Progress in renal transplantation
Christopher G. French, MD, Philip Belitsky, MD, Joseph G. Lawen
Department of Urology, QEII Health Science Center, Dalhousie University, Halifax, Nova Scotia
FRENCH CG, BELITSKY P, LAWEN JG. Progress in
Renal Transplantation. The Canadian Journal of
Urology. 2000;7(3):000-000.
Purpose: The improvements in renal transplantation
over the last 10 years have been one of the great success
stories in medicine. We have reviewed these successes
with a focus on the following: changes in demographics
of donors and recipients in Canada, the benefits of new
immunosuppressive regimes and the efforts to minimize
their toxicity and finally, our understanding of measures
to circumvent chronic rejection.
Materials and methods: A review of current
transplantation literature was performed and pertinent
data presented. As well, information from the Canadian
Organ Replacement Register was selected to provide an
overview of changes in renal transplantation in Canada.
Results: Despite the stable rate of transplantation in
Canada, the number of new patients starting dialysis each
year roughly equals the entire national renal transplant
waiting list. These patients are older and have more
complex co-morbidities, mandating prudent use of
immunosuppression so as to minimize toxicity. Standard
Introduction
Renal transplantation is the preferred treatment for
virtually all causes of end-stage renal disease (ESRD).
Since the description of the first renal transplants in non-
Accepted for publication May 2000
Address correspondence to Dr. Philip Belitsky, MD,
Professor of Urology, Dept. of Urology, Faculty of Medicine,
Dalhousie University, Rm.294 5 South, Victoria Building,
1278 Tower Road, Halifax, Nova Scotia B3H 2Y9
Tel: (902) 473-5469 Fax: (902) 473-5850
The Canadian Journal of Urology; 6(5); October 1999
triple therapy consists of a calcineurin inhibitor, an
antimetabolite and corticosteroids. Antibody therapy is
indicated in sensitized recipients and newer monoclonal
humanized antibodies offer less toxicity. Nonspecific
therapies are less favorable, due to unwanted side effects.
We can now identify subsets of patients who are most
likely to benefit from specific therapy. Newer non-
nephrotoxic agents hold promise for future regimens.
However, a paucity of large, multicenter, randomized
trials, tested against standard protocols, limits their
current indications. Many immunologic and non-
immunologic factors influence the outcome of renal
transplantation and play a role in the development of acute
and chronic rejection.
Conclusions: The challenges of renal transplantation
over the next 10 years are: 1) in the development of specific
therapies that can be altered according to patient
co-morbidities and other factors influencing outcome;
2) minimizing toxicity; 3) preventing chronic rejection;
and 4) improving our national organ donation network.
K e y Wo r d s : transplantation, k i d n e y,
immunosuppression
immunosuppressed patients by Hume, 50 years ago, we
have been witness to remarkable improvements in
clinical outcomes.1 Graft survival has increased and
episodes of acute rejection have decreased. We have a
better understanding of the complex immunological
processes involved in transplantations that have aided
the development of immunosuppression regimes
meant to target specific T-cell interactions and to interrupt
distinct biochemical pathways. There has been a paradigm
shift from broad nonspecific immunosuppression to new
combinations aimed at lowering overall doses and
maximizing outcomes, while minimizing toxicities.
Modern immunosuppression has catapulted the
 Figure 1 New Patients by Age Group (65-74 & 75+) and Dialysis Type
at Registration, Canada 1988 - 1998
RPMP (Age-specific Rate Per Million Population)
500
450
400
350
300
250
200
150
100
50
0
1988 1989 1990 1991 1992
Haemo Age 65-74
Peri Age 65-74
success of renal transplantation. This has provided the
necessary foundation for foreshortening the
development of transplantation of other organs. We
now live in era where the majority of deaths in
patients with a functioning graft are caused by
cardiovascular and infectious complications. Diabetes
is the number one cause of ESRD. As our population
ages, a greater number of older patients with more
complex co-morbidities will develop ESRD. 2,3
These factors emphasize the importance of limiting
the complications that shorten the lifespan of
transplant recipients.
The success of renal transplantation produces a
new set of problems. That is, we have far more patients
entering transplant annual waiting lists than there are
available kidneys. Many ethical questions arise when
we consider allocating organs to those with the most
favorable probable outcome. Most centers in Canada
primarily allocate cadaveric organs to those longest
on the waiting list, as opposed to those with favorable
characteristics. The boundaries of living donor
transplantation have broadened to include non-related
donors, which have undermined the importance of
histocompatibility. Similarly, there is acceptance of
marginal cadaveric renal donors at ages less than
