The Epidemiology, Outcomes, and Costs of Contemporary Kidney Transplantation

34 The Epidemiology, Outcomes, and Costs of Contemporary Kidney Transplantation Tarek Alhamad, MD, MS, David Axelrod, MD, MBA, Krista L. Lentine, MD, PhD OUTLINE Introduction, 539 Kidney Transplant Candidates: Characteristics and Trends, 539 Changes in the Transplant Waiting List, 540 Transplant Recipients: Characteristics and Trends, 540 Changes in Deceased Donor Organ Characteristics, Allocation, Utilization, and Access, 541 Living Donor Transplantation, 542 Immunosuppression: Trends and Current Practice, 543 Induction Immunosuppression, 543 Maintenance Immunosuppression, 544 Complications of Kidney Transplantation, 546 Posttransplant Outcomes, 547 Acute Rejection, 548

INTRODUCTION Although the successful transplantation of the Herrick twins in 1954 established the feasibility of kidney transplantation, widespread adoption required the introduction of effective immunosuppression medications, the ability to avoid preformed anti-HLA antibodies through crossmatching, and the systematic allocation of donated organs. Over the ensuing 70 years, kidney transplant outcomes have improved, and graft survival rates now routinely exceed 96% at 1 year.1 Long-term patient survival with kidney transplant significantly exceeds that achieved by hemodialysis at a lower cost to society.2,3 However, changes in recipient characteristics, donor quality, and treatment strategies have affected the resources required for successful transplantation, increasing the cost of transplant, especially for novel treatment strategies. 

KIDNEY TRANSPLANT CANDIDATES: CHARACTERISTICS AND TRENDS The complexity of candidates on the waiting list has changed markedly over the past 20 years. Once used primarily in young patients with glomerular disease, kidney transplant is now the treatment of choice for patients with long-standing chronic illness. Diabetes is the leading etiology of kidney failure among listed candidates (36%), followed by hypertension (24%), and glomerulonephritis (14%).1 Successful

Graft Survival, 549 Patient Survival, 549 Center Performance Grading, 549 Centers for Medicare & Medicaid Services, 549 Effect of Performance Monitoring, 549 Unmeasured and Novel Risk Factors, 550 Economics of Kidney Transplantation, 551 Economic Implications of Recipient Characteristics, 552 Economic Implications of Donor Characteristics, 552 Economic Implications of the Current Kidney Allocation System, 553 Economic Implications of Practice Innovation: ABO- and HLA-Incompatible Kidney Transplantation, 553 Conclusions, 553

kidney transplantation is routinely performed in patients previously believed to be too high risk to benefit, including the elderly and patients with significant pretransplant comorbidities. Transplant in patients aged 65 years and older improves survival compared with remaining on dialysis.4,5 Even transplant recipients aged 70 years and older experience lower mortality risk than waitlisted dialysis patients (age 70 to 74: hazard ratio [HR], 0.59; age ≥75: HR, 0.58).6 As a result, patients older than age 50 have become the fastest-growing cohort of waitlisted candidates, increasing from 34,871 patients in 2005 (56% of the list) to 64,408 in 2015 (66% of the list).7 The percentage of candidates aged 65 years or older rose from 14.5% in 2005 to 22% in 2015. Patients previously excluded from transplant due to medical comorbidities can now be successfully treated. Gill and colleagues demonstrated a significant survival benefit from transplant among patients who with existing ischemic heart disease (7.9 years), peripheral vascular disease (7.9 years), and or congestive heart failure (6.7 years) compared with long-term dialysis.8 These authors also demonstrated a 48% reduction in the risk for death by 1-year posttransplant in patients with body mass index (BMI) >40 kg/m2 compared with a 66% reduction in patients with BMI <40 kg/m2.9 Patients with prior failed allografts in need of retransplantation now comprise 13% of the waiting list, as the outcomes after retransplantation have improved sufficiently to consider this treatment option.

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SECTION IV  Transplantation

The proportion of candidates on the waiting list with more than 5 years of dialysis dependence increased from 11.4% in 2005 to 15.7% in 2015. Longer pretransplant dialysis contributes to waitlist mortality and is a risk factor for poor outcomes after transplant.10,11 Although prolonged waiting times contribute to the extended periods of dialysis, delay in timely referral for transplant evaluation also remains a major barrier to transplantation. Almost half of the patients newly listed for transplant have been on dialysis for more than 4 years.1 Lower socioeconomic status was associated with lower kidney transplant access, and residing farther from a transplant center or in rural regions is associated with lower deceased donor transplant access.12,13 Members of racial and ethnic minorities, such as African Americans, face barriers to transplant evaluation and delays in listing, exacerbating racial disparities in access to transplant.14,15 These differences begin at the local level. One recent study examined referral patterns for incident dialysis patients in Georgia and found that although the average rate of referral for evaluation within 1 year of dialysis was only 24%,16 rates varied from 0% to 75% across dialysis centers. Dialysis facilities with the lowest transplant referral rates were more likely to treat patients living in high poverty neighborhoods, had higher patient-to-social worker ratios, and were more likely nonprofit. 

in access to transplantation, marked differences in average waiting time and transplant rates persist. Patients in some areas of the United States experience disparities in transplant access, due, in part, to differences between the local supply of organs and demand for transplant. Other factors that contribute to differences in waiting times include the degree of competition between centers and aggressiveness in organ acceptance practices.18,19 Rates of living donor transplant also vary markedly, and are reduced in areas with low socioeconomic status, high minority populations, and greater obesity.20 The wait for transplant for an individual candidate is influenced by biological factors as well as regional variation in waiting list size and organ availability. High levels of allosensitization are associated with reduced access to transplant due to greater difficulty identifying compatible organs. Although the recent revision of the US kidney allocation system (KAS; discussed later) has been effective in increasing decreased donor transplant rates among the most highly sensitized (panel reactive antibody [PRA] level 98% to 100%), from 7% per 100 patient-years in 2013 to almost 30% in 2015,1 patients with slightly lower levels of sensitization continue to have reduced access to transplantation. The incidence of highly sensitized patients is likely to further increase as patients with prior transplants are considered for retransplantation. 

CHANGES IN THE TRANSPLANT WAITING LIST

TRANSPLANT RECIPIENTS: CHARACTERISTICS AND TRENDS

Unfortunately, the limited supply of deceased and living donor organs has not kept pace with growing demand for kidney transplant. As of May 2017, more than 117,000 patients were waiting for kidney transplantation, compared with 62,166 in 2005.1 The average national waiting time for a deceased donor organ exceeds 3.5 years.17 Despite the directive of the “Final Rule” issued by the Department of Health and Human Services for the Organ Procurement and Transplantation Network (OPTN)/ United Network for Organ Sharing (UNOS) to reduce disparity

In 2015, 18,597 adult and pediatric kidney transplants, including multiorgan transplants, were performed in the United States, an increase from 17,388 in 2005. Living donor transplant constituted 30% of the transplants in 2015, down slightly from its peak in 2004.1 Recipient demographics mirror that of the waiting list, as older patients now comprise a higher fraction of transplant recipients. Recipients older than 60 years of age increased from 15% in 1995 to 2000 to 31.5% in 2011 to 201621 (Fig. 34.1).

100%

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0%

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31–44

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FIG. 34.1  Evolution in the age distribution of US kidney transplant recipients over time. Prepared by the authors from Scientific Registry of Transplant Recipients data through December 2016.

CHAPTER 34  The Epidemiology, Outcomes, and Costs of Contemporary Kidney The proportion of non-Caucasian recipients has increased slowly over recent decades: 49% of recipients transplanted from 2010 to 2015 were white compared with 60.8% in 1995 to 2000. Mirroring the obesity epidemic in the general population, obese transplant recipients (BMI >30 kg/m2) increased from 13.5% between 1995 and 2000 to more than 33% of recipients in 2011 to 2016.22 Half of the transplants were performed in recipients whose end-stage renal disease (ESRD) was reported to be caused by diabetes and hypertension. Hypertension is also the most commonly reported comorbid condition among transplant recipients (72%), followed by diabetes (32%).8 The proportion of deceased donor kidney transplants in recipients with calculated panel reactive antibody (cPRA) 98% to 100% rose from 4.8% in 2014 to 14.6% in 2015,1 reflecting changes in the KAS to increase access for patients with highest levels of allosensitization. Recipients with cPRA 80% to 89% declined from 6.6% in 2014 to 3.2% in 2015, whereas recipients with a cPRA from 90% to 97% remained the same.23 

CHANGES IN DECEASED DONOR ORGAN CHARACTERISTICS, ALLOCATION, UTILIZATION, AND ACCESS The growing organ shortage has led to increased recovery of deceased donor organs with a higher risk of graft failure, delayed graft function (DGF), and primary nonfunction. Factors associated with higher rates of early kidney graft failure include donor age, comorbidities, premortem renal function, and associated medical comorbidities. The use of kidneys from donors older than 50 years of age, and particularly older than 65 years of age, is associated with increased risk for DGF, acute rejection, and graft loss.24-26 Grafts from older donors have more age-related changes of atherosclerosis and fewer functional nephrons. Therefore they have limited reserve to adapt to new insults in the setting of kidney transplant. It also is proposed that kidneys from older donors are more immunogenic than kidneys from younger donors, and thus have higher risk for rejection.24 Despite these effects on graft outcomes, the use of donors older than 50 years of age remained stable (approximately 25% of all decreased donors) between 2004 and 2015.1 The proportion of deceased donors with history of hypertension also remained at approximately 25% during this period. Most organs are recovered after brain death, a mechanism of death that offers the opportunity to sustain organ perfusion with oxygenated blood until the time of actual recovery followed by immediate cooling to minimize ischemic injury. Donors who do not meet the legal definition of brain death for whom organs are recovered after cessation of cardiac activity are known as donation after cardiac death (DCD). DCD donors are classified using the Maastricht categorization of controlled and uncontrolled cardiac death.27 Controlled DCD donors are those who suffer cardiac arrest after planned and witnessed withdrawal of support. Uncontrolled donors are those whose heart has stopped before arrival to the hospital, with or without successful resuscitation. In the United States, the vast majority of DCD donors are controlled donors. DCD has been associated with higher rates of DGF and primary nonfunction.28

541

After DGF recovery, however, recipients of DCD kidneys have long-term allograft and survival comparable to those of recipients of kidneys recovered after brain death, especially when organs are procured from donors younger than 50 years of age.29-31 DCD utilization has increased from 10% in 2005% to 18% in 2015, but varies widely between transplant programs and donation service areas. In December 2014, the OPTN implemented changes to the US KAS designed to improve the utility of deceased donor kidneys and equity in transplant access. As noted previously, sensitization is a barrier to transplant access because it reduces the likelihood of identifying an organ against which the candidate does not have preformed donor-specific antibodies. For minority race candidates, such as African Americans, who face barriers to transplant evaluation and listing, delays in listing reduces allocation priority and exacerbate racial disparities in access to transplant.14,15 Important changes incorporated in the revised KAS include defining the start of waiting time at the date of chronic dialysis initiation for patients who were already on dialysis. This change provides better equity for patients who were referred late or had delayed access to transplant services. Candidates receive an allocation point for every year of dialysis before registration. A sliding scale of increasing allocation points was incorporated for the most highly sensitized patients, such that candidates with calculated cPRA scores of 98%, 99%, and 100% receive 24.4, 50.1, and 202.1 points, respectively. This priority is designed to improve access to potentially compatible organs. To improve access for blood type B candidates, they are now being offered blood type A2 and A2B kidneys at transplant programs willing to accept such organs, based on evidence that transplantation care be safely performed without preconditioning treatments as the A2 antigen has a low level of expression on the cell membrane, rendering the A2 kidney similar to a blood group O kidney.32 The revised KAS also was designed to increase transplant utility through incorporation of “longevity matching” based on scores for organ quality and expected recipient survival. The previous binary division of deceased donors as standard and expanded criteria donors was replaced with continuous, more granular grading of organ quality using the kidney donor risk index (KDRI) based on 10 donor characteristics: age, height, weight, ethnicity, history of hypertension, history of diabetes, cause of death, serum creatinine, hepatitis C serology (HCV), and DCD.33 The KDRI provides an estimate of the relative risk for posttransplant kidney graft failure from a particular deceased donor compared with the median donor in the previous calendar year. Kidney donor profile index (KDPI) is estimated from KDRI as a percentage from 0% to 100%, designed to rank the quality of a specific donor organ relative to other kidneys; lower KDPI values are associated with better donor quality and vice versa. Kidneys with KDPI >85% are comparable to previously designated expanded criteria kidneys. A continuous scale also was developed to compute estimated posttransplant survival (EPTS) in transplant candidates based on candidate age, length of dialysis, diabetes, and prior solid organ transplant status.34 Lower EPTS score (on a scale ranging from 0% to 100%) indicates that the candidate is expected to benefit from more years of graft function

