genberg.qxp 9/7/07 10:00 am Page 58
Transplantation
Figure 3: Median Change in B-cell Detection by Flow Cytometry
limitations to LD transplantation
57
if the recipient has either AB0 or
HLA antibodies against the donor antigens. The presence of such
140
antibodies has frequently contraindicated LD donation, as these
antibodies give rise to a severe acute rejection. The immunological
120
CD19+ cells
barriers posed by AB0 and HLA account for an estimated 30–50% of
CD20+ cells
100
all LD rejections. Therefore, effective desensitisation eliminating the
donor-specific antibodies could yield a substantial increase in the
80
number of transplantations performed. For this reason, desensitisation
p<0.05 at all time
points compared to baseline protocols are being developed.
60
c
roL peripheral blood
40
Current desensitisation protocols are all based on the same principle: to
Cells/mi
remove existing antibodies and prevent rebound of antibodies in the
20
kidney recipient after transplantation. There are a number of apheresis
techniques available for the removal of antibodies. Generally, several
0
apheresis sessions are needed both prior to and after transplantation. To
to 2 to 6
10
c
ontrols
Day 0
8
to
1 to 13 4 to 16 7 to 20 2 to 26 8
to 31
4 to 43 prevent rebound, apheresis is combined with immunosuppressive
Day 1 to 3
W
e
ek 1
W
e
ek 3
W
e
ek 6 to 10
Month 3 to 6Month 6 to 7
Healthy
Month
Month 1Month 1Month 1Month 2Month 2Month 3
therapy, including oral immunosuppression, intravenous immunoglobulin
and antibody induction. Some centres also perform splenectomy.
58
Time in relation to rituiximab treatment
Splenectomy used to be mainstay therapy for the reduction of the
Change (median) in CD19+ and CD20+ cell count (cells/µl peripheral blood) after treatment
with rituximab. Immunophenotyping by flow cytometry. Day 0 = prior to treatment. Healthy
antibody-producing B-cell/plasma cell population, but is now being
controls = no treatment with rituximab or any other immunosuppressive. A profound and
replaced by rituximab. The donor-specific antibody levels are monitored,
sustained B-cell depletion is observed in kidney recipients treated with single-dose rituximab
in combination with tacrolimus, mycophenolate mofetil and corticosteroids.
and transplantation is performed when the antibodies are sufficiently
eliminated (see Figure 4). Usually, this process takes 1–2 weeks, making
Source: Genberg H, et al., 2006.
47
desensitisation almost exclusively limited to LD transplantation.
promising antibodies in transplantation include belatacept (CTLA4-Ig), a AB0-incompatible Kidney Transplantation
co-stimulatory blocker, and epratuzumab, a B-cell-depleting CD22 AB0-incompatible (AB0i) kidney transplantation has gained renewed
antibody. Belatacept in kidney transplantation is currently being interest over the past few years as new, more effective immunosuppressive
evaluated in phase I–III clinical trials. Use of epratuzumab is so far limited therapies have evolved. There are several protocols for AB0i kidney
to phase I and II trials in patients with leukaemia.
51
Monitoring Immunosuppressive Therapy
Antigen-specific immunoadsorption has
In clinical practice, immunosuppression is administered according to
a major advantage over plasmapheresis,
general schemes and dosing is based on body weight, body surface area
and/or drug concentration in blood. However, despite careful dosing and
since only AB0 antibodies are removed.
strict adherence to recommended drug levels, it is impossible to predict
Potentially serious complications of
the biological effects of the immunosuppression given. As a consequence,
clinical problems related to under- or over-immunosuppression are
coagulopathy secondary to
common. A method to determine the immunosuppressive status after
plasmapheresis are thereby avoided.
organ transplantation is therefore needed. Valid data regarding the
immunosuppressive status in combination with other clinical parameters
would most likely facilitate the monitoring and follow-up of transplant transplantation, all based on the principles described above. Japan has the
recipients, possibly improving long-term results. Today, only one assay to largest series of AB0i transplantations, with long-term results similar to
evaluate immunological risk is commercially available (ImmuKnow
®
, those for AB0-compatible (AB0c) LD transplantation.
59
The Japanese
Cylex Inc., Columbia, MD, US).
52,53
In this assay, adenosine tri-phosphate centres use either plasmapheresis or double-filtration plasmapheresis for
production in CD4+ T-cells after para-aminohippuric acid stimulation is antibody removal. To prevent rebound, splenectomy and/or rituximab and
measured. However, this assay yields only a limited and fairly unspecific standard immunosuppression is used.
estimate of the immunosuppressive status. Obviously, there is a great
need for other and possibly improved methods to determine In Europe, after the introduction of antigen-specific immunoadsorption
immunosuppressive status. using the Glycosorb AB0
®
system (Glycorex, Lund, Sweden) in 2001, the
field of AB0i kidney transplantation has grown quickly. Antigen-specific
Desensitisation immunoadsorption has a major advantage over plasmapheresis, since
There is a worldwide shortage of organs from DDs. Consequently, as only AB0 antibodies are removed. Potentially serious complications of
the demand for kidney transplantation is constantly growing,
54
coagulopathy secondary to plasmapheresis are thereby avoided. This
methods to expand the donor pool are becoming increasingly method has now been tested at around 20 centres worldwide, primarily
important. LD kidney transplantation is not only a means to expand in Europe, and more than 160 kidney transplantations have been
the donor pool but also offers superior patient and graft survival performed. We and others have shown that the short-term outcome of
compared with DD transplantation.
55,56
However, there are some these transplantations is very good, with a patient and graft survival equal
58 EUROPEAN RENAL DISEASE 2007