted as well as recipients of deceased donor kidneys and deceased donor DHCV+ kidneys, respectively, are shown in Table 1.
Table 1. Characteristics of patients with ESRD with Medicare as primary payer when placed on the kidney transplant waiting list, who presented to ESRD from April 1, 1995—to July 31 20001
| || All wait-listed patients|| Patients not transplanted|| P value||Deceased donor transplant recipients|| P value||Deceased donor DHCV+ transplant recipients|| P value|
|N||38,270||17,044|| ||16,495|| ||389|| |
|Male||61.3% (23,443)||59.9% (10,211)||<0.001||62.9% (10,437)||<0.001||75.3% (293)||<0.001|
|African American||30.4% (11,632)||37.7% (6429)||<0.001||25.8 (4280)||<0.001||58.4% (227)||<0.001|
|Diabetes as cause of ESRD||35.3% (13,521)||40% (6826)||<0.001||33.8 (5614)||<0.001||29.8% (116)||0.002|
|Age (years)||47.6 ± 13.8||50.1 ± 12.7||<0.001||46.3 ± 14.0||<0.001||51.2 ± 11.3||<0.001|
|Variables from the Medical Evidence Form2|
|Body mass index (kg/m2)||26.7 ± 6.2||27.3 ± 6.4||<0.001||26.2 ± 5.9||<0.001||26.0 ± 5.5||0.003|
|Serum albumin (gm/dL)||3.4 ± 0.7||3.3 ± 0.7||0.03||3.4 ± 0.7||0.21||3.2 ± 0.7||0.66|
|Hematocrit (%)||27.9 ± 5.7||27.7 ± 5.6||0.09||27.9 ± 5.7||0.96||28.2 ± 5.8||0.32|
|Hypertension||73.9% (27,852)||74.3 (12,670)||<0.001||73.2% (11,904)||0.006||77.0% (295)||0.16|
|Congestive heart failure||13.8% (5186)||16.5% (2820)||<0.001||11.9% (1930)||<0.001||15.9% (61)||0.22|
|Ischemic heart disease||8.9% (3334)||10.7% (1824)||<0.001||7.5% (1212)||<0.001||9.7% (37)||0.58|
|Smoking history (Y/N)||5.3% (1982)||5.4% (918)||0.12||5.4% (871)||0.5||8.4% (32)*||0.007|
|Hemodialysis (vs. peritoneal dialysis)||80.5% (30,955)||84.4% (14,378)*||<0.001||77.4% (12,834)||<0.001||86.1% (335)*||<0.001|
|Peripheral vascular disease||5.3% (1983)||6.4% (1099)*||<0.001||4.6% (747)*||<0.001||4.4% (17)||0.46|
|Medicare claims for HCV at the time of listing3||0.5% (180)||0.5% (92)||0.07||0.5% (80)||0.75||5.4% (21)*||<0.001|
|Recipient serology positive for HCV by UNOS (kidney transplant recipients only)||NA||NA||NA||4.3% (709)||NA||51.7% (201)*|| |
|Medicare claims for access||14.2% (5432)||16.9% (2886)||<0.001||13.5% (2234)*||0.001||17.7% (69)||0.042|
Death rates for the study population stratified according to transplantation status, donor source (DHCV+ vs DHCV−), and recipient age disclose that unadjusted death rates were much higher for recipients of DHCV+ kidneys than for recipients of deceased donor kidneys generally (Table 2). However, among the entire study cohort, receipt of a DHCV+ kidney was independently associated with improved survival compared with remaining on the renal transplant waiting list, (adjusted hazard ratio 0.76, 95% CI, 0.60–0.96) when Cox regression analysis of factors associated with patient mortality was carried out, analyzing solitary deceased donor kidney transplantation as a discrete time-dependent variable (adjusted for age, race, cause of ESRD, year of first dialysis, presence of congestive heart failure, ischemic heart disease, peripheral vascular disease, serum albumin level, and Medicare Claims for access-related complications and HCV, Table 3). Transplantation of all deceased donor kidneys was also associated with a survival advantage after adjustment for multiple covariates, (adjusted hazard ratio 0.47, 95% CI 0.44–0.50). Among patients aged 65 years and older, transplant of deceased donor kidneys was also associated with a significant survival advantage, although magnitude of benefit was somewhat smaller (adjusted hazard ratio 0.59, 95% CI 0.51–0.68).
