© 2013 Direct One Communications, Inc. All rights reserved. 1 What’s Hot, What’s New Joseph B....

© 2013 Direct One Communications, Inc. All rights reserved. 1

What’s Hot, What’s New

Joseph B. Lockridge, MD

University of California, San Francisco, Medical Center, San Francisco, California A REPORT FROM THE 2013 AMERICAN TRANSPLANT CONGRESS


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 respective G protein–coupled receptors (C3aR and C5aR) expressed on T cells to provide costimulatory signals that limit Treg cell function.

» Blocking C3a/C3aR and C5a/C5aR ligations favors induction and stability of murine and human Treg cells.2

» This potential pharmacologic target could facilitate transplant-related induction of immune tolerance to alloantigens.


Belatacept

Licensed in 2011, this novel selective T-cell costimulation blocker prevents rejection in adult kidney transplant recipients.

Results in improved renal function and a higher rate of acute rejection but similar patient and graft survival at 1 year when compared with cyclosporine.

Combining belatacept with a secondary costimulatory receptor antagonist (OX40L) improved graft survival in mice and rhesus macaques.3


T- and/or B-cell Regulation

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. » 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.

» IL-33 expands an ST2+ subset of Treg cells in vivo, and IL-33 mediates Treg expansion and Th2 polarization of CD4+ T cells via ST2+ CD11c+ dendritic cells.


Donor-specific Antibodies (DSAs)

Everly and colleagues5 collected sera longitudinally from 186 kidney transplant recipients.

Sera were retrospectively tested for human leukocyte antigen (HLA) immunoglobulin (Ig) G, IgM, and IgG3 antibodies.

In patients who developed IgG DSAs, persistence of IgM DSA along with an isotype switch to IgG3 DSA increased the risk of graft loss when compared with those without both persistent IgM and IgG3 isotype switching.


Renal Allograft Failure

The annual rate of renal allograft failure beyond the first year after surgery has remained constant.6

In the DeKAF study,7 the rate of antibody-mediated rejection reached 57% in patients with late allograft dysfunction and was associated with accelerated graft failure.

Gaston et al8 recently reported extended survival data on 469 patients in this study, concluding that:

» Allograft failure is uncommon in the absence of evidence of humoral immune reactivity.

» Preventing and treating alloimmune injury to promote long-term graft survival are important.


Kidneys for Highly Sensitized Patients

Gebel et al9 investigated whether compatible kidneys exist for highly sensitized patients on the deceased-donor waiting list with a calculated panel reactive antibody level of 100, then 99, 98, etc.

Of 13,591 deceased-donor kidneys available, 13,118 were appropriate for highly sensitized candidates, as compared with 1,517 actually transplanted under the current allocation system.

The authors concluded that most sensitized patients have virtually compatible donors and the likely barrier to transplant involves limits to our current allocation system, not the patient’s antibody profile.


Preformed DSAs and Graft Rejection

O’Leary and colleagues10,11 examined the impact of preformed DSAs on the risk of rejection and patient survival in 1,270 liver transplant recipients, finding that the presence of class II DSAs was associated with an increased risk of early rejection and that the presence of preformed class I or class II DSAs was an independent predictor of patient mortality.

Kaneku et al12 studied a de novo IgG3 subclass of DSAs to identify patients at risk of liver graft loss, concluding that the presence of de novo DSAs was associated with a decrease in graft survival and that the production of IgG3 DSAs was associated with an increased risk of graft failure.


Dual Organ Transplantation

Bestard and colleagues13 investigated whether sensitization affects simultaneous liver-kidney transplants (SLKTs) differently or if a protective phenomenon affects either organ post transplant.

Sensitized transplant recipients had a higher risk of renal allograft rejection when compared with unsensitized patients.

In a survival analysis, SLKT recipients with a percent PRA > 25% were at greater risk of renal allograft loss when compared with unsensitized patients.

Thus, liver allografts may not fully protect the renal allograft, especially among sensitized patients.


Donation After Cardiac Death (DCD)

Halldorson et al14 studied induction with antithymocyte globulin (ATG) or basiliximab as related to graft survival and ischemic cholangiopathy after DCD liver transplantation.

Survival of patients and grafts significantly increased in the ATG group.

Biliary complication- and ischemic cholangiopathy-free graft survival outcomes significantly improved with ATG induction.


Machine Perfusion of Liver Transplants

Knaak and colleagues15 compared standard cold static liver preservation with subnormothermic ex vivo liver perfusion (SNEVLP) on DCD pig liver transplant outcomes.

SNEVLP was associated with a reduction in aspartate transaminase levels, reduced markers of apoptosis and endothelial cell injury, and a reduction in bile-duct injury.

The reduction in reperfusion injury associated with this new technology opens the possibility for a role in expanding the current liver donor pool.


Uncontrolled DCD (uDCD) Outcomes

Andrés and colleagues16 instituted a uDCD program with local emergency services.

Transplant was possible for 69% of the total number of 254 procured kidneys.

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%.


Frailty Predicts 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 risk of early hospital readmission (EHR).

Altogether, 30.9% of patients were readmitted within 30 days of initial hospital discharge.

Recipients who were frail at the time of transplant, as judged by walking speed, exhaustion, decreased grip strength, low physical activity, and unexplained weight loss, were more likely to experience EHR.


Morphometric Age and Outcomes

Waits et al19 calculated a liver transplant recipient’s “morphometric” (as opposed to chronologic) age, using preoperative CT scans and such baseline features as trunk muscle size, muscle density, and vascular calcification, to predict clinical outcomes.

