- Email: [email protected]
Unintended Consequences in Use of Increased Risk Donor Kidneys in the New Kidney Allocation Era
Unintended Consequences in Use of Increased Risk Donor Kidneys in the New Kidney Allocation Era A.A. Rahnemai-Azara, J.D. Perkinsa, N. Lecab, C.D. Blosserb, C.K. Johnsonb, S.D. Morrisonc, R. Bakthavatsalama, A.P. Limayed, and L. Sibuleskya,* a Division of Transplant Surgery, Department of Surgery, University of Washington Medical Center, Seattle, Washington; bDivision of Nephrology, Department of Medicine, University of Washington Medical Center, Seattle, Washington; cDivision of Plastic Surgery, Department of Surgery, University of Washington Medical Center, Seattle, Washington; and dDivision of Allergy and Infectious Diseases, Department of Medicine, University of Washington Medical Center, Seattle, Washington
ABSTRACT Background. The new kidney allocation system (KAS) intends to allocate the top 20% of kidneys to younger recipients with longer life expectancy. We hypothesized that the new KAS would lead to greater allocation of Public Health Service (PHS) increased-risk donor organs to younger recipients. Methods. Analyses of the Organ Procurement and Transplantation Network data of patients who underwent primary deceased kidney transplantation were performed in preand post-KAS periods. Results. The allocation of PHS increased-risk kidney allografts in various age groups changed significantly after implementation of the new KAS, with an increased proportion of younger individuals receiving increased-risk kidneys (7% vs 10% in age group 20e29 y and 13% vs 18% in age group 30e39 y before and after KAS, respectively; P < .0001). This trend was reversed in recipients 50e59 years old, with 31% in the pre-KAS period compared with 26% after KAS (P < .0001). Conclusions. The new KAS resulted in a substantial increase in allocation of PHS increased-risk kidneys to candidates in younger age groups. Because increased-risk kidneys are generally underutilized, future efforts to optimize the utilization of these organs should target younger recipients and their providers.
I
N DECEMBER 2014, the Organ Procurement and Transplantation Network (OPTN) Kidney Transplantation Committee implemented a new deceased-donor kidney allocation system (KAS) in an effort to bridge the kidney gap and tackle utility and equity issues [1]. The new KAS is intended to improve the utilization of donated kidneys by expanding kidney allograft survival through matching the estimated post-transplantation survival (EPTS) and the kidney donor profile index (KDPI) scores [1,2]. One of the goals of the new system is to match the best 20% of younger highest-quality donor kidneys to younger candidates with the expected longest post-transplantation survival. Currently, increasing numbers of younger donors are considered to be Public Health Service (PHS) increasedrisk donors (IRDs) [3]. As a result of drug overdose 0041-1345/17 https://doi.org/10.1016/j.transproceed.2017.11.025
14
epidemic among the deceased donors younger than 40 years, the percentage of drug overdoses increased from 3.6% to 11.7% from 2003 to 2014 [3]. Despite having the highest overall donation rates, the mean number of organs transplanted per donor continues to be significantly lower among donors who died from drug overdose compared with donors who died from other causes, owing to the increased risk of transmission of blood-borne viruses, including hepatitis B virus (HBV), hepatitis C virus (HCV), and human immunodeficiency virus (HIV) [3]. Because of the increased
*Address correspondence to Lena Sibulesky, MD, FACS, Assistant Professor, Department of Surgery, University of Washington Medical Center, 1959 NE Pacific Street, Box 356410, Seattle, WA 98195. E-mail: [email protected] ª 2017 Elsevier Inc. All rights reserved. 230 Park Avenue, New York, NY 10169
Transplantation Proceedings, 50, 14e19 (2018)
NEW KIDNEY ALLOCATION SYSTEM CONSEQUENCES
risk of infectious disease transmission there is concern among transplant providers and patients in accepting these organs. There are no data available comparing the distribution pattern of PHS IRD kidneys among transplant recipients and their outcomes before and after the introduction of the new KAS and with the rise in the numbers of PHS IRDs. We hypothesized that KAS would lead to greater allocation of PHS IRD organs to younger recipients and that the outcomes of recipients of these organs would be excellent. The present study assessed the trends in PHS IRD allocation among kidney recipients before and after implementation of the new KAS. The second goal was to compare the effect of the new allocation policy on the PHS increased-risk graft and patient outcomes. METHODS This was a retrospective observational study comparing PHS IRD primary kidney transplant recipient data before (from January 1, 2005, to December 4, 2014) and after (from December 5, 2014, to March 31, 2016) implementation of the new KAS. United States donor, waitlisted candidates, and transplant recipient data for this analysis are from OPTN data released June 17, 2016, based on data collected through March 31, 2016. The United Network for Organ Sharing, the contractor for the OPTN, supplied these data. The interpretation and reporting of these data are the responsibility of the authors and in no way should be seen as an official policy of, or interpretation by, the OPTN or the US government. Statistical significance of overall changes in proportions was assessed by means of the likelihood ratio test in chi-square analysis. The Kaplan-Meier method with log-rank test was used to estimate and compare 1-year graft survival and patient survival rates between the groups after adjusting for recipient age, dialysis dependence, and presence of diabetes mellitus (DM), which are all three components of the EPTS score. Among the recipients during the study period, 1,079 had missing KDPI data. These patients were included in all analyses except for the comparison of KDPI data. Analyses were performed with the use of JMP Pro 13.0.0 (SAS Institute, Cary, North Carolina). A P value of < .05 was considered to be statistically significant.