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SECTION IV  Transplantation

compared with candidates with higher scores. To optimize utility, the revised KAS prioritizes candidates with the highest predicted posttransplant benefits (EPTS ≤20%) to receive offers for kidneys from donors with KDPI <20%. Assessment of the effects of the revised KAS over the first year postimplementation demonstrated the following trends: • Increased transplant rate among highly sensitized candidates (cPRA >98%), from 7 per 100 waitlist years in 2014 to 27 per 100 waitlist years in 2015.23 • Increased likelihood of transplantation among candidates aged 18 to 40 years (adjusted hazard ratio [aHR], 1.47; 95% confidence interval [CI], 1.38 to 1.57), but reduced access for candidates aged >50 years (aHR, 0.93; 95% CI, 0.87 to 0.98 for age 51 to 60 and aHR, 0.90; 95% CI, 0.85 to 0.96 for age >70).35 • Increases in the proportions of African American and Hispanic transplant recipients.35 Two-year post-KAS analysis demonstrates that African Americans and Hispanics are now transplanted in proportion to their representation on the waitlist.36 Importantly, these estimates do not consider disparities in access to transplant services and initial listing. • Increase in the correlation between donor age and recipient age, from 0.35 to 0.38.23 • Greater likelihood of waitlisted candidates with the top 20% of life expectancy (EPTS <20%) to undergo transplant with shorter waiting time: approximately 50% of these candidates underwent transplant by 3.2 years after listing, compared with an average waiting time of 4.5 years under the prior policy.37 The use of kidneys from infection risk donors (IRD) also has expanded in light of the ongoing organ shortage and the epidemic in opiate overdose-associated mortality. These are kidneys recovered from donors with behaviors associated with HIV, hepatitis B, and HCV infection, generally intravenous drug use, incarceration, and certain sexual practices. These behaviors were formally defined by the US Public Health Services (US PHS) and must be disclosed to potential recipients.38 A change from the Centers for Disease Control and Prevention criteria increased the number of organs defined as being recovered from “increased risk” donors. Strikingly, 20% of kidneys are now classified as US PHS increased risk.39 Notably, the vast majority of organs are screened with nucleic acid testing (NAT) to identify the presence of HIV or HCV, which has dramatically reduced the risk for unintentional disease transmission during the “window period.” Risk prediction tools to compare outcomes with dialysis may guide use of IRD organs in patients who can benefit.40 IRD kidneys often are high-quality organs from young donors with excellent long-term survival. Although not directly factored into the calculator, it is also notable that both HIV and HCV are treatable infections, such that the rare transmission can be managed, which is a consideration compared with the high mortality of dialysis. The UNOS Disease Transmission Advisory Committee (DTAC) recently released an educational resource to help patients and providers understand the risks and benefits associated with these organs.41 Kidneys from donors with known HCV can benefit HCV-positive recipients by markedly reducing time

to transplantation.42 Patients with HCV who accept an HCVpositive kidney wait an average of 395 days less than those who wait for an HCV-negative kidney. Recent experimental protocols have been introduced to allow transplantation of HCV-positive donor organs into HCV-negative recipients to expand access to organ from these donors, provided that recipients undergo posttransplant antiviral treatment.43,44 Other nonstandard organs that may provide benefit to some patients include kidneys procured from donors with high terminal creatinine due to acute tubular necrosis. These organs are frequently discarded. Analysis of the UNOS database from 1995 to 2007 showed that among donors with terminal creatinine >2 mg/dL, neither kidney was recovered in 44%, whereas when terminal creatinine was ≤1.5 mg/dL neither kidney was recovered in only 2%.45 However, emerging data show these kidneys can be safely used with recognition that a period of posttransplant dialysis will likely be needed. In one single-center experience, transplants from donors with terminal creatinine >2 mg/dL had a higher rate of DGF (66%) and longer DGF (median 10 days) compared with transplants from donors without acute kidney injury (DGF 27%, with median duration 8 days), but similar estimated glomerular filtration rate and graft survival at 1 year posttransplant.46 Unfortunately, the discard rate (i.e., the proportion of organs recovered but not used) has remained at approximately 20% despite the organ shortage and the changes in KAS described previously. The discard rate does vary with donor factors and quality measures, increasing with donor age and higher KDPI.1 Notably, the discard rate begins to rise earlier than risk for adverse outcomes: Whereas graft failure and DGF risk starts to accelerate at KDPI >70, the discard rates rise in a linear manner at KDPI >40 (Fig. 34.2).47 A caveat to this comparison is that transplant outcomes apply to the selected subset of higher risk organs that are used, but the observation raises that use should be considered. Despite higher rates of graft failure, high KDPI organs provide substantial benefit in appropriate populations. A recent study of national registry data by Massie et  al. showed that high-KDPI transplant, defined as KDPI >70, was associated with increased shortterm death risk over 6 months, but better long-term survival, compared with waiting for a higher-quality organ among older patients, diabetics, and those living in regions with prolonged waiting times.48 This study also found that the highestrisk organs (KDPI 91 to 100) benefit patients older than 50 years of age at centers with waiting times longer than 3 years.49 

LIVING DONOR TRANSPLANTATION Living kidney donors can be related, unrelated, nondirected, or participants in donor exchange (kidney paired donation [KPD]) programs. Living donor transplantation provides benefits over deceased donor kidney transplantation including faster access to transplant, which reduces time on dialysis and its associated risks, as well as superior long-term patient and allograft survival at the lowest cost.50 Unfortunately, living donor kidney transplantation in the United States has declined from a peak of 6000 in 2004 to current rates of approximately 5500 per year.1 Multiple barriers to living

CHAPTER 34  The Epidemiology, Outcomes, and Costs of Contemporary Kidney 100%

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–1 16 5 –2 21 0 –2 26 5 –3 31 0 –3 36 5 –4 41 0 –4 46 5 –5 51 0 –5 56 5 –6 61 0 –6 66 5 –7 71 0 –7 76 5 –8 81 0 –8 86 5 –9 91 0 – 96 95 –1 00

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Kidney Donor Profile Index Discard Rate

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FIG. 34.2  The discard rate rises more rapidly with higher KDPI than graft failure and DGF rates. Prepared by the authors from Scientific Registry of Transplant Recipients data from 2010 to 2016. DGF, Delayed graft function; KDPI, kidney donor profile index.

donor transplantation exist, including the transplant candidate’s ability to identify a willing donor, ensuring donor health and proper selection, and uncompensated costs for the donor.51 Based on clear evidence of recipient benefit and surveys supporting positive public perceptions of living donation, a number of recent initiatives are underway to increase awareness of living donor transplantation and reduce disincentives, including a 2015 American Society of Transplantation Consensus Statement promoting living donor transplantation as the “best treatment option” for eligible patients with kidney failure.52 The pool of potential living donors has been expanded through the widespread access to laparoscopic donor nephrectomy and the development of KPD programs for patients with willing but biologically incompatible donors. Laparoscopic nephrectomy offers reduced surgical risk, pain, and cost. The laparoscopic approach also has enabled expansion of the living donor pool to older patients and has reduced the fear of donation.53 KPD programs apply algorithms to exchange kidneys among two or more pairs of incompatible donors and recipients so that all candidates receive compatible organs.54 Paired donation has been the fastest growing living donor transplant modality, and currently comprises approximately 10% of living donor transplants per year.1 Survey of potential donors supports strong willingness of potential donors to participate in KPD to facilitate transplant access for their intended recipient.55 However, it is widely believe that KPD is underused: It is estimated that if all centers used paired donation at the rate of high-performing centers, another 1000 transplants could be performed per year.56 Entry of compatible pairs into KPD has been suggested as an approach to increase the pool of potential matches.57 Entry of biologically compatible pairs in KPD systems may result in the compatible recipient receiving a better matched organ or organ from a younger donor. Best practices for the living

kidney donor selection are out of the scope of this chapter; however, a comprehensive review is found in the 2017 Kidney Disease Improving Global Outcomes (KDIGO) “Guideline on the Evaluation and Care of Living Kidney Donors.”58 

IMMUNOSUPPRESSION: TRENDS AND CURRENT PRACTICE Induction Immunosuppression The success of kidney transplantation is largely the result of the advances of immunosuppression including better induction therapy and maintenance regimens. The KDIGO guideline recommends induction therapy in all kidney transplant recipients (1A).59 This guideline also recommends interleukin-2 receptor antibody (IL2rAb) for first-line induction therapy (1B), while offering a class 2B recommendation for use of cell-depleting agents in patients considered high risk for acute rejection. A higher risk for rejection has been associated with African American heritage, significant allosensitization, history of prior transplantation, longer cold ischemic time, younger recipient age, and DGF. In addition, the choice of maintenance medications influences the need for induction therapy. In 2015, 91% of kidney transplant recipients received induction therapy. Use of IL2rAb fell from 35% in 2004% to 20% in 2015, whereas use of T-cell depleting agents (including thymoglobulin, alemtuzumab) continued to increase, from 39.5% in 2004 to 70% in 2015.1 The percentage of recipients receiving no induction therapy continued to decline from 22% in 2004 reaching a low of 9.1% in 2015 (Fig. 34.3).60 Choice of induction therapy should be determined based on patient and donor characteristics. For instance, black, highly sensitized, or recipients who experience DGF are, appropriately, more likely to be treated with cell-depleting agents (alemtuzumab, thymoglobulin) than IL2rAb (Fig. 34.4).60 Alemtuzumab is more commonly used with steroid-free

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SECTION IV  Transplantation 60% 50%

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FIG. 34.3  National trends in kidney transplant induction over time. IL2rAb, interleukin-2 receptor blocking antibodies. (Reproduced with permission from Dharnidharkaa VR, Naik AS, Axelrod DA, et al. Center practice drives variation in choice of U.S. kidney transplant induction therapy: a retrospective analysis of contemporary practice. Transpl Int. 2018;31:198-211.) 60%

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IL2rAb

High-Risk Recipients Low-Risk Recipients ALEM

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FIG. 34.4  National trends in kidney transplant induction by recipient immunological risk profile. ALEM, Alemtuzumab; IL2rAb, interleukin-2 receptor blocking antibodies; TMG, thymoglobulin. High risk was defined as black race, PRA >20, or retransplantation. (Reproduced with permission from Dharnidharkaa VR, Naik AS, Axelrod DA, et al. Center practice drives variation in choice of U.S. kidney transplant induction therapy: a retrospective analysis of contemporary practice. Transpl Int. 2018;31:198-211.)

maintenance regimens (tacrolimus and antimetabolite), whereas induction may not be used in patients on triple maintenance therapy.61,62 Although low-risk patients, such as 2 haplotype-matched white recipients, may be transplanted safely with no induction, the majority of patients seem to benefit from induction treatment.63 However, recent evidence suggests that center practice patterns, rather than patient and donor characteristics, dominate the decision about whether or not to use induction agents, and if so, which one.60 