Table 2. Patient death rates in patients with ESRD with Medicare as primary payer when placed on the kidney transplant waiting list, who presented to ESRD from April 1, 1995 –to July 31, 2000, followed through September 30, 2001
| Categories|| N|| Deaths|| Follow-up time (years)||Death rate per 100 Patient years at risk (95% CI)|
|All patients on the kidney transplant waiting list||38,270||6716||116,331||5.77 (5.63–5.91)|
|Patients not transplanted||17,094||4753||40,861||11.63 (11.31–11.96)|
|Deceased donor recipients*||16,595||1689||59,406||2.84 (2.71–2.98)|
|Deceased donor recipients of DHCV+ kidneys*||389||72||1248||5.76 (4.57–7.26)|
|All patients on the kidney transplant waiting list age 65 years or older||3720||1131||9834||11.50 (10.85–12.19)|
|Deceased donor recipients age 65 years or older||1443||294||4575||6.43 (5.73–7.20)|
|Deceased donor recipients of DHCV+ kidneys* aged 65 years or older||58||25||157||15.91 (10.75–23.54)|
|All patients on the kidney transplant waiting list with Medicare claims for HCV at the time of listing||180||34||425||7.99 (5.71–11.12)|
Table 3. Cox regression analysis of the association of DHCV+ deceased donor kidney transplantation with mortality among patients placed on the kidney transplant waiting list with Medicare as primary payer, who presented with ESRD from April 1, 1995—to July 31, 2000
| ||P Value||AHR (95% CI)|
|Type of donor kidney1|
| Kidney transplantation from a DHCV+ donor2 (vs. remaining on dialysis, censoring for all other transplants)||0.025||0.76 (0.60–0.96)|
| Kidney transplantation from a deceased donor3 (vs. remaining on dialysis, censoring for all other transplants)||<0.001||0.47 (0.44–0.50)|
| Age (per increase in year)||<0.0001||1.03 (1.02–1.04)|
| Year of listing (per more recent year)||<0.0001||0.84 (0.82–0.86)|
| Diabetes as cause of ESRD (vs. non-diabetics)||<0.0001||1.98 (1.89–2.07)|
| African American recipient (vs. all other races)||<0.0001||0.71 (0.68–0.75)|
| Years of dialysis prior to transplant (per year)||<0.001||1.12 (1.09–1.14)|
|Variables from Medical Evidence Form 2728|
| PVD (vs. absent)||<0.0001||1.21 (1.12–1.30)|
| CHF (vs. absent)||<0.0001||1.21 (1.15–1.28)|
| Quartiles of serum albumin (per higher quartile)||<0.0001||0.87 (0.81–0.93)|
| BMI (per kg/m2)||0.003||0.99 (0.98–0.99)|
| Smoking (vs. absent)||<0.0001||1.34 (1.22–1.46)|
| Access complications at the time of listing4||<0.0001||1.22 (1.14–1.31)|
| HCV claims at time of listing4||0.20||1.25 (0.89–1.76)|
| N in model||36,717|| |
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The present analysis of Medicare beneficiaries enrolled on the kidney transplant waiting list indicates that transplantation from a hepatitis C positive donor (DHCV+) was associated with improved survival compared to remaining on dialysis. The benefit of transplantation with a DHCV+ kidney was not as substantial as transplantation with all deceased donor kidneys, adjusted for other factors known to be associated with survival. This benefit of DHCV+ kidneys was shown only in adjusted, not unadjusted analysis, because of the confounding of allocation of DHCV+ kidneys by several factors, most notably older recipient age, as well as unknown factors that may relate to subsequent survival. Unfortunately, we could not confirm this effect in HCV+ recipients, the subgroup analysis of greatest interest, due to the very small numbers of dialysis patients who had Medicare claims for HCV at the time of listing. Among dialysis patients, HCV testing is voluntary and is not the subject of routine surveillance, in contrast to HIV and hepatitis B viruses (8).