RESULTS Distribution of PHS IRDs Over Time
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Fig 1. NonePublic Health Service (PHS) and PHS increased-risk donor (IRD) kidney transplantation by year.
significantly lower: 37 24 versus 49 27 in non-IRD kidneys (P < .0001). Distribution of Increased-Risk Kidney Donors by Age Group Before and After KAS
Before changes in the KAS, from January 2005 to December 2014, the 20e29-year-old age group composed 34% of all PHS IRDs compared with 36% after KAS, and the 30e39-year-old age group composed 23% versus 27%, respectively (P < .0001). The percentages of IRDs in the age groups 40e49, 50e59, and 60 years were significantly lower after implementation of the new KAS (Fig 2). Overall Distribution of All Kidney Transplants by Age Group Before and After KAS
The distribution of all deceased kidney transplants performed in various age groups also changed significantly in these time periods. Over a 10-year period before KAS, a total of 100,291 kidney transplantations were performed, with 6,898 kidney transplantations (7%) in recipients 20e29 years old. The percentage of kidney transplantations in this age group significantly increased after KAS to 9% (1,322 out of 15,453 total transplants performed; P > .0001). In the recipients 30e39 years old, there were 13,465 out of 100,291 kidney transplantations performed (13%) before KAS versus 2,417 out of 15,453 (16%) after KAS (P < .0001).
Since 2011, the number and proportion of kidney transplants from PHS-IRDs has increased. Based on Scientific Registry of Transplant Recipients data, in 2011 there were 10,428 kidney transplantations with 1,135 (10.8%) transplantations with organs from PHS high-risk donors, and in 2015 there were 11,616 kidney transplants with 2,519 (21.7%) from infectious disease high-risk donors (P < .0001; Fig 1). Characteristics of IRDs
Compared with non-IRDs, PHS IRDs were significantly younger, with the average age 34 12 years versus 39 17 years (P < .0001). The mean KDPI of PHS IRDs was
Fig 2. Distribution of PHS IRDs by age before and after the new kidney allocation system. Abbreviations as in Fig 1.
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RAHNEMAI-AZAR, PERKINS, LECA ET AL
The number of kidney transplants performed in the 50e59year-old age group decreased from 30% to 26% in the preand post-KAS periods (P < .00001; Fig 3). Distribution of PHS IRD Kidney Transplants Performed by Age Group Before and After KAS
The distribution of PHS increased-risk kidney transplants performed in various age groups changed significantly before and after the new KAS implementation, with an increasing number of younger individuals receiving IRD kidneys. When analyzing PHS increased-risk kidney transplantations, 10,533 (11%) patients received IRD grafts in a 10-year period before the new KAS versus 3,419 (22%) after KAS. This change was more notable in younger age groups. In the age group of 20e29 years, 731 kidney recipients (7% of all 10,533 PHS IRDs) underwent kidney transplantation from increased-risk donors before the new KAS compared with 330 (10% of 3,419) after KAS (P < .0001). Before KAS, 1,383 candidates (13% of all 10,533 PHS IRDs) 30e39 years old received kidneys from IRDs versus 613 (18% of 3,419) after KAS (P < .0001). The trend was reversed in recipients 50e59 years old, with 3,228 (31% out of 10,533) transplanted before KAS versus 887 (26% out of 3 419) after KAS (P < .0001; Fig 4). Graft and Patient Survivals
Kaplan-Meier analysis demonstrated better graft survival for PHS increased-risk kidney grafts versus noneincreasedrisk grafts in both pre- and post-KAS eras (P < .0001 and P ¼ .009, respectively). No difference was noted in kidney recipient survival in either noneincreased-risk or increasedrisk groups before and after the new KAS after adjusting for recipient age, dialysis dependence, and presence of DM (all 3 components of the EPTS score; Figs 5 and 6). In multivariate analysis, PHS-IRD was an independent predictor of better graft survival but not patient survival in both eras. DISCUSSION
In 1994, the Centers for Disease Control and Prevention (CDC) released the first high-risk donors guidelines in an effort to minimize HIV transmission from organ donors to
Fig 3. Kidney transplantation distribution by age before and after the new kidney allocation system.
Fig 4. Distribution of kidney transplantation with PHS IRDs before and after the new kidney allocation system. Abbreviations as in Fig 1.
recipients [4]. Almost 20 years later, in 2013, the PHS expanded these guidelines to include screening of IRD, those who met any of the specific criteria for increased-risk behaviors for blood-borne viruses, including HBV, HCV, and HIV [5]. These guidelines were intended to identify donors at higher residual risk of harboring blood-borne viruses despite negative tests [6]. However, the actual risk of viral transmission in the presence of negative screening tests is expected to be very low and varies considerably by specific risk factor [7e10]. In recent years, there has been an increasing number of deceased donors, including a progressive increase in the number of IRDs [11]. This has been partly related to new IRD definitions by PHS, but most importantly there has been a steady increase in the number of IRDs, owing in large part to an increase in injection drug use and deaths from opioid overdoses [3,7,12]. As demonstrated by our results, the number of PHS increased-risk kidney donors increased from 10.8% in 2010 to 21.7% in 2015. Our analysis also revealed that the average age of IRDs was significantly lower than non-IRDs: 33.7 years versus 39.3 years. Considering that the majority of PHS IRDs are younger and otherwise healthy, the quality of grafts recovered from these donors appears to be superior to nonincreasedrisk donors [6,13,14]. Kucirka et al reported that from 2004 to 2008, 12% of kidney donors in the PHS/CDC increasedrisk category were expanded-criteria donors, compared with 25.6% in the non-IRD group [14]. Likewise, Duan et al demonstrated that PHS IRDs tend to have more characteristics associated with favorable graft function, such as younger age and lower serum creatinine [6]. Concerning deceased-donor kidneys, we demonstrated that the mean KDPI of IRD kidneys was significantly lower than non-IRD kidneys: 37% versus 49%. Furthermore, our analysis demonstrated that the recipients of IRD kidneys had a significantly better graft survival than the recipients of non-IRD kidneys (93% vs 91%). This finding confirms the results of previous studies showing improved allograft survival and similar short-term survival of patients between IRD and non-IRD groups [6,13].