Maintenance Immunosuppression Initially, maintenance immunosuppression was relatively standardized (cyclosporine, azathioprine, and corticosteroids) due to limited options available to transplant physicians. The nephrotoxicity of cyclosporine was recognized as a limiting factor in improving the long-term outcomes of kidney transplantation, as was the risk for skin cancer associated with azathioprine. The introduction of tacrolimus, mycophenolate, mammalian target of rapamycin inhibitors (mTORi: sirolimus and everolimus)

and belatacept has now given transplant providers a wider variety of choices and the potential for tailoring to optimize individual patient outcomes. However, in reality, the variation of regimens among transplant centers is largely driven by center practice and preference rather than patient demographic and transplant characteristics (Fig. 34.5).64 In national studies, despite similar patient and donor demographics, there is wide variation in selection of antirejection regimen. This variation emphasizes the need for more evidence-based practice, as well as collaborative clinical trials and secondary data analyses of contemporary practice to optimize posttransplant outcome.64 Here, we will review the trends of individual agent use and immunosuppression regimen preference among the transplant centers in the United States. Calcineurin inhibitors (CNIs) continue to form the cornerstone of maintenance immunosuppression medications despite the modest adoption of belatacept at some transplant centers. Among CNIs, tacrolimus has been the dominant medication and its use increased from 75% in 2004 to reach 97% in

CHAPTER 34  The Epidemiology, Outcomes, and Costs of Contemporary Kidney

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FIG. 34.5 Proportion of US patients receiving one of six mutually exclusive immunosuppression regimens during months 6 to 12 posttransplant. Each horizontal bar represents an individual center within US regions ordered by the proportion of patients who received triple immunosuppression (Tac + MPA/AZA + Pred). Overall percentage of regimen use at patient-level across centers: Tac + MPA/ AZA + Pred, 33.8%; Tac + MPA/AZA (No Pred), 25.8%; Tac without MPA/AZA, 11.3%; SRL-based, 9.9%; CSA-based, 7.8%; and other regimens, 11.6%. AZA, Azathioprine; CSA, cyclosporine; MPA, mycophenolate; Pred, prednisone; SRL, sirolimus; Tac, tacrolimus. (Reproduced with permission from Axelrod D, Naik AS, Schnitzler MA, et al. National variation in use of immunosuppression for kidney transplantation: a call for evidence-based regimen selection. Am J Transplant. 2016;16:2453-2462.)

2015.1 Tacrolimus has two new extended-release formulations to allow once-per-day dosing.65 However, the immediate-release formulation remains the most commonly used, possibly because it is available as a generic option. Mycophenolate has been established as the antimetabolite medication of choice, with one of two formulations (mycophenolate mofetil, mycophenolate sodium) comprising more than 95% of antimetabolite use. Less than 5% of recipients are prescribed azathioprine in current practice.1 Although the mycophenolate formulations are believed to differ in side-effect profile, clinical outcomes have not been shown to differ significantly.66 Modern renal transplant immunosuppression is generally based on a combination of two or more agents. One-third of

kidney transplant recipients transplanted from 2004 to 2010 received triple immunosuppression composed of tacrolimus, an antimetabolite, and corticosteroids.64 The second most commonly prescribed regimen in this period was tacrolimus and antimetabolite (steroid avoidance) in 26% of the recipients, followed by tacrolimus alone or tacrolimus plus prednisone (antimetabolite sparing) in 11.3%, mTORi-based (with or without CNI) in 9.9%, and cyclosporine-based in 7.8%. Although the use of these regimens varies significantly among transplant centers, the use of triple-therapy immunosuppression is more likely among patients with higher immunological risk such as highly sensitized patients, retransplant recipients, and those with a history of glomerulonephritis.64 The use of

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SECTION IV  Transplantation

mTORi-based regimens is more likely in patients with lower GFR at 6 months posttransplant. Overall, mTORi use in kidney transplant recipients declined from approximately 15% in 2004% to 5% in 2015.1 This decline is mainly driven by recognition of associations with increased risk for poor wound healing, acute rejection, and proteinuria without realization of substantial benefits in long-term allograft survival.67 Despite the wide variety of choices of immunosuppression medications, long-term graft survival remains limited by chronic transplant glomerulopathy, interstitial fibrosis/ tubular atrophy, inflammation, and subclinical cellular and antibody medicated rejection.68,69 Complications of immunosuppression, including infection and malignancy as discussed here, pose challenges for long-term patient survival. Further advances in medications and new strategies for posttransplant monitoring, being explored in the evolving field of biomarkers,70 are needed to improve the long-term outcomes after kidney transplantation. 

COMPLICATIONS OF KIDNEY TRANSPLANTATION The increased potency of contemporary immunosuppression has yielded substantial reductions in acute rejection rates. In the early 1980s, 50% to 60% of renal allograft recipients experienced at least one acute rejection episode compared with less than 15% today.71,72 In the ELITE-Symphony study, which simultaneously compared low- or high-dose cyclosporine-based to tacrolimus-based or sirolimus-based regimens, the acute rejection rates and graft failure rates were much higher in the nontacrolimus-based arms, contributing to widespread adoption of tacrolimus-based regimens.73 However, the benefits of preventing acute rejection are balanced by the risks for overimmunosuppression, including infection and malignancy.74,75 In this section, we review the epidemiology and effects of clinical complications such as infections, malignancy, and new-onset diabetes after transplant (NODAT). Urinary tract infections (UTIs), pneumonia, and sepsis occur in 10% to 30% of recipients in the first year after a kidney transplant.74,76,77 Analysis of infection diagnoses among Medicare-insured US kidney transplant recipients in 2000 to 2011 demonstrated an association with increased mortality in the first-year after transplant, ranging from 41% (aHR, 1.41; 95% CI, 1.25 to 1.56) for UTI alone, 6-fold risk for pneumonia, 12-fold risk for sepsis, and 34-fold risk (aHR, 34.38;, 95% CI, 30.35 to 38.95) for those with all three infections in the first year.78 Infections also significantly increase the first-year cost of kidney transplant care by $17,691 UTI alone, $40,000 to $50,000 for pneumonia or sepsis alone, and $134,773 for those with UTI, pneumonia. and sepsis in this period. Clinical and economic effects persist in years 2 to 3 posttransplant.78 Viral-derived malignancies, such as lymphoma, Kaposi sarcoma, lip cancer, and genitourinary tract cancer, are substantially more common in transplant patients than age-adjusted estimates in the general population or patients with chronic kidney disease and ESRD.79,80 Cancer has become second only to cardiovascular disease (CVD) as the leading

cause of posttransplant mortality, surpassing death from infection.81 Furthermore, although the risk for death from CVD appears to be stable or even decreasing despite higher comorbidity burdens among transplant recipients, cancer mortality after kidney transplant appears to be increasing over time.82,83 In addition to viral-linked cancers, there is an increased frequency of nonmelanoma skin cancers and certain solid organ tumors (including kidney, prostate, and colon carcinoma) compared with nontransplant populations.84,85 In a recent study of Medicare-insured US transplant recipients, the cumulative incidence of cancer diagnosed by 3 years posttransplant was 5.7% for nonmelanoma skin cancers, 1.9% for viral-linked, and 6.3% for almost all other cancers.86 Viral-linked cancer was associated with more than threefold increased risk in subsequent mortality within 3 years after transplant, and nearly twice the mortality risk after year 3. Nonmelanoma skin cancer was associated with 33% higher mortality beyond the third year posttransplant. Cancer also significantly increases the costs of posttransplant care. Newly diagnosed viral-linked cancer was associated with incremental costs, after adjustment for other recipient and donor characteristics. A diagnosis of a virallinked cancer resulted in $22,000 to $27,000 per year higher inpatient costs and $9000 to $11,000 per year higher outpatient costs per case.86 A newly diagnosed “other” cancer was associated with $14,500 to $18,000 per year higher inpatient expenses and $8000 to $9000 per year higher outpatient costs. Nonmelanoma skin cancers was associated only with increased outpatient expenditures, and the cost impact rose from approximately $1400 to $2000 per year in the year of diagnosis to $2500 to $2800 per year in subsequent years.86 Overall, cancer accounted for 3% to 5.5% of total inpatient Medicare expenditures and 1.5% to 3.3% of outpatient expenditures in the first 3 years posttransplant (Fig. 34.6). The risk for NODAT has been increasing with the incidence of obesity and racial minorities in the recipient population. The risk is highest in the first year after transplant, ranging from 15% to 30%.87-89 Subsequent annual incidence is approximately 5% per year. Risk factors for NODAT include potentially modifiable (e.g., BMI) as well as nonmodifiable factors (e.g., race/ ethnicity).90-92 NODAT has been associated with adverse outcomes after transplantation, including graft failure and death, as well as rejection, infection, and cardiovascular complications including myocardial infarction (MI) and congestive heart failure.75,93,94 NODAT also increases the cost of posttransplant care.95 The risk for developing NODAT is associated with African American race, Hispanic ethnicity, obesity, HCV infection, and pretransplant glucose intolerance. Multiple immunosuppressive agents have been implicated, but risk is highest with steroids and tacrolimus, particularly in African Americans. A population-based analysis of US kidney transplant recipients (2000 to 2011) demonstrated variation in the risk for posttransplant complications over 3 years according to initial immunosuppression regimen (Fig. 34.7).67 Compared with a regimen of thymoglobulin induction and maintenance tacrolimus, mycophenolate and prednisone, sirolimus-based immunosuppression was associated with increases

547

CHAPTER 34  The Epidemiology, Outcomes, and Costs of Contemporary Kidney

$25,000

$25,000

Inpatient

Outpatient

NMSC

Viral-driven

Other

$0

NMSC

$0

Other

$5,000

Viral-driven

$5,000

Inpatient

Other

$10,000

Viral-driven

$10,000

$15,000

NMSC

$15,000

$20,000

Other

$20,000

Second-Year Posttransplant Costs

Viral-driven

Marginal Cost Impact

$30,000

NMSC

Marginal Cost Impact

First-Year Posttransplant Costs $30,000

Outpatient

Third-Year Posttransplant Costs $30,000

Marginal Cost Impact

$25,000

NMSC, prevalent $20,000

NMSC, new in period $15,000

Viral-driven, prevalent

$10,000

Viral-driven, new in period

$5,000

Inpatient

Other

Viral-driven

NMSC

Other

Viral-driven

NMSC

$0

Other cancer, prevalent Other cancer, new in period

Outpatient

FIG. 34.6  Cost effects of posttransplant cancer. NMSC, nonmelanoma skin cancer. (Reproduced with permission from Dharnidharka VR, Naik AS, Axelrod D, et al. Clinical and economic consequences of early cancer after kidney transplantation in contemporary practice. Transplantation. 2017;101:858-866.)

in the 3-year risks for pneumonia (aHR, 1.45), sepsis (aHR, 1.40), diabetes (aHR, 1.20), acute rejection (aHR, 1.33), graft failure (aHR, 1.78), and patient death (aHR, 1.40), but 29% lower risk for skin cancer.67 Cyclosporine-based immunosuppression was associated with increased risks for pneumonia (aHR, 1.17), sepsis (aHR, 1.16), acute rejection (aHR, 1.43), and graft failure (aHR, 1.39), but 17% less risk for diabetes. Steroid-free immunosuppression was associated with the 11% reduced risk for pneumonia, 20% reduced risk for sepsis, and 33% reduced risk for diabetes, but 35% higher risk for graft failure.67 Azathioprine has been associated with nonmelanoma skin cancer.79 A recent case–control study of kidney and heart transplant recipients reported that azathioprine, but not mycophenolate, was associated with increased risk for nonmelanoma skin cancer, and that the association was independent of CNI choice.96

In summary, the choice of immunosuppression medication has an effect on the risk for posttransplant complications, cost, and graft survival. Further study is warranted to better guide the choice of immunosuppression and tailor efficacy and morbidity to the characteristics of the patient and the donor organ. 