5 and greater than 60 years of age. Organ donation
rates for industrialized countries, including Canada,
1993 1994 1995 1996 1997 1998
Haemo Age 75 plus
Peri Age 75 plus
unfortunately remain low. The critical nature of
increasing the public awareness and understanding
of issues surrounding brain death and the benefits of
a life-saving transplant has been recognized by both
governments and transplant scientists.
In this article we will discuss the advances in renal
transplantation that have occurred within the last
decade. We will focus on the following issues: changes
in demographics of donors and recipients; the benefits
of new immunosuppressive regimes; and the efforts
to minimize side effects and circumvent the insidious
graft deterioration seen in chronic rejection.
Demographics and outcomes
The total number of renal transplants per year has
remained relatively stable in Canada. In 1993 there were
890 renal transplants performed in Canadian patients.
Five years later, in 1997, that number rose to only 969.
The renal transplant rates per-million population (rpmp)
were 29.6 and 32.3 respectively. In 1997, the number of
new patients starting dialysis in Canada (hemodialysis
and peritoneal dialysis) was 3649, which is slightly
higher than the total number of patients on the waiting
list for transplantation, 3434.2 New dialysis rates are
climbing and with it are the average age of starting
dialysis (Figure 1). Elderly patients are more likely to
The Canadian Journal of Urology; 6(5); October 1999
start hemodialysis, thus increasing the overall cost of
TABLE 1. International organ donation rate (1997 data)
renal replacement therapy. Transplantation has been
clearly shown to decrease overall mortality, improve Country Population x 106 No. of donors PMP
quality of life, and lessen the financial burden to the
health care provider.
ET* 113.4 1634 14.4
One of our greatest challenges is in increasing the
number of kidneys available for transplantation. The France 58.8 993 16.9
sources of kidney transplants remains varied according
to center but, as living related donation increases, the Spain 39.99 1250 31.5
source of donors approaches an equal distribution of Switzerland 7 108 15.4
living related and cadaveric donors. Success in living
related transplantation is important but this is dwarfed UK and Ireland 62.71 846 13.5
by our failure to procure many organs at the time of
Australia 18.75 196 10.5
brain death. Canadian donation is on par with most
industrialized countries (Table 1) but falls behind the Canada 30.29 436 14.4
most successful by more than 50%. The Spanish
transplant organization boasts a per million population
cadaver donation rate of 31.5 compared to 14.4 in Organ donation rate is expressed in pmp (per million population).
Canada. Thus we need to educate our population and *ET – Eurotransplant: Germany, Austria, Belgium, Luxemburg,
implement strategies to increase these numbers. Netherlands
The results of living related transplantation are The source of data for these international organ donation
consistently better than cadaver transplants. The one- rates for 1997 (excluding Canada) is the ONT (National
year graft survival in each group approaches 100%. Organization of Transplants, Spain) International Data on
However, cadaveric transplants are at a much greater Organ Donation and Transplantation. The source of data for
risk of delayed graft function, acute rejection, and the Canadian organ donation rate is the 1999 CORR Report.
progressive deterioration. These all highlight the
importance of avoiding ischemic injury and
undermine the importance of histocompatibility. The
implications are that we now commonly perform
spouse to spouse, six antigen, mismatched, living TABLE 2. Factors influencing the outcome of renal
related transplants without fear of increased acute transplantation
rejection. The factors influencing the outcomes of
renal transplantation are listed in Table 2. Immunologic immunosuppression
The most important predictor of acute rejection in rejection
cadaveric transplantation is delayed graft function.
sensitization
Once there is an early immunological injury, chronic
matching for HLA
rejection becomes more likely. Each adverse event
increases the risk of functional compromise and
places the graft at risk for a different adverse event. In part immunologic delayed graft function
The maintenance of early graft function and the ischemic times
development of early pharmacological tolerance are recipient age
key factors for long-term graft survival. original disease
donor age
Immunosuppression
race
Advances in immunosuppression have led the bilateral nephrectomy
transplantation community to important crossroads
(Table 3). The introduction of Cyclosporin (Csa) by Calne Nonimmunologic compliance
as the mainstay of transplant immunosuppression cardiovascular disease
single handedly initiated the era of multiorgan center effect
transplantation. 4 The development of a new Csa clinical care
formulation, Neoral®, has improved bioavailability and
demonstrated to be superior to the previous oil-based
 TABLE 3. Current immunosuppressive agents for organ transplantation