NEW KIDNEY ALLOCATION SYSTEM CONSEQUENCES
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Fig 5. Kidney allograft survival with PHS IRD versus nonePHS IRD kidneys before and after the new kidney allocation system. Abbreviations as in Fig 1.
The primary goal of the new KAS was to extend the longevity of transplanted organs by allocating better-quality organs to patients with longer life expectancy (matching KDPI and EPTS scores) [2,15]. Although several studies, by releasing short-term results, demonstrated that the new KAS has been successful in accomplishing some of its goals, there are no data describing the trends and effect of allocation of IRDs after implementation of the new system [15,16]. Our findings demonstrate that there was a significant rise in IRD kidneys transplanted into adult recipients younger than 40 years and a significant decrease in recipients >50 years old. Although the results of demonstrate that these younger kidneys are placed as intended by KAS into younger recipients, it is unclear whether this effect is maximized, owing to the increased-risk status of these organs. Because it has previously been shown that recipient age, underlying health status, and dialysis time while waiting for transplant (3 major components of the EPTS score) were independent determinants of underutilization of these organs, our allocation and outcome data highlight the
importance of IRD-specific education in this population. It has been shown that having the knowledge and understanding about IRD organs could facilitate recipients’ decision making. The estimated risk of transmission of blood-borne viruses, such as HIV, HCV, and HBV, to recipients from IRD organs is very low, with only a few cases of donor-derived HCV transmissions reported over the past several years [17,18]. With recommended nucleic acid testing (NAT) testing of all donors, the risk of transmission of HCV from NAT-negative donors with needle exposure is reduced to 32.4 per 10,000 (0.32%). A donor that died from intravenous drug overdose has a risk of transmission possibly as high as 3% for HCV and lower for HIV and HBV [19]. With the introduction of the highly effective direct-acting antivirals (DAAs), HCV infection changed from an infrequently cured to a curable disease, with sustained virologic response rates >90%, including for treatment of HCV in organ transplant recipients [20]. Because of the overall low risk of infection, the use of an IRD may be warranted, given
Fig 6. Patient (kidney recipient) survival with PHS IRD vs nonePHS IRD kidneys before and after the new kidney allocation system. Abbreviation: ETPS, estimated post-transplantation survival; other abbreviations as in Fig 1.
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the younger age and better organ quality of some of these donors. The successful use of these donors has been described in kidney as well as other organ transplants with outcomes similar to non-IRD organs [6,21]. Besides providing specific information about the definition of PHS IRDs and the relative benefits and hazards posed by this type of donor (including the donor screening process and actual risk of infection transmission), the educational interventions should incorporate discussions about the patient’s current and projected quality of life, the best estimate of wait time for transplantation, different measures of post-transplantation IRD-related infectious surveillance, and available treatment options in case of infection. Moreover, education should also be provided to the health care providers. Several studies have emphasized the need for more formal education of nonphysician transplant providers (eg, nurses or physician assistants) about donors at increased risk of disease transmission [22,23]. Involving transplant infectious disease (ID) experts in transplant center policy and guidelines, close collaboration between the ID physicians and other members of the transplant team, and, as previously shown in the authors’ own experience, involving them in the early stages of the informed consent process of recipients of IRDs are likely to be important in increasing awareness about IRD-related issues and potentially improving utilization of these organs [7,23,24]. The main limitation of the present study is that only 15 months of data were available, because implementation of the new KAS did not begin until December 2014. The same limitation also applies to interpretation of the data comparing patient and graft survivals of IRD versus nonIRD kidneys in a new era. However, the fact that we observed a substantial and statistically significant increase in the number of IRD kidneys allocated to younger recipients in such a small time frame suggests that the increase was real. In addition, because of the observational nature of the study, we could only examine associations between the new allocation system and the rise in IRD volume in younger recipients without verifying a causal relationship. Therefore, we can not exclude the possibility of other factors that could contribute to these changes. CONCLUSION
The new KAS was designed to aid the transplant community in optimizing both the equity and utility of donated kidneys, both of which have long been challenges of transplantation. To achieve this mission, one of the primary goals of the KAS was longevity matching by allocating kidneys expected to last the longest (lower KDPI scores) to recipients expected to survive the longest after kidney transplantation (lower EPTS scores). The results of the present study demonstrated that after implementation of the new KAS, there has been a substantial increase in the number of the IRD kidneys (generally with lower KDPI) to kidney transplant candidates in younger age groups. In the studies conducted before the
