What's Hot, What's New

What's Hot, What's New

Joseph B. Lockridge, MD

University of California, San Francisco, Medical Center, San Francisco, California

The 2013 American Transplant Congress provided a forum for the presentation and discussion of numerous high-quality studies regarding organ and tissue transplantation and related disciplines. Basic science presentations included cutting-edge observations on innate mediators and regulators of alloimmunity, T-cell effectors in graft injury, and T- and/or B-cell regulation of the alloimmune response. Clinical presentations addressed challenges related to donor-specific antibodies, novel predictors of transplant outcomes, risks related to living-donor transplant, policy analysis, immunosuppression minimization, and tolerance induction. These topics reflect the expanding body of evidence to support the rapidly evolving field of transplantation science.

Dr. Lockridge Physicians, surgeons, pharmacists, scientists, and other healthcare professionals in the transplant community gathered at the 2013 American Transplant Congress, a joint meeting of the American Society of Transplantation and the American Society of Transplant Surgeons held in Seattle, Washington. The closing presentation of the American Transplant Congress highlighted basic science and clinical studies from over 1,700 presentations and abstracts reported by experts in the field.

BASIC SCIENCE
Based on a presentation by Robert Fairchild, PhD, Professor of Molecular Medicine, Cleveland Clinic, Cleveland, Ohio.

Over 500 abstracts and presentations in the basic sciences addressed a variety of topics related to immune-response pathways.

Innate Mediators and Regulators of Alloimmunity
Thymic-derived CD4+ Foxp3+ natural regulatory T (Treg) cells protect against pathogenic alloimmunity and facilitate tolerance induction in murine models of solid-organ and hematopoietic-cell transplantation.1 Complement activation products C3a and C5a bind their respective G protein–coupled receptors, C3aR and C5aR, which are expressed on T cells to provide costimulatory signals that limit Treg cell function.

van der Touw and colleagues2 studied T-cell–expressed C3aR/C5aR signaling and its impact on the generation and stability of alloreactive induced Treg cells. Their findings indicated that blocking C3a/C3aR and C5a/C5aR ligations favors the induction and stability of murine and human Treg cells. This potential pharmacologic target could facilitate induction of immune tolerance to alloantigens in the context of human solid-organ or hematopoietic-cell transplants.

Graft Injury Mediated by T Cells
Licensed in 2011, belatacept is a novel selective T-cell costimulation blocker used as an immunosuppressant to prevent rejection in adult kidney-transplant recipients. Long-term phase III trial data have shown that when compared with cyclosporine, use of belatacept results in improved renal function and a higher rate of acute rejection but similar patient and graft survival at 1 year. Kitchens and colleagues3 investigated whether a secondary costimulatory receptor antagonist, αOX40L, could synergize with belatacept to prolong transplant survival. This combined protocol increased graft survival in mice and rhesus macaques. The mechanism of action may involve inhibition of alloreactive memory T-cell function.

T- and/or B-cell Regulation of the Alloimmune Response
Matta and colleagues4 studied the importance of interleukin (IL)-33 acting on dendritic cells to support ST2+ Treg expansion. Wild-type and ST2-deficient dendritic cells were cultured with T cells, and then IL-33 was added to the culture. When dendritic cells lacked ST2 expression, they failed to significantly increase ST2+ Treg cells, even though the T cells expressed ST2 and could respond to IL-33. This scheme was introduced into an in vivo chimeric mouse model. The authors concluded that IL-33 expands an ST2+ subset of Treg cells in vivo, and IL-33 mediates Treg expansion and Th2 polarization of CD4+ T cells through ST2+ CD11c+ dendritic cells.

CLINICAL SCIENCE
Based on a presentation by Dorry Segev, MD, PhD, Associate Professor of Surgery, Epidemiology, and Biostatistics, Johns Hopkins University, Baltimore, Maryland.

Highlights from over 1,000 clinical abstracts and presentations covered many different subjects that relate directly to clinical practice.

Donor-specific Antibodies (DSAs)
To provide insight into the pathogenesis and natural history of the humoral immune maturation response in kidney transplant recipients, Everly and colleagues5 collected sera in a longitudinal fashion from a group of 186 participants. Sera were retrospectively tested for human leukocyte antigen (HLA) immunoglobulin (Ig)-G, IgM, and IgG3 antibodies. In patients who developed IgG DSAs, the persistence of IgM DSA along with an isotype switch to IgG3 DSA had an increased risk of graft loss when compared with those without both persistent IgM and IgG3 isotype switching.

