open access: Nature Reviews: Key Advances in Medicine

NEPHROLOGY
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(2010).
TRANSPLANTATION IN 2011
New agents, new ideas and new
hope
Titte R. Srinivas and Bruce Kaplan
The past year was marked by several excellent studies that represent
important therapeutic advances in kidney transplantation or that further
our understanding of the genetic basis of chronic allograft dysfunction,
clinical tolerance and outcomes of kidney transplantation.
Srinivas, T. R. & Kaplan, B. Nat. Rev. Nephrol. 8, 74–75 (2012); published online 20 December 2011;
doi:10.1038/nrneph.2011.215
The year 2011 was marked by the addition
of an important alternative to calcineurin
inhibitors for immuno suppression
in kidney transplantation. Calcineurin
inhibitor-based combina tions are the most
frequently utilized immuno suppressive
regimens in kidney transplantation, but
they carry a metabolic burden and may
be associated with both short-term and
possibly progressive diminution in graft
function. Belatacept is a costimulation
blocker that binds to CD80 and CD86
on antigen- presenting cells and provides
Key advances
■ 3-year follow-up of BENEFIT demonstrates
that belatacept provides superior renal
function outcomes to ciclosporin 3
■ Sensitized patients treated with a
desensitization regimen have better
survival than patients on dialysis
or sensitized patients who undergo
compatible transplantation 4
■ Discovery of APOL1 variants in African
Americans points to a biological
influence rather than race underlying
transplantation outcomes 6
■ Increased cold ischemia times of
extended criteria donor kidneys are
associated with delayed graft function,
but do not affect graft survival 10
effective immuno suppression while being
devoid of renal and nonrenal metabolic
adverse effects. 1 A phase III study of
belatacept (BENEFIT) published in 2010
reported superior renal function and an
improved cardiovascular and metabolic
risk profile compared with a ciclosporinbased
regimen. 2 In this trial, 686 de novo
kidney transplant recipients (of living and
standard criteria deceased donor kidneys)
were randomly assigned to more-intensive
or less-intensive belatacept regimens or to
ciclosporin. All patients received basiliximab
induction therapy, mycophenolate
mofetil and corticosteroids. Equivalent
rates of graft and patient survival were
noted despite an increased frequency and
severity of early rejection episodes and
increased frequency of post-transplant
lympho proliferative disorder associated
with belatacept. 2
Vincenti et al. have now reported on the
efficacy and safety of belatacept at 3 years
post-transplantation in the BENEFIT
study. 3 Graft survival was equivalent across
all regimens. At year 3 post- transplantation,
the mean estimated glomerular filtration
rate (eGFR) was 21 ml/min/1.73 m 2 higher
in the belatacept groups than in the ciclosporin
group. More importantly, from
month 3 through to month 36, the slope
of eGFR in the belatacept groups averaged
1.1 ml/min/1.73 m 2 per year versus
–2.0 ml/min/1.73 m 2 per year with ciclosporin.
Neither a significant increase in
acute rejection episodes nor new cases of
post-transplant lymphoproliferative disorder
after 18 months post-transplantation
were observed. 3 Taken together, these findings
are indeed gratifying and represent
the emergence of a non-nephrotoxic and
efficacious immunosuppressive regimen
in renal transplantation. This study also
demon strated a disconnect between rejection
rates and graft survival and function,
which either reflects short follow-up or
reasons that prompt reconsideration of
the relationship between classic T-cellmediated
rejection and outcomes. Although
initial results from BENEFIT are promising,
their generalizability to clinical practice at
large will depend on a paradigm shift from
oral maintenance therapy to infusion-based
therapy. As such, whether the promising
initial results are sustainable on logistical
and economic grounds needs further study.
Sensitized transplant candidates have
prolonged waiting times, a reduced
transplanta tion rate and an increased rate
of death compared with nonsensitized
candidates. Although numerous centers
report successful utilization of desensitization
regimens in renal transplantation,
they are plagued by the absence of suitable
control groups. Montgomery et al. compared
outcomes in 211 HLA-sensitized live
donor kidney transplant recipients treated
with low-dose intra venous immunoglobulin
and plasma pheresis with that of
two matched control groups drawn from
the United Network for Organ Sharing
kidney transplant waiting list who either
remained on dialysis (dialysis- only group)
or who were dialyzed or underwent
HLA-compatible renal transplantation
(dialysis-or- transplantation group). 4 In
the desensitized group, estimates of patient
survival were 90.6%, 85.7% and 80.6% at 1,
3 and 5 years, respectively, versus 91.1%,
67.2% and 51.5% in the dialysis-only
group and 93.1%, 77.0% and 65.6% in the
dialysis-or-transplantation group (overall
P