RAHNEMAI-AZAR, PERKINS, LECA ET AL
new allocation system, younger recipients were more likely to refuse IRD kidneys. Therefore, it is imperative to have specific IRD education and a standardized consent process to optimize the use of IRD kidneys in the new KAS era. Furthermore, because only 15 months of data were available at the time of this study, continued monitoring, analysis, and interpretation are essential to confirm our findings and identify possible shortcomings of the new KAS and opportunities for future policy refinements. We propose further investigation of IRD organ acceptance patterns by the younger recipients in the era of the new KAS so that its intended goals are fully realized. REFERENCES [1] Friedewald JJ, Samana CJ, Kasiske BL, Israni AK, Stewart D, Cherikh W, et al. The kidney allocation system. Surg Clin North Am 2013;93:1395e406. [2] Chopra B, Sureshkumar KK. Changing organ allocation policy for kidney transplantation in the United States. World J Transplant 2015;5:38e43. [3] Goldberg DS, Blumberg E, McCauley M, Abt P, Levine M. Improving organ utilization to help overcome the tragedies of the opioid epidemic. Am J Transplant 2016;16:2836e41. [4] Rogers Sr MF, Lawton KE, Moseley RR, Jones WK. Guidelines for preventing transmission of human immunodeficiency virus through transplantation of human tissue and organs. MMWR Recomm Rep 1994;43:1e7. [5] Seem DL, Lee I, Umscheid CA, Kuehnert MJ, United States Public Health Service. PHS guideline for reducing human immunodeficiency virus, hepatitis B virus, and hepatitis C virus transmission through organ transplantation. Public Health Rep 2013;128:247e343. [6] Duan KI, Englesbe MJ, Volk ML. Centers for Disease Control “high-risk” donors and kidney utilization. Am J Transplant 2010;10:416e20. [7] Sibulesky L, Javed I, Reyes JD, Limaye AP. Changing the paradigm of organ utilization from PHS increased-risk donors: an opportunity whose time has come? Clin Transplant 2015;29:724e7. [8] Kucirka LM, Singer AL, Segev DL. High infectious risk donors: what are the risks and when are they too high? Curr Opin Organ Transplant 2011;16:256e61. [9] Ellingson K, Seem D, Nowicki M, Strong DM, Kuehnert MJ, Organ Procurement Organization Nucleic Acid Testing Yield Project Team. Estimated risk of human immunodeficiency virus and hepatitis C virus infection among potential organ donors from 17 organ procurement organizations in the United States. Am J Transplant 2011;11:1201e8. [10] Freeman RB, Cohen JT. Transplantation risks and the real world: what does “high risk” really mean? Am J Transplant 2009;9: 23e30. [11] Organ Procurement and Transplantation Network. Available at: https://optn.transplant.hrsa.gov. [12] Kucirka LM, Bowring MG, Massie AB, Luo X, Nicholas LH, Segev DL. Landscape of deceased donors labeled increased risk for disease transmission under new guidelines. Am J Transplant 2015;15:3215e23. [13] Reese PP, Feldman HI, Asch DA, Halpern SD, Blumberg EA, Thomasson A, et al. Transplantation of kidneys from donors at increased risk for blood-borne viral infection: recipient outcomes and patterns of organ use. Am J Transplant 2009;9: 2338e45. [14] Kucirka LM, Alexander C, Namuyinga R, Hanrahan C, Montgomery RA, Segev DL. Viral nucleic acid testing (NAT) and OPO-level disposition of high-risk donor organs. Am J Transplant 2009;9:620e8.
NEW KIDNEY ALLOCATION SYSTEM CONSEQUENCES [15] Stewart DE, Kucheryavaya AY, Klassen DK, Turgeon NA, Formica RN, Aeder MI. Changes in deceased donor kidney transplantation one year after KAS implementation. Am J Transplant 2016;16:1834e47. [16] Wang CJ, Wetmore JB, Israni AK. Old versus new: progress in reaching the goals of the new kidney allocation system. Hum Immunol 2016;8:9e15. [17] Green M, Covington S, Taranto S, Wolfe C, Bell W, Biggins SW, et al. Donor-derived transmission events in 2013: a report of the Organ Procurement Transplant Network Ad Hoc Disease Transmission Advisory Committee. Transplantation 2015;99:282e7. [18] Wolfe CR, Michaels MG. Donor-derived hepatitis C transmission from NAT negative donorsdstill an unexpected event. Am J Transplant 2017;17:2989. [19] Annambhotla PD, Gurbaxani BM, Kuehnert MJ, Basavaraju SV. A model to estimate the probability of human immunodeficiency virus and hepatitis C infection despite negative nucleic acid testing among increased-risk organ donors. Transpl Infect Dis 2017;19(2). Published online March 27, 2017.
19 [20] Simmons B, Saleem J, Hill A, Riley RD, Cooke GS. Risk of late relapse or reinfection with hepatitis C virus after achieving a sustained virological response: a systematic review and meta-analysis. Clin Infect Dis 2016;62:683e94. [21] Fleetwood VA, Lusciks J, Poirier J, Hertl M, Chan EY. Utilization of Public Health Service increased risk donors yields equivalent outcomes in liver transplantation. J Transplant 2016;2016:9658904. [22] Ison MG, Abecassis M, Blumberg E, Davis C, Fishman JA, Freeman RB, et al. Achieving consensus on increased risk donors to improve access to organ transplantation. ASTS/AST Consensus Conference; Chicago, April 27, 2012. [23] Gordon EJ, Mullee J, Beauvais N, Warren E, Theodoropoulos N, McNatt G, et al. Education and informed consent about increased risk donor kidneys: a national survey of nonphysician transplant providers. Transpl Infect Dis 2014;16: 251e60. [24] Theodoropoulos N, Ladner DP, Ison MG. Screening recipients of increased-risk donor organs: a survey of transplant infectious diseases physician practices. Transpl Infect Dis 2013;15:545e9.