POSTTRANSPLANT OUTCOMES Solid organ transplantation is unique among medical specialties in the universal collection of clinical data. Through the mechanism of the OPTN as mandated by the National Organ Transplant Act (NOTA), transplant centers have been required to submit baseline and follow-up clinical data describing all patients listed for and receiving solid organ transplants in the United States since 1986.97 Posttransplant follow-up information is collected at 6 months after transplant, at the

548

SECTION IV  Transplantation

Pneumonia

*

Sepsis

‡

‡

‡

*

‡

‡ ‡ †‡ *

Pyelonephritis/UTI

* †

Skin cancer

‡

Other cancer

Viral-driven cancer

NODAT

*

†

Acute rejection

†*

‡

‡

‡ ‡

‡

Death-censored graft failure ‡

Patient death ‡

0%

10%

20%

Tac+MPA/AZA+Pred+TMG (Ref) Tac+MPA/AZA+Pred+No Induction Tac alone, Tac+Pred SRL-based

30%

40%

50%

60%

Tac+MPA/AZA+Pred+IL2 Tac+MPA/AZA+No Pred CSA-based

FIG. 34.7  Incidence of clinical events at 3 years posttransplant according to early immunosuppression. AZA, Azathioprine; CSA, cyclosporine; MPA, mycophenolate; NODAT, new-onset diabetes after transplant; Pred, prednisone; SRL, sirolimus; Tac, tacrolimus; UTI, urinary tract infection. (Reproduced with permission from Dharnidharka VR, Schnitzler MA, Chen J, et al. Differential risks for adverse outcomes 2 years after kidney transplantation based on initial immunosuppression regimen: a national study. Transpl Int. 2016;20:1226-1236.) *P < 0.05–0.002 †P = 0.001–0.0002 ‡P < 0.0001

first transplant anniversary and then annually. The Scientific Registry of Transplant Recipients (SRTR) augments OPTN data with national death and dialysis records. Major events that are applicable for outcomes studies include acute rejection, graft failure (defined by return to dialysis, retransplantation, or patient death), death-censored graft survival (defined by return to dialysis or retransplantation), and patient death.

Acute Rejection There are two types of acute rejection: T-cell mediated and antibody-mediated. Both types of rejection can occur early or late, individually, simultaneously, or sequentially. The incidence of acute rejection within the first year decreased for both living and deceased donor transplant recipients from 10% in 2009 to

2010 to 7.9% in 2013 to 2014. However, in a greater proportion of acute rejection episodes, renal function did not return to baseline after treatment, which was associated with an incremental increase in the relative hazard for graft survival.98,99 Acute rejection events recognized later after transplant have more serious graft loss implications, especially within the first 90 days after an acute rejection event.72 Even when successful, treatment of rejection is expensive. Examination of Medicare-insured US kidney transplant recipients in 2000 to 2007 found that antibody-treated (year 1: $22,407, year 2: $18,803, year 3: $13,909) and nonantibody-treated (year 1: $14,122, year 2: $7852, year 3: $8234) acute rejection events were associated with significant increases in the cost of care.48 These costs do not include the cost of return to dialysis for patients whose transplant never recovered. 

CHAPTER 34  The Epidemiology, Outcomes, and Costs of Contemporary Kidney

Graft Survival Graft loss within the first 12 months after transplant are primarily due to technical failures (very early), surgical compilations, primary nonfunction, severe rejection, or severe recurrent glomerulonephritis (such as recurrent focal segmental glomerulosclerosis). Beyond the first-year posttransplant, the main causes of graft loss are patient death and chronic allograft nephrology. Historically, improvements of long-term graft survival have not paralleled the robust improvements in short-term outcomes. However, the SRTR annual report issued in 2017 found that average longer-term graft and patient survival appears to be improving.1 Overall, 1-year deceased donor graft survival improved from 90% in 2005 to 94% in 2015, and 10-year graft survival improved from 41% in 2005 to 47% in 2015.1 Five-year graft survival for recipients of DCD organs was identical to recipients of organs from brain dead donors at 75%. One-year graft survival of living donor transplant recipients increased from 95% in 2005 to 98% in 2015, whereas 10-year graft survival improved from 55% in 1995 to 63% in 2005. Interestingly, the results for first deceased donor transplants were largely static, suggesting that these improvements in long-term outcomes were due to better outcomes among retransplant recipients.100 

Patient Survival In the first 3 months after kidney transplant, there is an increased risk for mortality compared with waiting on dialysis, reflecting the risk of undergoing surgery and starting immunosuppression. Beyond this period, the relative risk for death is lower in transplant recipients than in candidates on the waitlist, although the benefit varies by patient and donor factors.2 By 4 years, kidney transplant recipients have an average 70% reduction in mortality. One-year patient survival after deceased donor kidney transplantation has exceeded 95% in the past two decades and reached 97% in 2015.1 For living donor kidney transplant recipients, 1-year patient survival is now 99%. The most common causes of death with a functioning transplant are CVD, infection, and malignancy. 

CENTER PERFORMANCE GRADING The availability of national, comprehensive data on transplant outcomes has facilitated public reporting of transplant center-specific data. As required under NOTA, the SRTR produces program-specific reports describing outcomes at each transplant program. These data include detailed analyses of waitlist activity, transplant rates, graft survival, and patient survival. Because transplant recipient and donor characteristics vary substantially between centers, the SRTR has developed a complex risk adjustment methodology to attempt to account for differences in case mix. This methodology is used to calculate the center’s observed-to-expected (O/E) event ratios in comparison to other transplant programs. The current risk adjustment equation for kidney recipient outcomes uses 33 variables and 125 different coefficients (for different variable ranges, known as spline terms). In addition to public reporting, these data are provided to two regulatory bodies, the OPTN/UNOS Membership and Professional Standards Committee (MPSC) and the Centers for Medicare

549

BOX 34.1  OPTN/UNOS Membership and

Professional Standards Flagging Criteria

For large programs (≥10 transplants in a 2.5-year period), the MPSC will review a transplant program if it has a higher hazard ratio (HR) of mortality or graft failure than expected for that transplant program. The criteria used to identify programs with a hazard ratio that is higher than expected include either of the following: 1. The probability is >75% that the HR is >1.2. 2. The probability is >10% that the HR is >2.5. For small programs (<10 transplants in a 2.5-year period), the MPSC will review a transplant program if the program has one or more events.68 MPSC, Membership and Professional Standards; OPTN/UNOS, Organ Procurement and Transplantation Network/United Network for Organ Sharing.

BOX 34.2  Centers for Medicare &

Medicaid Services Performance Criteria 1) Observed/Expected >1.85 2) Observed/Expected >3 3) The probability that an observed excess (rather than difference) of observed events compared with expected events is likely due to random chance with a one-sided P < 0.05.

& Medicaid Services (CMS). The MPSC oversees the compliance of the transplant programs with federal regulations and OPTN policies. The MPSC uses the SRTR program-specific reports to identify programs that do not meet performance standards and should be considered for further review, probation, or, if egregious, be declared as a “Member Not in Good Standing,” which results in exclusion from deceased donor allocation.101,102 The MPSC uses a set of established criteria to “flag” programs for performance (Box 34.1).

Centers for Medicare & Medicaid Services The CMS oversees transplant programs that receive Medicare reimbursement, which includes most of the kidney transplant centers in the United States. In 2007 the CMS began periodic reviews of all Medicare-approved transplant programs.103 The SRTR provides analyses to CMS with separate models that use frequentist (rather than Bayesian) methods. Centers that meet all three of the following criteria (Box 34.2), in two out of five semiannual reports, are considered to be in violation of CMS’s conditions of participation (CoP). These centers are at risk for removal from the Medicare program and, most likely, being closed. 

Effect of Performance Monitoring The current posttransplant outcome review process creates disincentives for programs to transplant higher-risk recipients or nonstandard organs, due to concern that early graft failures or patient deaths will cause the program to be reviewed. Schold et al. examined center behavior after a poor performance evaluation, and found a striking increase in the frequency of waitlist removals, a reduction in total size of the waiting list, and reduced numbers of transplants.104 These

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SECTION IV  Transplantation

practices were associated with reduced access to transplant. In other words, more conservative patient and organ selection is a common response to poor prior performance, which may, or may not, be justified by critical review of the program’s data. A recent analysis prepared by the SRTR demonstrated that the use of higher-risk organs was not associated with a higher risk for regulatory citation by the MPSC.105 However, this analysis did not consider other outcomes of high-risk transplants, including the effects of public reporting of less-than-expected outcomes on private payer Center of Excellence network membership. To address these issues, the UNOS Board of Directors approved a new policy directing the MPSC to only review programs with poor outcomes for all kidney transplants performed if they remained a poor performing center after excluding “higher-risk” transplants, wherein a higher-risk transplant is defined by recipient EPTS score >80, or donor KDPI >85. In other words, the MPSC will not review kidney programs for outcomes if the only reason they did not meet the expected threshold for performance was the outcomes of higher-risk transplants. This proposal is designed to further protect centers that chose to use higher-risk organs in patients most likely to benefit compared with dialysis. Further study is needed to determine whether the perception of using higher-risk kidneys remains after starting these review criteria. It is important to recognize that without corresponding changes in CMS review criteria, the potential consequences of worse-than-expected performance remain severe as centers may still find themselves out of compliance with the CoP. CMS has indicated a willingness to consider the use of high-risk organs as a potential mitigating factor, which will result in the program escaping citation for less-thanexpected outcomes; however, this has not been tested. 

UNMEASURED AND NOVEL RISK FACTORS The pool of potential risk adjustment factors in the SRTR graft and patient survival models is constrained by data collected in the OPTN/UNOS registry. These data elements include only limited measures of comorbid conditions and no measures of medical or pharmaceutical care. An evolving body of literature suggests that supplementing the national transplant registry with additional data elements, such as pharmaceutical and medical billing claims, may provide novels measures of posttransplant risk. Symptomatic hypotension is a common complication in patients with ESRD, especially among those with prolonged dialysis dependence, which is not currently captured using UNOS data.106,107 Symptomatic hypotension has been estimated to complicate approximately 25% of hemodialysis treatments and may result in dialysis session interruptions and prevent delivery of adequate clearance and fluid removal.108 When standard interventions (such as dialysate sodium modeling, low-temperature fialysate) fail to prevent intradialytic hypotension, pharmacological treatment with midodrine may be used.109 Midodrine was recently examined as a marker for symptomatic hypotension before kidney transplant and was shown to be associated with graft failure and posttransplant death. Based on integrated national transplant registry data,