Class Mechanism/Ligand

Antibodies Polyclonal ALG/ATG Multiple T-cell sites

Monoclonal OKT3 CD3 (murine)
Basiliximab IL-2 receptor (human/murine)
Daclisumab IL-2 receptor (human)

Calcineurin inhibitors Cyclosporin Cyclophilin and inhibits IL-2 transcription

Tacrolimus FKBP and inhibits IL-2 transcription

Antimetabolites Azathioprine inhibits DNA/RNA synthesis

Mycophenolate de-novo purine synthesis

Corticosteroids inhibits expression of IL-1,2 and 6 genes

Other Rapamycin blocks IL-2 signal, antiproliferative

FTY720 signal transduction/lymphocyte homing
Soluble MHC recognition of self
Oligonucleotide blocks transcription (ICAM-1)

product. 5 Standard maintenance immunosuppression
varies with each center but the most widely used
combination of immunosuppression remains a triple
therapy regimen of a calcineurin inhibitor (Csa or
tacrolimus), an antimetabolite (mycophenolate mofetil
(MMF) or azathioprine (Aza)) and corticosteroids. The
specific antimetabolite MMF has proven to be superior
to Aza in efficacy and many authors feel that the use
of Aza will likely become of historical interest only.
Induction therapies with antibodies remain
a controversial issue. Patients with higher risk
profiles such as pediatric recipients, or with prior
sensitization due to blood transfusion, childbirth, or
previous transplants, warrant consideration. Yet
studies suggest that rejection may only be delayed
during therapy. Antibodies should not be used as a
safeguard against rejection in the face of poor
maintenance drug exposure. The role of antibody
therapy in the treatment of acute rejection
refractory to pulse steroids is indisputable. The
drawbacks of antibody therapy are related to cost,
overimmunosuppression, and the immediate host
reaction, which include a higher risk of viral infection,
post transplant lymphoproliferative disorder (PTLD),
cytokine release syndrome, and nephrotoxicity. 6
Humanized monoclonal antibodies which target the
IL-2 receptor, however, have minimized the side
effects associated with cytokine release. Newer agents
which target lymphocyte adhesion and co-stimulation
are under current investigation.
Calcineurin inhibitors such as Csa and tacrolimus
are the backbone of modern immunosuppression.
Csa binds cyclophilin, an intracellular protein,
thereby inhibiting calcineurin, which is necessary
for the phosphorylation of DNA binding proteins.
This alters the cells ability to transcribe IL-2, thus
inhibiting T-cell activation. The absorption of the fat
soluble Csa is dependant on bile salt function, so
protocols for liver transplantation preferentially
include tacrolimus, which is less dependant on bile
formation. Csa and tacrolimus are absorbed from
the gastrointestinal tract with tremendous
interindividual variability and this mandates the
need for close monitoring of blood levels. Absorption
profiles vary between individuals so that traditional
trough monitoring is not a true surrogate of 24 hr
drug exposure. Grafts can undergo acute rejection
with high trough levels and show no signs of toxicity
or, alternatively, renal function may deteriorate
due to nephrotoxicity despite subtherapeutic trough
levels.7,8,9 The key to avoiding drug toxicity or acute
rejection lies with fitting drug doses to the proper
therapeutic window. Recent evidence suggests that
monitoring the area under the concentration-time
curve (AUC) or alternatively estimating AUC by
measuring 3 hr post dose levels can achieve these
objectives.10 Calcineurin is ubiquitous; toxicity such
as hypertension, nephrotoxicity, neurotoxicity,
neoplasia, hyperglycemia, hyperlipidemia, hirsutism,
and gingival hyperplasia are common side-effects.
When comparing the toxicity profile between
tacrolimus and Csa, tacrolimus does not cause
hirsutism but may increase neurotoxicity and
hyperglycemia but equal nephrotoxicity.11 Health
related quality of life might be improved with
tacrolimus versus Csa, due to the difference in
hirsutism.12 The comparison of Csa and tacrolimus in
randomized controlled trials has demonstrated that