ABSTRACT Background. The new kidney allocation system (KAS) intends to allocate the top 20% of kidneys to younger recipients with longer life expectancy. We hypothesized that the new KAS would lead to greater allocation of Public Health Service (PHS) increased-risk donor organs to younger recipients. Methods. Analyses of the Organ Procurement and Transplantation Network data of patients who underwent primary deceased kidney transplantation were performed in preand post-KAS periods. Results. The allocation of PHS increased-risk kidney allografts in various age groups changed significantly after implementation of the new KAS, with an increased proportion of younger individuals receiving increased-risk kidneys (7% vs 10% in age group 20e29 y and 13% vs 18% in age group 30e39 y before and after KAS, respectively; P < .0001). This trend was reversed in recipients 50e59 years old, with 31% in the pre-KAS period compared with 26% after KAS (P < .0001). Conclusions. The new KAS resulted in a substantial increase in allocation of PHS increased-risk kidneys to candidates in younger age groups. Because increased-risk kidneys are generally underutilized, future efforts to optimize the utilization of these organs should target younger recipients and their providers.
I
N DECEMBER 2014, the Organ Procurement and Transplantation Network (OPTN) Kidney Transplantation Committee implemented a new deceased-donor kidney allocation system (KAS) in an effort to bridge the kidney gap and tackle utility and equity issues [1]. The new KAS is intended to improve the utilization of donated kidneys by expanding kidney allograft survival through matching the estimated post-transplantation survival (EPTS) and the kidney donor profile index (KDPI) scores [1,2]. One of the goals of the new system is to match the best 20% of younger highest-quality donor kidneys to younger candidates with the expected longest post-transplantation survival. Currently, increasing numbers of younger donors are considered to be Public Health Service (PHS) increasedrisk donors (IRDs) [3]. As a result of drug overdose 0041-1345/17 https://doi.org/10.1016/j.transproceed.2017.11.025
14
epidemic among the deceased donors younger than 40 years, the percentage of drug overdoses increased from 3.6% to 11.7% from 2003 to 2014 [3]. Despite having the highest overall donation rates, the mean number of organs transplanted per donor continues to be significantly lower among donors who died from drug overdose compared with donors who died from other causes, owing to the increased risk of transmission of blood-borne viruses, including hepatitis B virus (HBV), hepatitis C virus (HCV), and human immunodeficiency virus (HIV) [3]. Because of the increased
*Address correspondence to Lena Sibulesky, MD, FACS, Assistant Professor, Department of Surgery, University of Washington Medical Center, 1959 NE Pacific Street, Box 356410, Seattle, WA 98195. E-mail: [email protected] ª 2017 Elsevier Inc. All rights reserved. 230 Park Avenue, New York, NY 10169
Transplantation Proceedings, 50, 14e19 (2018)
NEW KIDNEY ALLOCATION SYSTEM CONSEQUENCES
risk of infectious disease transmission there is concern among transplant providers and patients in accepting these organs. There are no data available comparing the distribution pattern of PHS IRD kidneys among transplant recipients and their outcomes before and after the introduction of the new KAS and with the rise in the numbers of PHS IRDs. We hypothesized that KAS would lead to greater allocation of PHS IRD organs to younger recipients and that the outcomes of recipients of these organs would be excellent. The present study assessed the trends in PHS IRD allocation among kidney recipients before and after implementation of the new KAS. The second goal was to compare the effect of the new allocation policy on the PHS increased-risk graft and patient outcomes. METHODS This was a retrospective observational study comparing PHS IRD primary kidney transplant recipient data before (from January 1, 2005, to December 4, 2014) and after (from December 5, 2014, to March 31, 2016) implementation of the new KAS. United States donor, waitlisted candidates, and transplant recipient data for this analysis are from OPTN data released June 17, 2016, based on data collected through March 31, 2016. The United Network for Organ Sharing, the contractor for the OPTN, supplied these data. The interpretation and reporting of these data are the responsibility of the authors and in no way should be seen as an official policy of, or interpretation by, the OPTN or the US government. Statistical significance of overall changes in proportions was assessed by means of the likelihood ratio test in chi-square analysis. The Kaplan-Meier method with log-rank test was used to estimate and compare 1-year graft survival and patient survival rates between the groups after adjusting for recipient age, dialysis dependence, and presence of diabetes mellitus (DM), which are all three components of the EPTS score. Among the recipients during the study period, 1,079 had missing KDPI data. These patients were included in all analyses except for the comparison of KDPI data. Analyses were performed with the use of JMP Pro 13.0.0 (SAS Institute, Cary, North Carolina). A P value of < .05 was considered to be statistically significant.