The annual rate of renal allograft failure beyond the first year has remained constant for some time.6 In the Long-term Deterioration of Kidney Allograft Function (DeKAF) Study, Gaston and colleagues7 reported that the rate of antibody-mediated rejection reached 57% in patients with late allograft dysfunction and that evidence of rejection was associated with accelerated graft failure.

Gaston et al8 recently reported extended survival data on the 469 patients who underwent for-cause renal biopsy 1 year or longer after transplant. In patients with biopsy-confirmed C4d positivity and DSA positivity (C4d+/DSA+), death-censored graft failure approached 70% at 5 years post biopsy. Patients with C4d+/DSA and C4d/DSA+ profiling had similar graft survival as groups at 5 years post-biopsy and significantly worse graft survival when compared with the C4d/DSA group. These findings suggest that allograft failure is uncommon in the absence of evidence of humoral immune reactivity and highlight the importance of preventing and treating alloimmune injury to promote long-term graft survival.

Gebel et al9 investigated whether compatible kidneys exist for highly sensitized patients on the deceased-donor waiting list or whether these compatible kidneys simply are not available. Using 2010 wait-list data, investigators conducted a simulation of all adult candidates on the kidney wait list during 2010 whose calculated panel reactive antibody (cPRA) was ≥ 80% (n = 18,708). In this allocation scheme, deceased-donor kidneys were offered as priority to candidates with cPRA = 100, then 99, 98, etc. Of 13,591 deceased-donor kidneys available, 13,118 were appropriate to offer to highly sensitized candidates, as compared with the 1,517 actually transplanted (after offer) under the current allocation system. The investigators concluded that most sensitized patients have virtually compatible donors and that the likely barrier to transplant involves limits to our current allocation system, not the antibody profile.

In liver-transplant recipients, O’Leary and colleagues10,11 examined the impact of preformed DSAs on the risk of rejection and patient survival. In an analysis of 1,270 patients studied between 2000 and 2009, the presence of class II DSAs was associated with an increased risk of early rejection. Additionally, multivariate analysis demonstrated that preformed class I or class II DSAs was an independent predictor of patient death.

The presence of a de novo IgG3 subclass of DSA was studied by Kaneku and colleagues12 to identify patients at risk of graft loss after liver transplantation. In 1,099 liver transplant participants, the presence of de novo DSAs was associated with a decrease in graft survival. The production of the IgG3 subclass of DSA in these patients also was associated with an increased risk of graft failure.

In patients who underwent simultaneous liver-kidney transplant (SLKT), Bestard and colleagues13 investigated whether sensitization affects kidney and liver transplants differently or if a protective phenomenon is associated with either organ post transplant. In this single-center, consecutive cohort of 39 SLKT patients, sensitized transplant recipients had an increased risk of renal allograft rejection when compared with unsensitized patients. Similarly, in a survival analysis, SLKT recipients with a percent PRA > 25% were at increased risk of renal allograft loss when compared with unsensitized patients. Thus, liver allografts may not be fully protective of the renal allograft in terms of rejection or function, especially among sensitized patients.

Donation After Cardiac Death (DCD)
Halldorson et al14 studied whether induction therapy with antithymocyte globulin (ATG) was associated with a difference in graft survival and ischemic cholangiopathy after DCD liver transplantation when compared with basiliximab induction. Survival of patients and grafts significantly increased in the ATG treatment group when compared with the cohort using basiliximab. Biliary complication- and ischemic cholangiopathy-free graft survival outcomes also significantly improved with ATG induction.

Machine perfusion has evolved from kidney preservation to the field of liver transplantation. Knaak and colleagues15 compared the impact of standard cold static liver preservation with subnormothermic ex vivo liver perfusion (SNEVLP) on DCD pig liver transplant outcomes. After induction of cardiac arrest as a model of DCD organ retrieval, pig liver grafts underwent either standard preservation or SNEVLP. Hepatocyte, endothelial-cell, and bile duct injury were assessed by aspartate transaminase (AST) levels and biopsy results. SNEVLP-treated livers exhibited a lower level of AST at each hour up to 8 hours post transplant. These low levels were reflected by the histologic findings, including reduced markers of apoptosis and endothelial cell injury and a reduction in bile duct injury in the SNEVLP group, compared with 10-h cold static preservation. The data suggest a reduction in reperfusion injury with this new technology, which opens the possibility for a role in expanding the current liver donor pool.