outpatient pharmacy fill records from a pharmaceutical claims clearinghouse, and Medicare billing claims, patients who filled midodrine before transplant were found to have twice the risk of developing DGF and 3.5 times the risk for death at 3 months posttransplant than nonusers.110 Similar patterns of graft failure and death occurred at 12 months posttransplantation. Pretransplant midodrine exposure also was associated with other medical complications after transplant including hypotension, acute MI, ventricular arrhythmia, and cardiac arrest. The effects of midodrine use before transplant was augmented in the recipients of nonstandard organs (ECD, DCD, and high KDPI >85%) compared with standard-criteria donor allografts.110 CVD remains poorly characterized in the UNOS data despite the high prevalence of significant disease in kidney transplant candidates. The OPTN/UNOS registry collects only limited measures of baseline CVD and no measures of posttransplant CVD, which significantly affects posttransplant survival. The incidence of death-censored graft failure after a posttransplant MI is 8.7% at 1 year and 12.9% at 2 years after infarction, whereas all-cause graft loss after posttransplant MI is 30.7% at 1 year and 38.8% at 2 years.75 Clopidogrel is a medication indicated for MI, stroke, or refractory ischemia in patients with non-ST-segment elevation acute coronary syndrome as well as unstable angina, including those who are managed medically and those with coronary revascularization. According to the drug monograph, it is also indicated to reduce the rate of death from any of the above causes and reduce the rate of combined endpoints of death, reinfarction, or stroke in patients with ST-elevation MI, as well as to reduce the rate of combined endpoint of new ischemic stroke or MI, and other vascular deaths in patients with history of recent MI or stroke, or established peripheral vascular disease.111 A recent study of integrated national registry and pharmacy fill data found that clopidogrel use within 90 days of transplant was associated with a 61% increased risk for mortality and 23% increased risk for graft failure.113 Risks were higher with clopidogrel use >90 days before transplantation (111% for death, 59% for graft loss). The use of prescription opioids is emerging as another novel risk factor in transplant patients. Although opioid analgesics serve an important role in management of both acute and chronic pain, patients with chronic kidney disease are prone to more complications related to the misuse, abuse, and inherent potential toxicity of prescription opioids due to altered drug protein binding, metabolism, and excretion, leading to accumulation of parent agents and potentially toxic metabolites.114,115 Recent studies based on integration of US transplant registry with pharmacy fill records showed that 29% of the kidney transplant recipients filled an opioid prescription in the year before transplant. The highest quartile of opioid use before kidney transplantation was associated with increased posttransplant death (aHR, 2.3; 95% CI, 1.7 to 3.1) and graft loss (aHR, 1.7; 95% CI, 1.4 to 2.3).116 Pretransplant opioid use was associated with posttransplant ventricular arrhythmias, hypotension, hypercapnia, mental status changes, drug abuse and dependence, alcohol abuse, accidents, and noncompliance (Fig. 34.8).117 From the perspective of performance grading, the effects of unmeasured risk factors such as symptomatic hypotension,

CHAPTER 34  The Epidemiology, Outcomes, and Costs of Contemporary Kidney

551

Adjusted Hazard Ratio (aHR)

8.0 5.0 4.0

Level 1 Level 2

3.0

Level 3 Level 4

2.0 1.0 0.0

Ventricular Arrhythmias

Cardiac Arrest

Hypotension

Hypercapnia

Aspiration Pneumonia

Adjusted Hazard Ratio (aHR)

8.0 5.0 4.0

Level 1 Level 2

3.0

Level 3 Level 4

2.0 1.0 0.0

Mental Status Changes

Illicit Drug Abuse

Alcohol Abuse

Accidents

Noncompliance

FIG. 34.8  Associations of pretransplant opioid use with posttransplant complications, adjusted for recipient, donor, and transplant factors. (Reproduced with permission from Lentine KL, Lam NN, Xiao H, et al. Associations of pre-transplant prescription narcotic abuse with clinical complications after kidney transplantation. Am J Nephrol. 2015;41:165-176.)

CVDS, and opioid use suggest that current risk adjustment methods inadequately characterize risk for transplantation in high-risk patients. Importantly, the SRTR models also do not adjust for risk for innovative practices such as ABO blood type and crossmatch-incompatible transplantation, which increase the odds of posttransplant graft loss, but provide the only meaningful opportunity for transplant for many patients. Although any changes to the OPTN/UNOS data collection is a slow process due to the need to balance considerations of center-reporting burdens and governmental oversight of changes to the registry, supplementation of the registry through data linkages should be considered. Candidates with unmeasured risk factors warrant careful pretransplant evaluation, implementation of strategies to optimize clinical status and mitigate risks (e.g., cessation of opiate use), and focused monitoring of clinical status after transplant to limit the risks for death and graft loss. 

ECONOMICS OF KIDNEY TRANSPLANTATION The many innovations in transplant science have not been matched with parallel developments in the financing of care for patients with ESRD. In this section, we review the history

of ESRD care financing, the economic implications of evolving recipient and donor populations, and the economic challenges to practice innovation. In the early 1960s, neither kidney transplantation nor dialysis was covered by insurance. The costs of both treatments were far in excess of what patients could afford. Therefore access to renal replacement therapy (RRT) was limited to those with private resources and many patients died without treatment.119 In response, nephrologist Carl Gottschalk was asked to evaluate methods to expand access to dialysis care. The Gottschalk Committee recommended that the federal government subsidize dialysis using the recently created Medicare program as the payment mechanism.120 When first enacted by Congress in 1972, only 10,000 Americans were on dialysis, with an annual cost of roughly $280 million.120 By the end of 2014, the number of Americans living with ESRD exceeded 675,000.121 Nearly 472,000 of the 675,000 Americans currently receiving RRT are on dialysis (hemodialysis or peritoneal dialysis), at an annual cost of nearly $40 billion.58 Medicare payments for ESRD exceed $30 billion annually, accounting for 7.1% of annual Medicare costs, despite the fact that ESRD affects about 1% of Medicare beneficiaries.58,122,123 Medicare

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SECTION IV  Transplantation

coverage for chronic kidney disease begins when patients initiate RRT. For patients with existing private health coverage, Medicare remains a secondary payer for the first 30 months of dialysis treatment. After 30 months, Medicare becomes the primary insurer. A small number of patients are covered only by state Medicaid programs despite being on dialysis, if they have not had accrued a sufficient number of working years to quality for Medicare, are not US citizens, or are children. As early as 1967, Gottschalk’s committee concluded that kidney transplantation was preferable to dialysis, based on both its clinical effectiveness and reduced cost.119 The average payment for a transplant and subsequent care over the first year after transplant was $158,138 for private payers and $99,826 for Medicare.124 However, in the years following transplant, patients with functioning transplants incur an average annual healthcare spending of only $17,798 and $17,145 for private and Medicare patients, respectively. This compares favorably to annual spending for dialysis and associated care, which exceeds $87,500 per patient per year. In addition, successful transplantation may allow patients to return to work and reduce the rates of rehospitalization and disease progression. Therefore kidney transplant reduces the lifetime cost of ESRD care for payers and society. 

ECONOMIC IMPLICATIONS OF RECIPIENT CHARACTERISTICS Recipient age, comorbidities including obesity, and allosensitization are important factors that affect the clinical and economic benefits of kidney transplant. As noted previously, older patients have been shown to benefit from transplant over dialysis. However, older and frail patients have a greater incidence of complications, prolonged hospital stays, and readmissions with any renal replacement modality, all of which contribute to decreased economic savings in the setting of kidney transplant. Frail patients have 61% higher risk for early hospital readmission posttransplant, as well as a 1.94-fold increased risk for DGF.125,126 These complications result in higher costs. Patients over the age of 60 years increase the average cost of the transplant episode by $4643 and care during the first year by $18,481.127 EPTS scores predict economic as well as clinical outcomes. A recent analysis of cost-accounting data among academic transplant centers captured in the University HealthSystem Consortium found that recipient EPTS was strongly associated with costs incurred during the transplant episode after multivariate adjustment.128 Compared with patients with EPTS <20, EPTS resulted in significant, graded increases in incremental costs (20 to 50: $1095; 50 to 85 $2292; >85: $5257; P < 0.005 for all). Higher cPRA levels also bore strong, graded associations with higher transplant costs, such that cPRA 98 to 100 was associated with $9097 higher incremental expenditure (P < 0.0001). Recipient characteristics associated with lower per-transplant costs included polycystic kidney disease, female gender, and working at the time of transplant. Although obese patients can benefit from transplantation over dialysis, obesity is associated with increased risk

for complications and resource utilization during the early and later posttransplant periods. Examination of data for 767 privately insured transplant recipients in 2000 to 2007 found that mean length of stay increased 8.4 days among normal weight to 13.3 days among extremely morbidly obese patients.129 Another single-center series reported that surgical site infections after kidney transplantation increased from 8.5% of patients with a BMI 20 to 25 kg/m2 to over 40% in patients with a BMI >40 kg/m2.130 Development of a surgical site infection resulted in a $24,454 increase in cost and a $4278 decrease in hospital margin after transplant. Multiple studies have identified association of obesity with increased risk for DGF and the need for dialysis, including a study of registry data for 11,836 recipients reporting graded associations of BMI >25 kg/m2 with progressively higher DGF risk, such that those with pretransplant BMI >40 kg/m2 had nearly three times the odds of DGF (adjusted odds ratio [aOR], 2.78; 95% CI, 1.88 to 4.12) after extensive multivariate adjustment, markedly increasing the cost of transplantation.131 

ECONOMIC IMPLICATIONS OF DONOR CHARACTERISTICS Although appropriate use of nonstandard kidneys could reduce waiting time and decrease the death rates for patients with high likelihood of waitlist mortality, such as elderly patients, those with diabetes, and those with long expected waiting times for transplantation, many patients who could benefit from listing for nonstandard organs are not listed for consideration of such offers.132 One barrier to the use of nonstandard kidneys is the significant cost of posttransplant complications, including the need for dialysis, readmission, and decreased allograft survival resulting in an earlier return to dialysis, which do not result in higher payments as the Medicare Diagnosis Related Group (DRG) payment for kidney transplant is not adjusted for complexity.133 From the transplant center’s perspective, these organs result in marked increases in costs without adequate compensation. Analysis of national cost accounting data, demonstrates that older donor age ($62 per year, P < 0.0001), death from anoxic injury, higher terminal creatinine ($956 per mg/dL increase, P < 0.0001), and DCD ($6182, P < 0.0001) were independently associated with higher costs.127 However, transplants using kidneys placed on a pulsatile perfusion pump are $2039 less expensive in recent practice (P < 0.0001).128 Living donor kidney transplantation is associated with substantial savings to the healthcare system through provision of the improved long-term recipient survival and reduced early complication rates.134 Current estimates based on Medicare spending indicate that each living donor transplant performed for a Medicare recipient saves at least $94,579 and adds 3.5 quality-adjusted life years (QALYs) compared with deceased donor transplantation. Considering improved quality of life and functioning, the total economic benefits of living donor transplant have been estimated at $250,000 to $1.3 million per recipient.134-136 Because living donors themselves incur many types of direct and indirect costs in the donation

CHAPTER 34  The Epidemiology, Outcomes, and Costs of Contemporary Kidney process, including for travel, medications, lost income, and dependent care,137 removing financial disincentives to donation for all donors is an important priority.138 Although some endorse trials of financial incentives as the most potentially impactful approach to increase living donation,136,139,140 testing of incentives in the United States would require amendment of NOTA, which prohibits organ exchange for “valuable consideration.”141 Importantly, NOTA does not prohibit “reasonable payments associated with the expenses of travel, housing, and lost wages incurred by the donor,” and a new trial assessing the impact of reimbursement of lost wages, supported by the National Living Donor Assistance Act, was announced in December 2016.71 

ECONOMIC IMPLICATIONS OF THE CURRENT KIDNEY ALLOCATION SYSTEM The use of the KDPI and EPTS to explicitly direct young donor organs into healthier recipients with improved longterm survival incorporated into the new KAS has important clinical and economic implications.142,143 Under previous allocation policy, average lifetime costs and benefits per transplanted patient, discounted to 2012 US dollars, was estimated at $342,799 and 5.42 QALY, yielding US $63,775 in costs per QALY gained. The KAS system is expected to reduce lifetime costs by $2090 and increase lifetime QALYs by 0.03, further reducing this cost per QALY.37 Because graft survival is improved in candidates in the top 20% of life expectancy (EPTS <20%) compared with those in the bottom 80%, and rates of return to dialysis are lower, simulations of KAS predict a 7% increase in average median patient life-years per transplant and a 2.8% increase in average median allograft survival.144 The value of avoiding additional ESRD care of the current policy is expected to be $271 million during the first year and $55 million during each subsequent year.37 These savings are expected to accrue primarily to Medicare, which would have covered patients with long waiting times, because under the new policy candidates with EPTS <20% are more likely to undergo transplant with a better organ and to have a lower incidence of graft failure requiring retransplantation. There is expected to be a small or modest increase in total private payer ESRD costs. The current KAS was based on historical organ acceptance and decline patterns, and future organ behavior will be an important factor in the ultimate long-term benefits of the revised KAS. 