RESULTS Distribution of PHS IRDs Over Time
15
Fig 1. NonePublic Health Service (PHS) and PHS increased-risk donor (IRD) kidney transplantation by year.
significantly lower: 37 24 versus 49 27 in non-IRD kidneys (P < .0001). Distribution of Increased-Risk Kidney Donors by Age Group Before and After KAS
Before changes in the KAS, from January 2005 to December 2014, the 20e29-year-old age group composed 34% of all PHS IRDs compared with 36% after KAS, and the 30e39-year-old age group composed 23% versus 27%, respectively (P < .0001). The percentages of IRDs in the age groups 40e49, 50e59, and 60 years were significantly lower after implementation of the new KAS (Fig 2). Overall Distribution of All Kidney Transplants by Age Group Before and After KAS
The distribution of all deceased kidney transplants performed in various age groups also changed significantly in these time periods. Over a 10-year period before KAS, a total of 100,291 kidney transplantations were performed, with 6,898 kidney transplantations (7%) in recipients 20e29 years old. The percentage of kidney transplantations in this age group significantly increased after KAS to 9% (1,322 out of 15,453 total transplants performed; P > .0001). In the recipients 30e39 years old, there were 13,465 out of 100,291 kidney transplantations performed (13%) before KAS versus 2,417 out of 15,453 (16%) after KAS (P < .0001).
Since 2011, the number and proportion of kidney transplants from PHS-IRDs has increased. Based on Scientific Registry of Transplant Recipients data, in 2011 there were 10,428 kidney transplantations with 1,135 (10.8%) transplantations with organs from PHS high-risk donors, and in 2015 there were 11,616 kidney transplants with 2,519 (21.7%) from infectious disease high-risk donors (P < .0001; Fig 1). Characteristics of IRDs
Compared with non-IRDs, PHS IRDs were significantly younger, with the average age 34 12 years versus 39 17 years (P < .0001). The mean KDPI of PHS IRDs was
Fig 2. Distribution of PHS IRDs by age before and after the new kidney allocation system. Abbreviations as in Fig 1.
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The number of kidney transplants performed in the 50e59year-old age group decreased from 30% to 26% in the preand post-KAS periods (P < .00001; Fig 3). Distribution of PHS IRD Kidney Transplants Performed by Age Group Before and After KAS
The distribution of PHS increased-risk kidney transplants performed in various age groups changed significantly before and after the new KAS implementation, with an increasing number of younger individuals receiving IRD kidneys. When analyzing PHS increased-risk kidney transplantations, 10,533 (11%) patients received IRD grafts in a 10-year period before the new KAS versus 3,419 (22%) after KAS. This change was more notable in younger age groups. In the age group of 20e29 years, 731 kidney recipients (7% of all 10,533 PHS IRDs) underwent kidney transplantation from increased-risk donors before the new KAS compared with 330 (10% of 3,419) after KAS (P < .0001). Before KAS, 1,383 candidates (13% of all 10,533 PHS IRDs) 30e39 years old received kidneys from IRDs versus 613 (18% of 3,419) after KAS (P < .0001). The trend was reversed in recipients 50e59 years old, with 3,228 (31% out of 10,533) transplanted before KAS versus 887 (26% out of 3 419) after KAS (P < .0001; Fig 4). Graft and Patient Survivals
Kaplan-Meier analysis demonstrated better graft survival for PHS increased-risk kidney grafts versus noneincreasedrisk grafts in both pre- and post-KAS eras (P < .0001 and P ¼ .009, respectively). No difference was noted in kidney recipient survival in either noneincreased-risk or increasedrisk groups before and after the new KAS after adjusting for recipient age, dialysis dependence, and presence of DM (all 3 components of the EPTS score; Figs 5 and 6). In multivariate analysis, PHS-IRD was an independent predictor of better graft survival but not patient survival in both eras. DISCUSSION
In 1994, the Centers for Disease Control and Prevention (CDC) released the first high-risk donors guidelines in an effort to minimize HIV transmission from organ donors to
Fig 3. Kidney transplantation distribution by age before and after the new kidney allocation system.
Fig 4. Distribution of kidney transplantation with PHS IRDs before and after the new kidney allocation system. Abbreviations as in Fig 1.
recipients [4]. Almost 20 years later, in 2013, the PHS expanded these guidelines to include screening of IRD, those who met any of the specific criteria for increased-risk behaviors for blood-borne viruses, including HBV, HCV, and HIV [5]. These guidelines were intended to identify donors at higher residual risk of harboring blood-borne viruses despite negative tests [6]. However, the actual risk of viral transmission in the presence of negative screening tests is expected to be very low and varies considerably by specific risk factor [7e10]. In recent years, there has been an increasing number of deceased donors, including a progressive increase in the number of IRDs [11]. This has been partly related to new IRD definitions by PHS, but most importantly there has been a steady increase in the number of IRDs, owing in large part to an increase in injection drug use and deaths from opioid overdoses [3,7,12]. As demonstrated by our results, the number of PHS increased-risk kidney donors increased from 10.8% in 2010 to 21.7% in 2015. Our analysis also revealed that the average age of IRDs was significantly lower than non-IRDs: 33.7 years versus 39.3 years. Considering that the majority of PHS IRDs are younger and otherwise healthy, the quality of grafts recovered from these donors appears to be superior to nonincreasedrisk donors [6,13,14]. Kucirka et al reported that from 2004 to 2008, 12% of kidney donors in the PHS/CDC increasedrisk category were expanded-criteria donors, compared with 25.6% in the non-IRD group [14]. Likewise, Duan et al demonstrated that PHS IRDs tend to have more characteristics associated with favorable graft function, such as younger age and lower serum creatinine [6]. Concerning deceased-donor kidneys, we demonstrated that the mean KDPI of IRD kidneys was significantly lower than non-IRD kidneys: 37% versus 49%. Furthermore, our analysis demonstrated that the recipients of IRD kidneys had a significantly better graft survival than the recipients of non-IRD kidneys (93% vs 91%). This finding confirms the results of previous studies showing improved allograft survival and similar short-term survival of patients between IRD and non-IRD groups [6,13].