To address the expansion of the currently static deceased-donor kidney pool, Andrés and colleagues16 reported outcomes data among uncontrolled DCD (uDCD) in Spain. Starting in 2005, investigators from Hospital 12 Octubre in Madrid instituted a uDCD program with local emergency services. In situations outside the hospital, after irreversible cardiac arrest is diagnosed (after at least 30 minutes of cardiopulmonary resuscitation), the transplant coordinator is called, and donation conditions are evaluated. If no contraindications exist, these irreversible cardiac arrest patients are rapidly transported to the hospital under cardiac massage and mechanical ventilation. Upon admission to the intensive-care unit, the absence of a heartbeat is confirmed according to Spanish law, and medical and legal death is certified. Cardiopulmonary bypass is then instituted via femoral cannulation. Consent is sought from the patient’s family, who also is offered the right to refuse the donation. Organ procurement then proceeds.

In this single-center study, transplant was possible for 69% of the total number of 254 procured kidneys. The most common reason for discard was ischemia. Rates of primary nonfunction, delayed graft function, and acute rejection were 8%, 88%, and 12%, respectively. At 18-month follow-up, kidney grafts of 87% of patients survived, the mean serum creatinine level was 1.4 mg/dL, and overall patient survival was 98%. Nevertheless, the role of uDCD organ allocation remains controversial, and the particularly high risk of primary nonfunction (8%) is noteworthy.

However, the growing wait list for both kidney and liver transplants and the adverse consequences of remaining on a wait list highlight challenges within our current system. First, expansion of the donor pool remains a challenge in the transplant community. Future directions will require creative strategies and may include novel coordination and procurement programs such as those described previously. Second, the implementation of these novel programs may present problems with cultural barriers and safety improvements. Still, safety concerns may supply another impetus for current research of therapies to prevent and treat ischemia-reperfusion injury.

Novel Predictors of Transplant Outcomes
Frailty has been validated as a predictor of morbidity and mortality among patients with end-stage renal disease (ESRD).17 McAdams-DeMarco and colleagues18 assessed similar criteria in 446 kidney-transplant recipients to evaluate the risk of early hospital readmission (EHR) after transplantation. Based on a registry model, patients were assessed for frailty using such criteria as decreased walking speed, exhaustion, decreased grip strength, low physical activity, and unexplained weight loss. In all, 30.9% of patients were readmitted within 30 days of initial hospital discharge. Transplant recipients who were frail at the time of transplant were more likely to experience EHR than were those who were not considered to be frail (46.3% vs 27.5%; P = 0.001). The identification of these frail patients may lead to a suitable population for targeted monitoring to reduce EHR rates.

During a plenary session, Waits et al19 presented a method for calculating a liver-transplant recipient’s “morphometric” (as opposed to chronologic) age to predict clinical outcomes. Using routine preoperative computed tomography scans, baseline morphometric characteristics such as trunk muscle size, muscle density, and vascular calcification were assessed in 348 liver-transplant candidates. After adjusting for other relevant covariates, morphometric age was a significant predictor of 1-year (odds ratio [OR] = 1.05; P < 0.001) and 5-year mortality (OR = 1.04; P < 0.001). Among the chronologically middle-aged tercile, there was a marked difference in 1- and 5-year survival between patients who were determined to be morphometrically young as compared with those who were morphometrically old.

Cardiovascular outcomes continue to be the most important cause of mortality among the kidney transplant population.20 Pelletier and colleagues21 analyzed a cohort of kidney transplant recipients between 2002 and 2008 and incorporated cardiovascular comorbidity variables in their model to assess 1-year patient survival and graft loss. These variables included pretransplant myocardial infarction, decreased left-ventricular ejection fraction (LVEF), coronary artery revascularization, lower extremity amputation and vascular bypass, carotid arterial disease, and diabetes mellitus types 1 and 2. This model was compared with that of the Scientific Registry of Transplant Recipients (SRTR; http://srtr.org/), which currently does not incorporate cardiovascular risk variables in its hazard model for 1-year patient survival. The addition of these cardiovascular variables significantly improved discrimination in the SRTR model for 1-year patient survival. The strongest predictors of 1-year survival among deceased-donor kidney-transplant recipients were LVEF, type 2 diabetes, and myocardial infarction.

Recurrence of Hepatitis C After Liver Transplantation
The recurrence of hepatitis C virus (HCV) infection in liver transplant recipients is a universal problem that causes significant reduction in both graft and patient survival. Triple therapy with pegylated interferon, ribavirin, and a protease inhibitor has been validated in the nontransplant population to treat HCV infection.