ECONOMIC IMPLICATIONS OF PRACTICE INNOVATION: ABO- AND HLA-INCOMPATIBLE KIDNEY TRANSPLANTATION Recently large registry analyses in Japan, Europe, and the United States demonstrated that long-term outcomes following ABO incompatible (ABOi) kidney transplant are similar to outcomes of ABO compatible transplantation at 10 years, although the incidence of some early complications is higher.145 Among the perceived barriers to the expanded use of ABOi transplantation is the cost of the treatment protocols.

553

A 2011 US registry analysis identified 738 patients who had undergone living donor ABOi transplants from 1995 to 2010, representing only 1.5% of all US living donor transplant procedures.146 The average overall cost of the transplant episode, excluding organ acquisition, was significantly higher for ABOi transplantation ($65,080 vs. $32,039; P < 0.001).147 In addition, ABOi transplantation was independently associated with incrementally higher posttransplant spending (year 1: $25,044; year 2: $10,496; year 3: $7307; P < 0.01) (Fig. 34.9). The use of KPD programs is more cost-effective than ABOi; however, for cases for whom a compatible exchange cannot be found, ABOi is less expensive than long-term dialysis. As already discussed, access to kidney transplantation remains severely limited in highly sensitized patients, such that currently, sensitized recipients (PRA >80%) comprise >14% of the active deceased donor waiting list.7 Incompatible living donor kidney transplantation (ILDKT) is enabled by desensitization procedures using transplant plasmapheresis and intravenous immunoglobulin, with/without rituximab (anti-CD20) administration.148,149 After transplant, these patients frequently require additional plasmapheresis treatments and potentially expensive adjunctive therapies. Despite higher rates of graft loss than compatible living donor transplants, multicenter clinical registry studies have confirmed an overall survival advantage of ILDKT recipients compared with matched waitlist controls: 80.6% at 8 years for ILDKT compared with 30.5% at 8 years for those remaining on the waiting list.148 A recent study of a national cohort of ILDKT recipients with linked hospital cost accounting data from the University HealthSystem Consortium and Medicare claims highlight the increased costs of ILDKT.150 Overall, ILKDT was associated with an increase in the hospital cost to perform the transplant ($151,024 vs. $106,636) compared with matched compatible transplant controls.150 The differential in cost between ILDKT and compatible transplantation increased with donor-specific antibody titer levels. The cost was 20% higher in patients with low titer (Luminex assay positive but negative-flow cytometric crossmatch), 26% higher for moderate titer (positive-flow cytometric crossmatch but negative cytotoxic crossmatch), and 39% higher for high titer (positive cytotoxic crossmatch) ILDKT compared with costs for compatible transplants. Although Medicare payment was incrementally higher for these transplants, the additional payment did not compensate for the additional cost of care in most cases. 

CONCLUSIONS Kidney transplantation, especially from a living donor, remains the best treatment for kidney failure and improves the quality and quantity of life over dialysis at the lowest costs to the healthcare system. As disparities in the demand for and the available supply of donated organs continue to grow, there is a need for increased attention to resolving disparities in transplant access based on factors such as socioeconomic status and place of residence. This growth in the waiting list has been associated with greater complexity of the

554

SECTION IV  Transplantation Transplant Costs

$80,000

$80,000

$70,000

$70,000

$60,000

$60,000

$50,000

$50,000

$40,000

$40,000

$30,000

$30,000

$20,000

$20,000

$10,000

$10,000 $0

$0 ABOc

A

A2i

ABOi

ABOc

B

A2i

ABOi

Third-Year Costs

Second-Year Costs

$80,000

$80,000

$70,000

$70,000

$60,000

$60,000

$50,000

$50,000

$40,000

$40,000

$30,000

$30,000

$20,000

$20,000

$10,000

$10,000

$0

C

First-Year Costs

$0 ABOc

A2i

ABOi

D

ABOc

A2i

ABOi

FIG. 34.9  Average adjusted costs according to donor-recipient blood type compatibility during the transplant events and posttransplant periods. (Reproduced with permission from Axelrod D, Segev DL, Xiao H, et al. Economic impacts of ABO-incompatible live donor kidney transplantation: a national study of Medicare-insured recipients. Am J Transplant. 2016;16:1465-1473.)

population in need of transplant and pressure to increase use of nonstandard organs, which in turn increase the risks and costs of transplantation. Increased regulatory oversight and performance grading is intended to optimize use of scarce organs, but can lead to unintended consequences of risk aversion, higher discard rates, and decreased access for higher risk patients. Attention to uncaptured risk in performance grading is needed to sustain innovation in transplant practice without penalizing centers that attempt to advance the science of transplantation. Despite the clear long-term benefit of transplantation, transplant centers face significant economic disincentives to develop innovative protocols, use nonstandard organs, and employ novel technologies. Policymakers should consider the creation of risk-adjusted payment for renal transplant, similar to that of liver and heart transplant, to ensure that access is preserved for all candidates. The inclusion of supplemental payments for providers that successfully

use organs from higher risk donors (e.g., KPDI >85) would ensure that financial considerations no longer contribute to organ discard but, instead, drive innovation.

ACKNOWLEDGMENTS DA and KLL received support from NIH/NIDDK R01DK102981 “Choosing Immune Suppression in Renal Transplantation by Efficacy and Morbidity.” The authors acknowledge R01 coinvestigators, including Vikas Dharnidharka, Mark Schnitzler, Daniel Brennan, and Dorry Segev. They acknowledge Bertram Kasiske and the SRTR for their valuable collaboration, and transplant outcomes research collaborators including Abhijit Naik, Ngan Lam, Henry Randall, Rosemary Ouseph, Huiling Xiao, and Zidong Zhang. A full list of references is available at www.expertconsult.com.

REFERENCES 1. Hart A, Smith J, Skeans M, et al. OPTN/SRTR 2015 Annual data report: kidney. Am J Transplant. 2017;17:21–116. 2. Wolfe RA, Ashby VB, Milford EL, et al. Comparison of mortality in all patients on dialysis, patients on dialysis awaiting transplantation, and recipients of a first cadaveric transplant. N Engl J Med. 1999;341:1725–1730. 3. Schnitzler M, Skeans M, Axelrod D, et al. OPTN/SRTR 2015 Annual data report: economics. Am J Transplant. 2017;17:425–502. 4. Lloveras J, Arcos E, Comas J, Crespo M, Pascual J. A paired survival analysis comparing hemodialysis and kidney transplantation from deceased elderly donors older than 65 years. Transplantation. 2015;99:991–996. 5. Gill J, Schaeffner E, Chadban S, et al. Quantification of the early risk of death in elderly kidney transplant recipients. Am J Transplant. 2013;13:427–432. 6. Rao PS, Merion RM, Ashby VB, Port FK, Wolfe RA, Kayler LK. Renal transplantation in elderly patients older than 70 years of age: results from the scientific registry of transplant recipients. Transplantation. 2007;83:1069–1074. 7. Matas AJ, Smith JM, Skeans MA, et al. OPTN/SRTR 2013 Annual data report: kidney. Am J Transplant. 2015;15(suppl 2): 1–34. 8. Gill JS, Tonelli M, Johnson N, Kiberd B, Landsberg D, Pereira BJ. The impact of waiting time and comorbid conditions on the survival benefit of kidney transplantation. Kidney Int. 2005;68:2345–2351. 9. Gill JS, Lan J, Dong J, et al. The survival benefit of kidney transplantation in obese patients. Am J Transplant. 2013;13:2083–2090. 10. Goldfarb-Rumyantzev A, Hurdle JF, Scandling J, et al. Duration of end-stage renal disease and kidney transplant outcome. Nephrol Dial Transplant. 2004;20:167–175. 11. Meier-Kriesche H-U, Kaplan B. Waiting time on dialysis as the strongest modifiable risk factor for renal transplant outcomes: a paired donor kidney analysis1. Transplantation. 2002;74:1377–1381. 12. Axelrod DA, Dzebisashvili N, Schnitzler MA, et al. The interplay of socioeconomic status, distance to center, and interdonor service area travel on kidney transplant access and outcomes. Clin J Am Soc Nephrol. 2010;5:2276–2288. 13. Axelrod DA, Guidinger MK, Finlayson S, et al. Rates of solid-organ wait-listing, transplantation, and survival among residents of rural and urban areas. JAMA. 2008;299:202–207. 14. Kasiske BL, Snyder JJ, Matas AJ, Ellison MD, Gill JS, Kausz AT. Preemptive kidney transplantation: the advantage and the advantaged. J Am Soc Nephrol. 2002;13:1358–1364. 15. Kasiske BL, Ellison M. Race and socioeconomic factors influencing early placement on the kidney transplant waiting list. J Am Soc Nephrol. 1998;9:2142–2147. 16. Patzer RE, Plantinga LC, Paul S, et al. Variation in dialysis facility referral for kidney transplantation among patients with end-stage renal disease in georgia. JAMA. 2015;314:582–594. 17. Horwedel TA, Bowman LJ, Saab G, Brennan DC. Benefits of sulfamethoxazole-trimethoprim prophylaxis on rates of sepsis after kidney transplant. Transpl Infect Dis. 2014;16:261–269. 18. Hall EC, James NT, Wang JMG, et al. Center-level factors and racial disparities in living donor kidney transplantation. Am J Kidney Dis. 2012;59:849–857.

19. Axelrod DA, Dzebisashvili N, Schnitzler MA, et al. The interplay of socioeconomic status, distance to center, and interdonor service area travel on kidney transplant access and outcomes. Clin J Am Soc Nephrol. 2010:CJN. 04940610. 20. Klein A, Messersmith E, Ratner L, Kochik R, Baliga P, Ojo A. Organ donation and utilization in the United States, 1999– 2008. Am J Transplant. 2010;10:973–986. 21. Lentine KL, Yuan H, Tuttle-Newhall JE, et al. Quantifying prognostic impact of prescription opioid use before kidney transplantation through linked registry and pharmaceutical claims data. Transplantation. 2015;99:187–196. 22. Lentine KL, Delos Santos R, Axelrod D, Schnitzler MA, Brennan DC, Tuttle-Newhall JE. Obesity and kidney transplant candidates: how big is too big for transplantation? Am J Nephrol. 2012;36:575–586. 23. Hart A, Gustafson S, Skeans M, et al. OPTN/SRTR 2015 Annual data report: early effects of the new kidney allocation system. Am J Transplant. 2017;17:543–564. 24. DE FIJTER JW, Mallat MJ, Doxiadis II , et al. Increased immunogenicity and cause of graft loss of old donor kidneys. Clin J Am Soc Nephrol. 2001;12:1538–1546. 25. Oppenheimer F, Aljama P, Asensio Peinado C, Bustamante Bustamante J, Crespo Albiach JF, Guirado Perich L. The impact of donor age on the results of renal transplantation. Nephrol Dial Transplant. 2004;19:iii11-iii5. 26. Terasaki PI, Gjertson DW, Cecka JM, Takemoto S, Cho YW. Significance of the donor age effect on kidney transplants. Clin Transplant. 1997;11:366–372. 27. Thuong M, Ruiz A, Evrard P, et al. New classification of donation after circulatory death donors definitions and terminology. Transpl Int. 2016;29:749–759. 28. Snoeijs MG, Winkens B, Heemskerk MB, et al. Kidney transplantation from donors after cardiac death: a 25-year experience. Transplantation. 2010;90:1106–1112. 29. Weber M, Dindo D, Demartines N, Amb hl PM, Clavien PA. Kidney transplantation from donors without a heartbeat. N Engl J Med. 2002;347:248–255. 30. Meier-Kriesche HU, Schold JD, Gaston RS, Wadstrom J, Kaplan B. Kidneys from deceased donors: maximizing the value of a scarce resource. Am J Transplant. 2005;5:1725–1730. 31. Tojimbara T, Fuchinoue S, Iwadoh K, et al. Improved outcomes of renal transplantation from cardiac death donors: a 30-year single center experience. Am J Transplant. 2007;7:609–617. 32. Bryan CF, Cherikh WS, Sesok-Pizzini DA. A2 /A2 B to B Renal transplantation: past, present, and future directions. Am J Transplant. 2016;16:11–20. 33. Whiting JF, Woodward RS, Zavala EY, et al. Economic cost of expanded criteria donors in cadaveric renal transplantation: analysis of medicare payments.[see comment]. Transplantation. 2000;70:755–760. 34. Kasiske BL, Snyder JJ, Gilbertson D, Matas AJ. Diabetes mellitus after kidney transplantation in the united states. Am J Transplant. 2003;3:178–185. 35. Massie AB, Luo X, Lonze BE, et al. Early changes in kidney distribution under the new allocation system. J Am Soc Nephrol: JASN. 2016;27:2495–2501. 36. UNOS Kidney News, July 12, 2017. Odds for receiving a kidney transplant now equal for black, white and Hispanic candidates. Available at: https://www.unos. org/odds-equal-of-kidney-transplant-for-minorities/. Accessed July 15, 2017.