NEW KIDNEY ALLOCATION SYSTEM CONSEQUENCES
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Fig 5. Kidney allograft survival with PHS IRD versus nonePHS IRD kidneys before and after the new kidney allocation system. Abbreviations as in Fig 1.
The primary goal of the new KAS was to extend the longevity of transplanted organs by allocating better-quality organs to patients with longer life expectancy (matching KDPI and EPTS scores) [2,15]. Although several studies, by releasing short-term results, demonstrated that the new KAS has been successful in accomplishing some of its goals, there are no data describing the trends and effect of allocation of IRDs after implementation of the new system [15,16]. Our findings demonstrate that there was a significant rise in IRD kidneys transplanted into adult recipients younger than 40 years and a significant decrease in recipients >50 years old. Although the results of demonstrate that these younger kidneys are placed as intended by KAS into younger recipients, it is unclear whether this effect is maximized, owing to the increased-risk status of these organs. Because it has previously been shown that recipient age, underlying health status, and dialysis time while waiting for transplant (3 major components of the EPTS score) were independent determinants of underutilization of these organs, our allocation and outcome data highlight the
importance of IRD-specific education in this population. It has been shown that having the knowledge and understanding about IRD organs could facilitate recipients’ decision making. The estimated risk of transmission of blood-borne viruses, such as HIV, HCV, and HBV, to recipients from IRD organs is very low, with only a few cases of donor-derived HCV transmissions reported over the past several years [17,18]. With recommended nucleic acid testing (NAT) testing of all donors, the risk of transmission of HCV from NAT-negative donors with needle exposure is reduced to 32.4 per 10,000 (0.32%). A donor that died from intravenous drug overdose has a risk of transmission possibly as high as 3% for HCV and lower for HIV and HBV [19]. With the introduction of the highly effective direct-acting antivirals (DAAs), HCV infection changed from an infrequently cured to a curable disease, with sustained virologic response rates >90%, including for treatment of HCV in organ transplant recipients [20]. Because of the overall low risk of infection, the use of an IRD may be warranted, given
Fig 6. Patient (kidney recipient) survival with PHS IRD vs nonePHS IRD kidneys before and after the new kidney allocation system. Abbreviation: ETPS, estimated post-transplantation survival; other abbreviations as in Fig 1.
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the younger age and better organ quality of some of these donors. The successful use of these donors has been described in kidney as well as other organ transplants with outcomes similar to non-IRD organs [6,21]. Besides providing specific information about the definition of PHS IRDs and the relative benefits and hazards posed by this type of donor (including the donor screening process and actual risk of infection transmission), the educational interventions should incorporate discussions about the patient’s current and projected quality of life, the best estimate of wait time for transplantation, different measures of post-transplantation IRD-related infectious surveillance, and available treatment options in case of infection. Moreover, education should also be provided to the health care providers. Several studies have emphasized the need for more formal education of nonphysician transplant providers (eg, nurses or physician assistants) about donors at increased risk of disease transmission [22,23]. Involving transplant infectious disease (ID) experts in transplant center policy and guidelines, close collaboration between the ID physicians and other members of the transplant team, and, as previously shown in the authors’ own experience, involving them in the early stages of the informed consent process of recipients of IRDs are likely to be important in increasing awareness about IRD-related issues and potentially improving utilization of these organs [7,23,24]. The main limitation of the present study is that only 15 months of data were available, because implementation of the new KAS did not begin until December 2014. The same limitation also applies to interpretation of the data comparing patient and graft survivals of IRD versus nonIRD kidneys in a new era. However, the fact that we observed a substantial and statistically significant increase in the number of IRD kidneys allocated to younger recipients in such a small time frame suggests that the increase was real. In addition, because of the observational nature of the study, we could only examine associations between the new allocation system and the rise in IRD volume in younger recipients without verifying a causal relationship. Therefore, we can not exclude the possibility of other factors that could contribute to these changes. CONCLUSION
The new KAS was designed to aid the transplant community in optimizing both the equity and utility of donated kidneys, both of which have long been challenges of transplantation. To achieve this mission, one of the primary goals of the KAS was longevity matching by allocating kidneys expected to last the longest (lower KDPI scores) to recipients expected to survive the longest after kidney transplantation (lower EPTS scores). The results of the present study demonstrated that after implementation of the new KAS, there has been a substantial increase in the number of the IRD kidneys (generally with lower KDPI) to kidney transplant candidates in younger age groups. In the studies conducted before the
