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
© 2013 Direct One Communications, Inc. All rights reserved.
1
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.
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2
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
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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 IL33 mediates Treg expansion and Th2 polarization of CD4+ T
cells via ST2+ CD11c+ dendritic cells.
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4
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.
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5
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.
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6
Kidneys for Highly Sensitized Patients

Gebel et al9 investigated whether compatible kidneys
exist for highly sensitized patients on the deceaseddonor 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.
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7
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.
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8
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.
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9
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 cholangiopathyfree graft survival outcomes significantly improved
with ATG induction.
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10
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.
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11
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%.
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12
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.
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13
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.
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14
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.
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15
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.
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16
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.
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17
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, nondonor 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.
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18
Complications of Living Kidney Donation

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%).
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19
Complications of Living Kidney Donation

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.
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20
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.
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21
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.
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22
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.
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23
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.
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24
References
1.
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 posttransplant 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.
© 2013 Direct One Communications, Inc. All rights reserved.
25
References
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. 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.
© 2013 Direct One Communications, Inc. All rights reserved.
26
References
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. 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.
© 2013 Direct One Communications, Inc. All rights reserved.
27
References
26. 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.
28