554.e1

554.e2

REFERENCES

37. Smith JM, Schnitzler MA, Gustafson SK, et al. Cost implications of new national allocation policy for deceased donor kidneys in the United States. Transplantation. 2016;100: 879–885. 38. Seem DL, Lee I, Umscheid CA, Kuehnert MJ. Excerpt from PHS guideline for reducing HIV, HBV and HCV transmission through organ transplantation. J Am Soc Nephrol. 2013;13:1953–1962. 39. 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;15:3215–3223. 40. Chow EK, Massie AB, Muzaale AD, et al. Identifying appropriate recipients for CDC infectious risk donor kidneys. Am J Transplant. 2013;13:1227–1234. 41. Gill JS, Tinckam K, Fortin MC, et al. Reciprocity to increase participation of compatible living donor and recipient pairs in kidney paired donation. Am J Transplant. 2017;17:1723–1728. 42. Kucirka LM, Singer AL, Ros RL, Montgomery RA, Dagher NN, Segev DL. Underutilization of hepatitis C-positive kidneys for hepatitis C-positive recipients. Am J Transplant. 2010;10:1238–1246. 43. Levitsky J, Formica R, Bloom R, et al. The american society of transplantation consensus conference on the use of hepatitis C viremic donors in solid organ transplantation. Am J Transplant. 2017. 44. Goldberg DS, Abt PL, Blumberg EA, et al. Trial of transplantation of HCV-infected kidneys into uninfected recipients. N Engl J Med. 2017;376:2394–2395. 45. Kayler L, Garzon P, Magliocca J, et al. Outcomes and utilization of kidneys from deceased donors with acute kidney injury. Am J Transplant. 2009;9:367–373. 46. Heilman RL, Smith M, Kurian S, et al. Transplanting kidneys from deceased donors with severe acute kidney injury. Am J Transplant. 2015;15:2143–2151. 47. D.Stewart CS, Cherikh W, Formica R, Friedewald J. Has displaying KDPI in Donornet® led to a spike in discard rates for lower quality kidneys? Am J Transplant. 2013;13(S5): 123–124. 48. Gheorghian A, Schnitzler MA, Axelrod DA, Kalsekar A, L’Italien G, Lentine KL. The implications of acute rejection and reduced allograft function on health care expenditures in contemporary US kidney transplantation. Transplantation. 2012;94:241–249. 49. Lamb KE, Lodhi S, Meier-Kriesche HU. Long-term renal allograft survival in the United States: a critical reappraisal. Am J Transplant. 2011;11:450–462. 50. U. S. Renal Data System. USRDS 2015 Annual Data Report: End-stage Renal Disease (ESRD) in the United States. Ch 7: Transplantation. Bethesda, MD: National Institutes of Health, National Institute of Diabetes and Digestive and Kidney Diseases; 2016. Available at: https://www.usrds.org/2016/view/v2_07.aspx. Accessed July 2, 2017. 51. Tushla L, Rudow DL, Milton J, Rodrigue JR, Schold JD, Hays R. Living-donor kidney transplantation: reducing financial barriers to live kidney donation—recommendations from a consensus conference. Clin J Am Soc Nephrol. 2015;10:1696– 1702. 52. LaPointe Rudow D, Hays R, Baliga P, et al. Consensus conference on best practices in live kidney donation: recommendations to optimize education, access, and care. Am J Transplant. 2015;15:914–922.

53. Jacobs SC, Ramey JR, Sklar GN, Bartlett ST. Laparoscopic kidney donation from patients older than 60 years. J Am Coll Surg. 2004;198:892–897. 54. Ashlagi I, Gilchrist DS, Roth AE, Rees MA. Nonsimultaneous chains and dominos in kidney-paired donation—revisited. Am J Transplant. 2011;11:984–994. 55. Waterman AD, Schenk EA, Barrett AC, et al. Incompatible kidney donor candidates’ willingness to participate in donor-exchange and non-directed donation. Am J Transplant. 2006;6:1631–1638. 56. Massie AB, Gentry SE, Montgomery RA, Bingaman AA, Segev DL. Center-level utilization of kidney paired donation. Am J Transplant. 2013;13:1317–1322. 57. Gentry SE, Segev DL, Simmerling M, Montgomery RA. Expanding kidney paired donation through participation by compatible pairs. Am J Transplant. 2007;7:2361–2370. 58. Lentine KL, Kasiske BL, Levey AS, et al. KDIGO Clinical practice guideline on the evaluation and care of living kidney donors. [In press] Transplantation. 2017;101(8S Suppl 1):S1–S109. 59. Group KDIGOTW. KDIGO Clinical practice guideline for the care of kidney transplant recipients. Am J Transplant. 2009;9: S1. 60. Dharnidharkaa VR, Naik AS, Axelrod DA, et al. Center practice drives variation in choice of U.S. kidney transplant induction therapy: a retrospective analysis of contemporary practice. Transpl Int. 2018;31:198–211. 61. Kaufman DB, Leventhal JR, Axelrod D, Gallon LG, Parker MA, Stuart FP. Alemtuzumab induction and prednisone-free maintenance immunotherapy in kidney transplantation: comparison with basiliximab induction—long-term results. Am J Transplant. 2005;5:2539–2548. 62. Hanaway MJ, Woodle ES, Mulgaonkar S, et al. Alemtuzumab induction in renal transplantation. N Engl J Med. 2011;364:1909–1919. 63. Brifkani Z, Brennan DC, Lentine KL, et al. The privilege of induction avoidance and calcineurin inhibitors withdrawal in 2 haplotype HLA matched white kidney transplantation. Transplantation Direct. 2017:3. 64. Axelrod D, Naik AS, Schnitzler MA, et al. National variation in use of immunosuppression for kidney transplantation: a call for evidence-based regimen selection. Am J Transplant. 2016;16:2453–2462. 65. Budde K, Bunnapradist S, Grinyo J, et al. Novel once-daily extended-release tacrolimus (LCPT) versus twice-daily tacrolimus in de novo kidney transplants: one-year results of phase iii, double-blind, randomized trial. Am J Transplant. 2014;14:2796–2806. 66. Tornatore KM, Meaney CJ, Wilding GE, et al. Influence of sex and race on mycophenolic acid pharmacokinetics in stable African American and Caucasian renal transplant recipients. Clin Pharmacokinet. 2015;54:423–434. 67. Dharnidharka VR, Schnitzler MA, Chen J, et al. Differential risks for adverse outcomes 3 years after kidney transplantation based on initial immunosuppression regimen: a national study. Transpl Int. 2016;29:1226–1236. 68. Lodhi S, Lamb K, Meier-Kriesche H. Solid organ allograft survival improvement in the United States: the long-term does not mirror the dramatic short-term success. Am J Transplant. 2011;11:1226–1235. 69. Stegall MD, Gaston RS, Cosio FG, Matas A. Through a glass darkly: seeking clarity in preventing late kidney transplant failure. J Am Soc Nephrol. 2015;26:20–29.

REFERENCES 70. Menon MC, Murphy B, Heeger PS. Moving biomarkers toward clinical implementation in kidney transplantation. J Am Soc Nephrol: JASN. 2017;28:735–747. 71. Nankivell BJ, Alexander SI. Rejection of the kidney allograft. N Engl J Med. 2010;363:1451–1462. 72. Lentine KL, Gheorghian A, Axelrod D, Kalsekar A, L’Italien G, Schnitzler MA. The implications of acute rejection for allograft survival in contemporary U.S. kidney transplantation. Transplantation. 2012;94:369–376. 73. Ekberg H, Tedesco-Silva H, Demirbas A, et al. Reduced exposure to calcineurin inhibitors in renal transplantation. N Engl J Med. 2007;357:2562–2575. 74. Alangaden GJ, Thyagarajan R, Gruber SA, et al. Infectious complications after kidney transplantation: current epidemiology and associated risk factors. Clin Transplant. 2006;20:401–409. 75. Lentine KL, Brennan DC, Schnitzler MA. Incidence and predictors of myocardial infarction after kidney transplantation. J Am Soc Nephrol. 2005;16:496–506. 76. Ariza-Heredia EJ, Beam EN, Lesnick TG, Kremers WK, Cosio FG, Razonable RR. Urinary tract infections in kidney transplant recipients: role of gender, urological abnormalities, and antimicrobial prophylaxis. Ann Transplant. 2013;18:195–204. 77. Pourmand G, Salem S, Mehrsai A, Taherimahmoudi M, Ebrahimi R, Pourmand M. Infectious complications after kidney transplantation: a single-center experience. Transpl Infect Dis. 2007;9:302–309. 78. Naik AS, Dharnidharka VR, Schnitzler MA, et al. Clinical and economic consequences of first-year urinary tract infections, sepsis, and pneumonia in contemporary kidney transplantation practice. Transpl Int. 2016;29:241–252. 79. Kasiske BL, Snyder JJ, Gilbertson DT, Wang C. Cancer after kidney transplantation in the united states. Am J Transplant. 2004;4:905–913. 80. Vajdic CM, McDonald SP, McCredie MR, et al. Cancer incidence before and after kidney transplantation. Jama. 2006;296:2823–2831. 81. Acuna SA, Fernandes KA, Daly C, et al. Cancer mortality among recipients of solid-organ transplantation in Ontario, Canada. JAMA Oncol. 2016;2:463–469. 82. Pilmore H, Dent H, Chang S, McDonald SP, Chadban SJ. Reduction in cardiovascular death after kidney transplantation. Transplantation. 2010;89:851–857. 83. Lam NN, Kim SJ, Knoll GA, et al. The risk of cardiovascular disease is not increasing over time despite aging and higher comorbidity burden of kidney transplant recipients. Transplantation. 2017;101:588–596. 84. Engels EA, Pfeiffer RM, Fraumeni JF, et al. Spectrum of cancer risk among US solid organ transplant recipients. Jama. 2011;306:1891–1901. 85. Hall EC, Engels EA, Pfeiffer RM, Segev DL. Association of antibody induction immunosuppression with cancer after kidney transplantation. Transplantation. 2015;99:1051. 86. Dharnidharka VR, Naik AS, Axelrod D, et al. Clinical and economic consequences of early cancer after kidney transplantation in contemporary practice. Transplantation. 2017;101:858–866. 87. Kuo H-T, Sampaio MS, Vincenti F, Bunnapradist S. Associations of pretransplant diabetes mellitus, new-onset diabetes after transplant, and acute rejection with transplant outcomes: an analysis of the organ procurement and transplant network/ united network for organ sharing (OPTN/UNOS) database. Am J Kidney Dis. 2010;56:1127–1139.