Little is known about the use of triple therapy in patients who have received a liver transplant. In a multicenter trial, O’Leary and colleagues22 evaluated the safety and efficacy of triple HCV therapy in 121 liver-transplant recipients with HCV genotype 1. The authors reported that 62% of participants achieved an extended rapid viral response by week 12. The authors noted that triple therapy in this cohort requires intense monitoring and is associated with common adverse effects and a 1.7% risk of death. Results on sustained virologic response will be forthcoming.

In a single-center study, Aqel et al23 studied a protocol of boceprevir-based triple therapy to treat HCV recurrence in liver-transplant patients. Among the 16 patients enrolled, there was a 38% extended viral response at 12 weeks; in an intent-to-treat analysis, 23% had achieved a sustained viral response by 72 weeks.

Both studies showed hope for the applicability of triple therapy to the transplant population, but optimal response rates remain questionable. Additionally, rates of adverse effects were significant, including cytopenias and acute kidney injury.

Live Kidney Donation
Limitations to assessing the long-term risk of complications following live kidney donation include the difficulty of matching appropriate healthy, non-donor controls for comparison. Historically, the risk of developing ESRD after live kidney donation has been assessed, as it compared live kidney donors with the general population. This strategy may be misleading, as the general population tends to be less healthy than the carefully screened live kidney donor population.

To address this problem, Muzaale and colleagues24 used an algorithm that included age, gender, race, education, body mass index, systolic blood pressure, and smoking history to generate controls from National Health and Nutrition Examination Survey (NHANES) data. Kidney donors (n = 96,217) from the Organ Procurement and Transplantation Network (OPTN) reports were matched to these generated controls. The incidence of ESRD at 15 years was eightfold higher for live kidney donors (0.31%) than for healthy matched controls (0.04%). Black donors had the highest incidence of ESRD (0.75%), and white donors had the lowest incidence of ESRD (0.23%).

When evaluating the risk-benefit profile of live donation, especially with the emerging strategies of kidney paired exchanges for sensitized patients, it is important for the transplant clinician to evaluate the quality of the donated kidney. Khamash and colleagues25 studied the impact of donor size, donor-age differences, and donor glomerular filtration rate (GFR) variables. In multivariate analysis, all variables were associated with an increased risk of 1-year post-transplant GFR < 40 mL/min. These factors should provide additional insight to the transplant clinician assessing the quality of donors in exchange programs.

Immunosuppression Minimization
De Simone and colleagues26 studied the potential for mammalian target of rapamycin inhibitors such as everolimus to reduce calcineurin-inhibitor nephrotoxicity in liver transplant recipients. The authors extended their previously published 12-month results to 24-month follow-up.27 In this multicenter, open-label study, 719 liver transplant recipients were randomized to receive standard tacrolimus monotherapy, everolimus with reduced tacrolimus, or everolimus with tacrolimus withdrawal. Superior renal function was observed with everolimus therapy and reduced use of tacrolimus when compared with standard tacrolimus therapy. In addition, the rate of biopsy-proven acute rejection was higher among the standard-therapy tacrolimus cohort, compared with the other two groups.

Transplantation Tolerance
The goal of transplantation tolerance is to achieve normal histology and function of the donor allograft without immunosuppressive drug therapy while reducing the risk of rejection. Transplantation tolerance has been studied with a wide variety of immunologic protocols in laboratory animals, and these protocols currently are being tested for their safety and efficacy in human transplant recipients. Development and testing of these protocols are an active area of current investigation.

Kawai and colleagues28 reported long-term outcomes of a tolerance induction protocol using B-cell depletion in HLA-mismatched kidney transplant recipients. The conditioning regimen consisted of rituximab, cyclophosphamide, and total-body irradiation. Living kidney and bone-marrow transplantation followed; additional doses of rituximab were given post transplant. By 8–14 months after transplant surgery, 7 of 10 patients successfully discontinued immunosuppressive medication.

Scandling and colleagues29 presented outcomes of an ongoing safety and efficacy study testing their tolerance induction regimen using hematopoietic stem cell transplantation with kidney transplantation. The protocol consists of a conditioning regimen given after living-donor kidney transplantation with total lymphoid irradiation and followed by infusion of purified donor CD34+ hematopoietic progenitor cells and T cells. HLA-mismatched donor-recipient pairs were included in the study. In 29 patients using this protocol, no grafts were lost due to rejection 3 months to 12 years (median, 4.1 years) following transplantation, and graft function has remained excellent. Of the 29 patients, 15 were withdrawn completely from immunosuppressive medication. The investigators reported no episodes of graft-versus-host disease (GVHD) and a low incidence of serious adverse events.