Use of Medicare claims for HCV filed at the time of listing preserved the temporal relationships necessary for valid survival analysis, but does not account for the large proportion of dialysis patients who develop positive HCV serology while on dialysis. According to the recent DOPPS (a prospective observational) study, the prevalence of HCV among American dialysis patients at the start of dialysis was 7.3%, while the prevalence of HCV among those who had been on dialysis for 10 years of more was 22.5%, and was 39% for those who had been on dialysis for 15 years or more (9). Comparable trends have also been reported from European regional studies (10). While such increases in HCV positivity may reflect period effects as well as duration effects (i.e. patients on dialysis 10 years ago were much more likely to receive blood transfusions or be exposed to other HCV risk factors than patients are currently), long-term dialysis care is significantly associated with higher rates of HCV seroconversion.
It has been generally thought that DHCV+ kidneys are safe to use in HCV+ and elderly recipients, due to latency of clinical liver disease after transmission of HCV infection as well as the diminished life expectancy of elderly recipients (11). Receipt of a DHCV+ kidney by elderly wait-listed patients offered no survival benefit compared to remaining on dialysis in this study, and was associated with higher mortality than DHCV− kidneys. Current recommendations discourage use of DHCV+ kidneys in elderly recipients who are HCV negative (12), and the present study cannot address this specific issue. However, dialysis patients with a negative result for HCV testing at one point in time may not be retested later, even before a renal transplant. On the other hand, the development of HCV seroconversion, even many years after listing, may affect whether a patient is offered a DHCV+ kidney. Therefore, for the data sources we used, true recipient HCV status may be insensitive, and it may not be possible to fully define the impact of DHCV+ kidneys on survival of HCV+ dialysis patients.
The present study has several limitations in addition to those of recipient HCV status. A key to the validity of the present analysis is whether the comparison group of patients who did not receive DHCV+ kidneys is a reasonably equivalent group. The methods we have used are the same other investigators have used previously in assessing the relative survival of transplantation compared with remaining on the waiting list (13). The report of Wolfe et al. (13) adjusted only for age, race, gender, transplant center, and cause of renal disease, and assumed that patients who were listed for transplant were otherwise equivalent. However, these assumptions may not be accurate in terms of selection of patients to receive a DHCV+ kidney. Therefore, we also adjusted for comorbid conditions in CMS Form 2728 as well as access-related complications. This is an additional step that, to our knowledge, others have not considered (6). In addition, the relative survival benefit of transplantation with DHCV+ kidneys could be either overestimated or underestimated in this analysis due to patient selection factors not captured in data reporting. Those factors associated with DHCV+ transplantation and the high mortality associated with DHCV+ transplantation in unadjusted analysis (Table 2, equivalent to mortality of all wait-listed patients) emphasize that patients' selection for DHCV+ kidneys is quite different than for recipients of DHCV− kidney transplants, and such differences may be impossible to define in any analysis. Details on the use of antiviral therapy, treatment response rates and results of more definitive diagnostic tests such as PCR, RNA, or liver biopsy results, were simply not available. These findings should be verified with more cases in the future, especially for HCV+ recipients, and also with longer follow-up, given the relatively short follow-up post-transplant in the present study.
In conclusion, while the use of DHCV+ kidneys is associated with an increased risk of mortality compared to use of DHCV− kidneys (1,2), the present study found that use of DHCV+ kidneys is associated with improved survival compared with remaining on dialysis. Since most DHCV+ kidneys are given to recipients who are themselves HCV+, these implications may primarily apply to HCV+ recipients. The present study's findings are thus consistent with current recommendations that DHCV+ kidneys can be used for HCV+ recipients, but probably should be avoided for HCV− recipients (12). However, allocation of DHCV+ kidneys is presently center-specific and guidelines for using these organs may require more information than is presently reported to UNOS, CMS or the USRDS. Clearly, some patients benefit from transplantation of DHCV+ kidneys, yet it may not be timely to suggest that such organs should be given to non-selected groups of patients.