After adjusting for other relevant covariates, morphometric age was a significant predictor of both 1-year and 5-year mortality.

Among the chronologically middle-aged tercile, there was a marked difference in 1- and 5-year survival between morphometrically young and old patients.


Cardiovascular Factors and Outcomes

Pelletier and colleagues20 assessed 1-year patient survival and graft loss in kidney transplant recipients by including various cardiovascular comorbidity characteristics as additional risk factors in the Scientific Registry of Transplant Recipients (SRTR) model for predicting 1-year patient survival.

The addition of these variables significantly improved discrimination in the SRTR model.

The strongest predictors of 1-year survival among deceased-donor kidney recipients were a reduction in left-ventricular ejection fraction, the presence of type 2 diabetes, and myocardial infarction.


Hepatitis C Virus (HCV) Infection

O’Leary and others21 evaluated the safety and efficacy of triple HCV therapy (pegylated interferon, ribavirin, and protease inhibition) in 121 liver transplant recipients with HCV genotype 1.

In all, 62% of participants in this study achieved an extended rapid viral response by week 12.

The authors cautioned, however, that triple therapy in this cohort requires intense monitoring and is associated with common adverse effects and a 1.7% risk of death.


HCV Recurrence After Liver Transplant

Aqel et al22 studied boceprevir-based triple therapy to treat HCV recurrence in liver transplant patients.

Among 16 patients enrolled, there was a 38% extended viral response at 12 weeks.

In an intent-to-treat analysis, 23% of the patients achieved a sustained viral response by 72 weeks.

Both studies showed hope for applicability of triple therapy to the transplant population, but optimal response rates remain questionable.

Rates of adverse effects were significant, including cytopenias and acute kidney injury.


Complications of Living Kidney Donation

Limitations to assessing the long-term risk of complications after live kidney donation include the difficulty of matching appropriate healthy, non-donor controls for comparison.

The risk of developing ESRD after living-donor kidney transplantation was assessed by comparing living kidney donors with the general population.

However, this strategy may be misleading because the general population tends to be less healthy than carefully screened living kidney donors.



Muzaale and colleagues23 used an algorithm that included age, gender, race, education, body mass index, systolic blood pressure, and smoking history to generate controls from NHANES data.

In all, 96,217 kidney donors from OPTN reports were matched to these generated controls.

The incidence of ESRD at 15 years was 8-fold higher for living 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 (0.23%).



When evaluating the risk-benefit profile of living kidney donation, transplant clinicians must evaluate the quality of the donated kidney.

Khamash and colleagues24 studied the impact of donor size, donor-age differences, and donor glomerular filtration rate (GFR) on renal function post transplant.

In a multivariate analysis, all of these variables in living donors were associated with an increased risk of renal impairment (GFR < 40 mL/min) 1 year after surgery.


CNI Minimization with Everolimus

De Simone et al25 studied the potential of everolimus in reducing calcineurin inhibitor (CNI) nephrotoxicity in 719 liver transplant recipients, extending their previous 12-month results26 to 24-month follow-up.

Superior renal function was observed with everolimus therapy and reduced tacrolimus exposure when compared with standard tacrolimus monotherapy.

The rate of biopsy-proven acute rejection was higher in the cohort receiving standard-dose tacrolimus than among the groups treated with everolimus and reduced-dose tacrolimus therapy or everolimus with tacrolimus withdrawal.


Tolerance Induction: B-cell Depletion

Kawai and others27 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 were followed with additional rituximab doses given post transplant.

By 8–14 months after transplant surgery, 7 of 10 patients were able to successfully discontinue immunosuppressive therapy.


Tolerance Induction: Stem Cell Transplant

Scandling et al28 used a conditioning regimen with total lymphoid irradiation followed by infusion of purified donor CD34+ hematopoietic progenitor cells and T cells.

In 29 patients, no grafts were lost due to rejection

3 months to 12 years following transplantation, and graft function has remained excellent.

Altogether, 15 of the 29 patients were withdrawn completely from immunosuppressive medication.

No episodes of graft-versus-host disease (GVHD) and a low incidence of serious adverse events were reported.


Tolerance Induction: Stem Cell Transplant

Leventhal et al29 reported results from a phase II trial in 19 patients given tolerogenic CD8+/TCR– facilitating cells and conditioning with fludarabine and cyclophosphamide followed by kidney transplantation.

Altogether, 8 of the 19 patients were withdrawn from immunosuppressive medication without adverse consequences.

Five patients did not sustain chimerism for longer than 6 months, with three exhibiting graft rejection.

No episodes of GVHD were reported.


References1. Roncarolo MG, Battaglia M. Regulatory T-cell immunotherapy for tolerance to self antigens and

alloantigens in humans. Nat Rev Immunol. 2007;7:585–598.

2. van der Touw W, Cravedi P, Kwan WH, Paz-Artal E, Merad M, Heeger PS. Cutting edge: receptors for C3a and C5a modulate stability of alloantigen-reactive induced regulatory T cells. J Immunol. 2013;190:5921–5925.

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.


References10. 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. Kaneku H, O'Leary J, Bañuelos N, et al. Impact of de novo IgG3 DSA in graft survival after liver transplantation. 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.


References18. 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. 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.

21. 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.

22. 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.

23. 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.

24. 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.

25. 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.


References26. 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.

27. 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.

28. 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.

29. 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.

© 2013 Direct One Communications, Inc. All rights reserved. 1 What’s Hot, What’s New Joseph B....

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