Using another tolerance induction protocol, Leventhal and colleagues30 reported their phase II results in recipients of living-donor kidney transplants. The induction protocol uses tolerogenic CD8+/TCR facilitating cells and conditioning with fludarabine and cyclophosphamide, followed by kidney transplant. Hematopoietic CD34+ cells and facilitating cells from the donor are transplanted on day 1 after kidney transplant. HLA-mismatched donor-recipient pairs were included in this study. Of 19 patients, 8 have been able to withdraw from using immunosuppressive medication without adverse consequences. Five patients did not sustain chimerism for longer than 6 months, and three of these patients exhibited graft rejection on the protocol biopsy. No episodes of GVHD were reported.

CONCLUSION
The 2013 American Transplant Congress provided a forum for basic scientists and clinical researchers to present and discuss the newest, most innovative advances in the transplant field. Investigators presented the latest medical progress regarding innate mediators and regulators of alloimmunity, T-cell effectors and cell regulation of the alloimmune response, DSAs, novel predictors of clinical outcomes, live-donor transplant risk, analysis of policy, minimization of immunosuppression, and induction of tolerance.

REFERENCES

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  3. Kitchens W, Wakwe W, Breeden C, et al. Combined costimulatory and OX40L blockade significantly prolongs transplant survival in mice and non-human primates. Presented at the 2013 American Transplant Congress; May 18–22, 2013; Seattle, Washington. Abstract 64.
  4. Matta B, Mahews L, Rosborough B, Turnquist H. IL-33 expands ST2+ regulatory T cells promoting allograft survival directly and indirectly through actions on myeloid dendritic cells. Presented at the 2013 American Transplant Congress; May 18–22, 2013; Seattle, Washington. Abstract 440.
  5. Everly M, Rebellato L, Briley K, et al. Identifying the most dangerous DSA: a 12-year longitudinal post-transplant study of IgM, IgG, and IgG isotype HLA alloantibodies in primary renal transplant recipients. Presented at the 2013 American Transplant Congress; May 18–22, 2013; Seattle, Washington. Abstract 169.
  6. 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.
  7. Gaston RS, Cecka JM, Kasiske BL, et al. Evidence for antibody-mediated injury as a major determinant of late kidney allograft failure. Transplantation. 2010;90:68–74.
  8. Gaston R, Leduc R, Cosio F, et al. Antibody-mediated injury is the major cause of late kidney allograft failure. Presented at the 2013 American Transplant Congress; May 18–22, 2013; Seattle, Washington. Abstract 34.
  9. Gebel H, Kasiske B, Gustafson S, et al. Allocating deceased donor kidneys to high PRA patients: a simulation. Presented at the 2013 American Transplant Congress; May 18–22, 2013; Seattle, Washington. Abstract 479.
  10. O’Leary J, Kaneku H, Jennings L, Susskind B, Terasaki P, Klintmalm G. High MFI preformed class II HLA donor specific alloantibodies increase the risk of early rejection and death after liver transplantation. Presented at the 2013 American Transplant Congress; May 18–22, 2013; Seattle, Washington. Abstract 278.
  11. MacDonald D, Jackson S, Matas A, Spong R, Kukla A, Ibrahim H. Long term outcomes of young (<18 years) kidney donors: a matched cohort analysis. Presented at the 2013 American Transplant Congress; May 18–22, 2013; Seattle, Washington. Abstract 190.
  12. Lohlun J, Mingmalairak C, Lake J, et al. Liver transplantation for severe hepatopulmonary syndrome. Presented at the 2013 American Transplant Congress; May 18–22, 2013; Seattle, Washington. Abstract 146.
  13. Bestard O, Cruzado J, Taco O, et al. Liver allografts do not always protect from kidney allograft rejection in sensitized recipients of simultaneous liver-kidney transplants. Presented at the 2013 American Transplant Congress; May 18–22, 2013; Seattle, Washington. Abstract 267.
  14. Halldorson J, Bakthavatsalam R, Dick A, Rayhill S, Perkins J, Reyes J. Antithymocyte globulin induction is associated with improved graft survival and reduced ischemic cholangiopathy after DCD liver transplantation as compared to basiliximab. Presented at the 2013 American Transplant Congress; May 18–22, 2013; Seattle, Washington. Abstract 280.