RAHNEMAI-AZAR, PERKINS, LECA ET AL
new allocation system, younger recipients were more likely to refuse IRD kidneys. Therefore, it is imperative to have specific IRD education and a standardized consent process to optimize the use of IRD kidneys in the new KAS era. Furthermore, because only 15 months of data were available at the time of this study, continued monitoring, analysis, and interpretation are essential to confirm our findings and identify possible shortcomings of the new KAS and opportunities for future policy refinements. We propose further investigation of IRD organ acceptance patterns by the younger recipients in the era of the new KAS so that its intended goals are fully realized. REFERENCES [1] Friedewald JJ, Samana CJ, Kasiske BL, Israni AK, Stewart D, Cherikh W, et al. The kidney allocation system. Surg Clin North Am 2013;93:1395e406. [2] Chopra B, Sureshkumar KK. Changing organ allocation policy for kidney transplantation in the United States. World J Transplant 2015;5:38e43. [3] Goldberg DS, Blumberg E, McCauley M, Abt P, Levine M. Improving organ utilization to help overcome the tragedies of the opioid epidemic. Am J Transplant 2016;16:2836e41. [4] Rogers Sr MF, Lawton KE, Moseley RR, Jones WK. Guidelines for preventing transmission of human immunodeficiency virus through transplantation of human tissue and organs. MMWR Recomm Rep 1994;43:1e7. [5] Seem DL, Lee I, Umscheid CA, Kuehnert MJ, United States Public Health Service. PHS guideline for reducing human immunodeficiency virus, hepatitis B virus, and hepatitis C virus transmission through organ transplantation. Public Health Rep 2013;128:247e343. [6] Duan KI, Englesbe MJ, Volk ML. Centers for Disease Control “high-risk” donors and kidney utilization. Am J Transplant 2010;10:416e20. [7] Sibulesky L, Javed I, Reyes JD, Limaye AP. Changing the paradigm of organ utilization from PHS increased-risk donors: an opportunity whose time has come? Clin Transplant 2015;29:724e7. [8] Kucirka LM, Singer AL, Segev DL. High infectious risk donors: what are the risks and when are they too high? Curr Opin Organ Transplant 2011;16:256e61. [9] Ellingson K, Seem D, Nowicki M, Strong DM, Kuehnert MJ, Organ Procurement Organization Nucleic Acid Testing Yield Project Team. Estimated risk of human immunodeficiency virus and hepatitis C virus infection among potential organ donors from 17 organ procurement organizations in the United States. Am J Transplant 2011;11:1201e8. [10] Freeman RB, Cohen JT. Transplantation risks and the real world: what does “high risk” really mean? Am J Transplant 2009;9: 23e30. [11] Organ Procurement and Transplantation Network. Available at: https://optn.transplant.hrsa.gov. [12] Kucirka LM, Bowring MG, Massie AB, Luo X, Nicholas LH, Segev DL. Landscape of deceased donors labeled increased risk for disease transmission under new guidelines. Am J Transplant 2015;15:3215e23. [13] Reese PP, Feldman HI, Asch DA, Halpern SD, Blumberg EA, Thomasson A, et al. Transplantation of kidneys from donors at increased risk for blood-borne viral infection: recipient outcomes and patterns of organ use. Am J Transplant 2009;9: 2338e45. [14] Kucirka LM, Alexander C, Namuyinga R, Hanrahan C, Montgomery RA, Segev DL. Viral nucleic acid testing (NAT) and OPO-level disposition of high-risk donor organs. Am J Transplant 2009;9:620e8.
NEW KIDNEY ALLOCATION SYSTEM CONSEQUENCES [15] Stewart DE, Kucheryavaya AY, Klassen DK, Turgeon NA, Formica RN, Aeder MI. Changes in deceased donor kidney transplantation one year after KAS implementation. Am J Transplant 2016;16:1834e47. [16] Wang CJ, Wetmore JB, Israni AK. Old versus new: progress in reaching the goals of the new kidney allocation system. Hum Immunol 2016;8:9e15. [17] Green M, Covington S, Taranto S, Wolfe C, Bell W, Biggins SW, et al. Donor-derived transmission events in 2013: a report of the Organ Procurement Transplant Network Ad Hoc Disease Transmission Advisory Committee. Transplantation 2015;99:282e7. [18] Wolfe CR, Michaels MG. Donor-derived hepatitis C transmission from NAT negative donorsdstill an unexpected event. Am J Transplant 2017;17:2989. [19] Annambhotla PD, Gurbaxani BM, Kuehnert MJ, Basavaraju SV. A model to estimate the probability of human immunodeficiency virus and hepatitis C infection despite negative nucleic acid testing among increased-risk organ donors. Transpl Infect Dis 2017;19(2). Published online March 27, 2017.
19 [20] Simmons B, Saleem J, Hill A, Riley RD, Cooke GS. Risk of late relapse or reinfection with hepatitis C virus after achieving a sustained virological response: a systematic review and meta-analysis. Clin Infect Dis 2016;62:683e94. [21] Fleetwood VA, Lusciks J, Poirier J, Hertl M, Chan EY. Utilization of Public Health Service increased risk donors yields equivalent outcomes in liver transplantation. J Transplant 2016;2016:9658904. [22] Ison MG, Abecassis M, Blumberg E, Davis C, Fishman JA, Freeman RB, et al. Achieving consensus on increased risk donors to improve access to organ transplantation. ASTS/AST Consensus Conference; Chicago, April 27, 2012. [23] Gordon EJ, Mullee J, Beauvais N, Warren E, Theodoropoulos N, McNatt G, et al. Education and informed consent about increased risk donor kidneys: a national survey of nonphysician transplant providers. Transpl Infect Dis 2014;16: 251e60. [24] Theodoropoulos N, Ladner DP, Ison MG. Screening recipients of increased-risk donor organs: a survey of transplant infectious diseases physician practices. Transpl Infect Dis 2013;15:545e9.