554.e3

88. Davidson J, Wilkinson A, Dantal J, et al. New-onset diabetes after transplantation: 2003 international consensus guidelines. Transplantation. 2003;75:SS3–SS24. 89. Pirsch J, Henning A, First M, et al. New-onset diabetes after transplantation: results from a double-blind early corticosteroid withdrawal trial. Am J Transplant. 2015;15:1982–1990. 90. Luan F, Zhang H, Schaubel D, et al. Comparative risk of impaired glucose metabolism associated with cyclosporine versus tacrolimus in the late posttransplant period. Am J Transplant. 2008;8:1871–1877. 91. Boudreaux JP, Mchugh L, Canafax DM, et al. The impact of cyclosporine and combination immunosuppression on the incidence of posttransplant diabetes in renal allograft recipients. Transplantation. 1987;44:376–380. 92. Luan FL, Steffick DE, Ojo AO. New-onset diabetes mellitus in kidney transplant recipients discharged on steroid-free immunosuppression. Transplantation. 2011;91:334–341. 93. Lentine KL, Schnitzler MA, Abbott KC, et al. De novo congestive heart failure after kidney transplantation: A common condition with poor prognostic implications. Am J Kidney Dis. 2005;46:720–733. 94. Lentine KL, Schnitzler MA, Abbott KC, et al. Incidence, predictors, and associated outcomes of atrial fibrillation after kidney transplantation. Clin J Am Soc Nephrol. 2006;1:288– 296. 95. Woodward RS, Schnitzler MA, Baty J, et al. Incidence and cost of new onset diabetes mellitus among U.S. wait-listed and transplanted renal allograft recipients. Am J Transplant. 2003;3:590–598. 96. Coghill A, Johnson L, Berg D, Resler A, Leca N, Madeleine M. Immunosuppressive medications and squamous cell skin carcinoma: nested case-control study within the skin cancer after organ transplant (SCOT) cohort. Am J Transplant. 2016;16:565–573. 97. Schnitzler MA, Skeans MA, Axelrod DA, et al. OPTN/ SRTR 2013 Annual data report: economics. Am J Transplant. 2015;15(suppl 2):1–24. 98. Meier-Kriesche HU, Schold JD, Kaplan B. Long-term renal allograft survival: have we made significant progress or is it time to rethink our analytic and therapeutic strategies? Am J Transplant. 2004;4:1289–1295. 99. Meier-Kriesche HU, Schold JD, Srinivas TR, Kaplan B. Lack of improvement in renal allograft survival despite a marked decrease in acute rejection rates over the most recent era. Am J Transplant. 2004;4:378–383. 100. Hariharan S, Johnson CP, Bresnahan BA, Taranto SE, McIntosh MJ, Stablein D. Improved graft survival after renal transplantation in the United States, 1988 to 1996. N Engl J Med. 2000;342:605–612. 101. Alhamad T, Spatz C, Uemura T, Lehman E, Farooq U. The outcomes of simultaneous liver and kidney transplantation using donation after cardiac death organs. Transplantation. 2014;98:1190–1198. 102. Alhamad T, Uemura T, Lehman E, Spatz C, Farooq U. Utilization of donors after cardiac death organs for simultaneous liver and kidney transplantation. Transplantation. 2015;99:e40–e41. 103. Alhamad T, Blandon J, Meza AT, Bilbao JE, Hernandez GT. Acute kidney injury with oxalate deposition in a patient with a high anion gap metabolic acidosis and a normal osmolal gap. J Nephropathol. 2013;2:139–143.

554.e4

REFERENCES

104. Schold JD, Buccini LD, Srinivas TR, et al. The association of center performance evaluations and kidney transplant volume in the United States. Am J Transplant. 2013;13:67–75. 105. Snyder JJ, Salkowski N, Wey A, et al. Effects of high-risk kidneys on scientific registry of transplant recipients program quality reports. Am J Transplant. 2016;16:2646–2653. 106. Sands JJ, Usvyat LA, Sullivan T, et al. Intradialytic hypotension: Frequency, sources of variation and correlation with clinical outcome. Hemodial Int. 2014;18:415–422. 107. Degoulet P, Reach I, Di Giulio S, et al. Epidemiology of dialysis induced hypotension. Proc Eur Dial Transplant Assoc. 1980;18:133–138. 108. Passauer J, Büssemaker E, Gross P. Dialysis hypotension: do we see light at the end of the tunnel? Nephrol Dial Transplant. 1998;13:3024–3029. 109. Prakash S, Garg AX, Heidenheim AP, House AA. Midodrine appears to be safe and effective for dialysis-induced hypotension: a systematic review. Nephrol Dial Transplant. 2004;19:2553–2558. 110. Alhamad T, Brennan DC, Brifkani Z, et al. Pretransplant midodrine use: a newly identified risk marker for complications after kidney transplantation. Transplantation. 2016;100:1086– 1093. 111. Plavix monograph, 2012. Updated version available (March 9, 2018): http://products.sanofi.ca/en/plavix.pdf. 112. Deleted in pages. 113. Williams JM, Tuttle-Newhall JE, Schnitzler M, et al. Clopidogrel use as a risk factor for poor outcomes after kidney transplantation. Am J Surg. 2014;208:556–562. 114. Barakzoy AS, Moss AH. Efficacy of the world health organization analgesic ladder to treat pain in end-stage renal disease. J Am Soc Nephrol. 2006;17:3198–3203. 115. Dean M. Opioids in renal failure and dialysis patients. J Pain Symptom Manage. 2004;28:497–504. 116. Lentine KL, Yuan H, Tuttle-Newhall JE, et al. Quantifying prognostic impact of prescription opioid use before kidney transplantation through linked registry and pharmaceutical claims data. Transplantation. 2015;99:187–196. 117. Deleted in pages. 118. Lentine KL, Lam NN, Xiao H, et al. Associations of pretransplant prescription narcotic use with clinical complications after kidney transplantation. Am J Nephrol. 2015;41:165– 176. 119. Rettig RA. Special treatment—the story of medicare’s ESRD entitlement. Minn Med. 2011;94:36–38. 120. Ross W. God panels and the history of hemodialysis in America: a cautionary tale. virtual mentor. 2012;14:890–896. 121. Wall AE, Veale JL, Melcher ML. Advanced donation programs and deceased donor initiated chains - 2 innovations in kidney paired donation. Transplantation. 2017;101(12):2818–2824. 122. Saran R, Li Y, Robinson B, et al. US Renal data system 2014 annual data report: epidemiology of kidney disease in the United States. Am J Kidney Dis. 2015;65. A7. 123. System. USRD. 2015 USRDS annual data report: epidemiology of kidney disease in the United States. In: National Institutes of Health NIoDaDaKD. 2015. Bethesda, MD. 124. Anual data report. http://www.usrds.org/2015/view/ Default.aspx. 2015. 125. McAdams-DeMarco MA, Law A, King E, et al. Frailty and mortality in kidney transplant recipients. Am J Transplant. 2015;15:149–154.

126. Garonzik-Wang JM, Govindan P, Grinnan JW, et al. Frailty and delayed graft function in kidney transplant recipients. Arch Surg. 2012;147:190–193. 127. Buchanan PM, Lentine KL, Burroughs TE, Schnitzler MA, Salvalaggio PR. Association of lower costs of pulsatile machine perfusion in renal transplantation from expanded criteria donors. Am J Transplant. 2008;8:2391–2401. 128. Axelrod DA, Schnitzler MA, Xiao H, et al. The changing financial landscape of renal transplant practice: a national cohort analysis. Am J Transplant. 2017;17:377–389. 129. Ercole PM, Buchanan PM, Lentine KL, Burroughs TE, Schnitzler MA, Modanlou KA. Costs and outcomes of privately-insured kidney transplant recipients by body mass index. 003. S4:003. J Nephrol Therapeutic. 2012 [in press]. https://doi.org/10.4172/2161-0959.S4. 130. Ho D, Lynch RJ, Ranney DN, Magar A, Kubus J, Englesbe MJ. Financial impact of surgical site infection after kidney transplantation: implications for quality improvement initiative design. J Am Coll Surg. 2010;211:99–104. 131. Molnar MZ, Kovesdy CP, Mucsi I, et al. Higher recipient body mass index is associated with post-transplant delayed kidney graft function. Kidney Int. 2011;80:218–224. 132. Ojo AO, Hanson JA, Meier-Kriesche H-U, et al. Survival in recipients of marginal cadaveric donor kidneys compared with other recipients and wait-listed transplant candidates. Clin J Am Soc Nephrol. 2001;12:589–597. 133. Siedlecki A, Irish W, Brennan DC. Delayed graft function in the kidney transplant. Am J Transplant. 2011;11:2279– 2296. 134. Matas AJ, Schnitzler M. Payment for living donor (vendor) kidneys: a cost-effectiveness analysis. Am J Transplant. 2004;4:216–221. 135. Rees MA, Schnitzler MA, Zavala EY, et al. Call to develop a standard acquisition charge model for kidney paired donation. Am J Transplant. 2012;12:1392–1397. 136. Held PJ, McCormick F, Ojo A, Roberts JP. A cost-benefit analysis of government compensation of kidney donors. Am J Transplant. 2015. 137. Lapointe Rudow D, Cohen D. Practical approaches to mitigating economic barriers to living kidney donation for patients and programs. Curr Transpl Rep. 2017:24–31. 138. Lentine KL, Mandelbrot DA. Moving from intuition to data: building the evidence to support and increase living donor kidney transplantation. Clin J Am Soc Nephrol. 2017 [in press]. 139. Matas AJ, Schnitzler M, Daar AS. Payment for living kidney donors (vendors) is not an abstract ethical discussion occurring in a vacuum. Am J Transplant. 2004;4:1380–1381. 140. Delmonico FL, Arnold R, Scheper-Hughes N, Siminoff LA, Kahn J, Youngner SJ. Ethical incentives—not payment—for organ donation. N Engl J Med. 2002;346:2002–2005. 141. Bonventre JV, Yang L. Cellular pathophysiology of ischemic acute kidney injury. J Clin Invest. 2011;121:4210–4221. 142. Israni AK, Salkowski N, Gustafson S, et al. New national allocation policy for deceased donor kidneys in the United States and possible effect on patient outcomes. J Am Soc Nephrol: JASN. 2014;25:1842–1848. 143. Friedewald JJ, Samana CJ, Kasiske BL, et al. The kidney allocation system. Surg Clin North Am. 2013;93:1395–1406. 144. Israni AK, Salkowski N, Gustafson S, et al. New national allocation policy for deceased donor kidneys in the United States and possible effect on patient outcomes. J Am Soc Nephrol. 2014;25:1842–1848.

REFERENCES 145. Takahashi K, Saito K. ABO-incompatible kidney transplantation. Transplantation reviews. 2013;27:1–8. 146. Montgomery JR, Berger JC, Warren DS, James NT, Montgomery RA, Segev DL. Outcomes of ABO-incompatible kidney transplantation in the United States. Transplantation. 2012;93:603–609. 147. Axelrod D, Segev DL, Xiao H, et al. Economic impacts of ABO-incompatible live donor kidney transplantation: a national study of Medicare-insured recipients. Am J Transplant. 2016;16:1465–1473.

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148. Montgomery RA, Lonze BE, King KE, et al. Desensitization in HLA-incompatible kidney recipients and survival. N Engl J Med. 2011;365:318–326. 149. Jordan SC, Choi J, Vo A. Achieving incompatible transplantation through desensitization: current perspectives and future directions. Immunotherapy. 2015;7:377–398. 150. Axelrod D, Lentine KL, Schnitzler MA, et al. The incremental cost of incompatible living donor kidney transplant: a national cohort analysis. Am J Transplant. 2017;17(12):3123–3130.