  15. Knaak J, Boehnert M, Spetzler V, et al. Subnormothermic ex vivo liver perfusion (SNEVLP) reduces ischemia/reperfusion injury in livers retrieved after cardiac death. Presented at the 2013 American Transplant Congress; May 18–22, 2013; Seattle, Washington. Abstract 289.
  16. Andrés A, Molina M, Gonzalez E, et al. Effectiveness in kidney donation of the Uncontrolled Donation after Cardiac Death (UDCD) Program with out-of-hospital deceased people. Presented at the 2013 American Transplant Congress; May 18–22, 2013; Seattle, Washington. Abstract 535.
  17. Johansen KL, Chertow GM, Jin C, Kutner NG. Significance of frailty among dialysis patients. J Am Soc Nephrol. 2007;18:2960–2967.
  18. McAdams-DeMarco M, Law A, Salter M, Walston J, Segev D. Frailty and early hospital readmission after another kidney transplantation. Presented at the 2013 American Transplant Congress; May 18–22, 2013; Seattle, Washington. Abstract 92.
  19. Waits S, Kim E, Terjimanian M, et al. Morphometric age as a predictor of post liver transplant survival. Presented at the 2013 American Transplant Congress; May 18–22, 2013; Seattle, Washington. Abstract 567.
  20. Lentine KL, Costa SP, Weir MR, et al; American Heart Association Council on the Kidney in Cardiovascular Disease and Council on Peripheral Vascular Disease. Cardiac disease evaluation and management among kidney and liver transplantation candidates. J Am Coll Cardiol. 2012;60:434–480.
  21. Pelletier R, Rajab A, Pesavento T, Henry M. Pre-transplant cardiovascular risk factors improve the SRTR Cox proportional hazard model for 1 year patient survival after deceased donor kidney transplant. Presented at the 2013 American Transplant Congress; May 18–22, 2013; Seattle, Washington. Abstract 333.
  22. O’Leary J, Verna E, Burton J, et al. A high rate of eRVR with protease inhibitor-triple HCV therapy in liver transplant recipients: a multicenter study from CRUSH-C. Presented at the 2013 American Transplant Congress; May 18–22, 2013; Seattle, Washington. Abstract 5.
  23. Aqel B, Carey E, Douglas D, et al. Preliminary experience utilizing boceprevir with pegylated interferon and ribavirin for treatment of recurrent hepatitis C genotype 1 after liver transplantation. Presented at the 2013 American Transplant Congress; May 18–22, 2013; Seattle, Washington. Abstract 365.
  24. Muzaale A, Massie A, Wainright J, McBride M, Wang M, Segev D. Long-term risk of ESRD attributable to live kidney donation: matching with healthy non-donors. Presented at the 2013 American Transplant Congress; May 18–22, 2013; Seattle, Washington. Abstract 565.
  25. Khamash K, Heilman R, Chakkera H, et al. Small donor size adversely impacts kidney allograft function following living donor kidney transplant. Presented at the 2013 American Transplant Congress; May 18–22, 2013; Seattle, Washington. Abstract 74.
  26. De Simone P, Detry O, Kintmalm G, et al. Superior renal function sustained for 24 months through early everolimus-facilitated reduction of tacrolimus versus standard tacrolimus in de novo liver transplant recipients: results of a randomized trial. Presented at the 2013 American Transplant Congress; May 18–22, 2013; Seattle, Washington. Abstract 450.
  27. De Simone P, Nevens F, De Carlis L, et al. Everolimus with reduced tacrolimus improves renal function in de novo liver transplant recipients: a randomized controlled trial. H2304 Study Group. Am J Transplant. 2012;12:3008–3020.
  28. Kawai T, Sachs DH, Sykes M, Cosimi AB. HLA-mismatched renal transplantation without maintenance immunosuppression. Immune Tolerance Network. N Engl J Med. 2013;368:1850–1852.
  29. Scandling J, Busque S, Shori A, et al. Uniform long-term graft survival in a clinical trial of the induction of tolerance to kidney transplants. Presented at the 2013 American Transplant Congress; May 18–22, 2013; Seattle, Washington. Abstract 548.
  30. Leventhal J, Abecassis M, Miller J, et al. Update on phase 2 clinical trial to induce tolerance to mismatched living donor renal transplant recipients. Presented at the 2013 American Transplant Congress; May 18–22, 2013; Seattle, Washington. Abstract 549.

Dr. Lockridge is a Clinical Lecturer and Fellow in Nephrology in the Department of Medicine, University of California, San Francisco, Medical Center, San Francisco, California.

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