they are equally efficacious.13,14 The trials in renal
transplantation have failed to control adequately for
dosing differences and to define drug exposure. Thus,
claims of differences in acute rejection rates continue
to be a topic of debate.
Mycophenolate Mofetil has been a major advance
in immunosuppression and has effectively replaced
azathioprine due to its antimetabolite specificity. The
advantage is its selective effect on lymphocyte
activation. The two principle mechanisms of action
are its inhibition of purine synthesis via the de novo
pathway, and for its potent, selective inhibition of the
type II inosine monophosphate dehydrogenase
(IMPDH), which is the enzyme upregulated with cell
activation.15 Three large-scale clinical trials and a
number of smaller trials have shown MMF to be safe
and more efficacious compared to Aza when combined
with Csa and corticosteroids for the prevention of acute
rejection in kidney allografts.16-21 Other unproven
benefits of MMF include the associated inhibition of
adhesion molecules, antibody production and medial
smooth muscle proliferation. These cellular effects may
play a role in the future reduction of chronic rejection.
Corticosteroids remain a controversial area of
immunosuppression. It has provided the mainstay
of immunosuppression for many years and attempts
to withdraw from them have been tarnished by poorly
controlled trials and dismal results. The mechanism
of action is in the ability of corticosteroids to block
multiple cytokines that have a direct and indirect effect
on IL-2 production from T-cells. Steroids are used in
perioperative and maintenance immunosuppression
and in the treatment of acute rejection. Long-term
therapy with corticosteroids have a considerable effect
on morbidity: hypertension, hyperlipidemia, diabetes,
opportunistic infections, osteoporosis, hirsutism,
Cushing’s syndrome and growth abnormalities in
children are all well documented side-effects.
Regimens attempting to withdraw corticosteroids
have been accumulating. The topic has received a
renewed interest due to the multitude of potent
immunosuppression options currently available. Of
the two large prospective randomized multicenter
trials that have been conducted the most discouraging
data comes from the Canadian multicenter trial. There,
at 90 days, patients were randomized to receive
placebo or low-dose alternate day prednisone. In the
placebo group, 50 patients (19.2%) lost their graft in
comparison to the prednisone group, in which 38
patients (14.4%) lost their graft. The actuarial 5-year
graft and patient survival rates were 73% and 85%,
respectively, in the placebo group, versus 92%
and 94%, in the prednisone group. After a mean of
1.4 years, 143 patients in the placebo group and 123
patients in the prednisone group had discontinued
the test therapy or had their treatment group
decoded.22-26
Studies of tacrolimus based steroid withdrawal
have demonstrated that a select population of
patients can achieve steroid free status. In the
largest uncontrolled study involving 379 adult and
80 pediatric patients who kept their allografts for
longer than 3 weeks patients were withdrawn from
corticosteroids. In the adult group, 76% were
successfully withdrawn from corticosteroids and
their 3-year graft and patient survival rates were
94% and 98%, respectively. The 24% of patients
remaining on Corticosteroids had a 3-year graft and
patient survival rates were 50% and 80%,
respectively. In the pediatric group, 92.5% were
withdrawn from corticosteroids and 70% were able
to remain off them. The authors noted that adverse
selection factors (i.e., rejection, delayed graft
function, high panel reactive antibody levels, and
retransplantation) were more prevalent in the
patients remaining on corticosteroids. 27-29 Therefore
only a select subpopulation of patients in the study
were permitted to enter the steroid withdrawal group.
There has never been a randomized, controlled, trial
of steroid withdrawal comparing Csa and tacrolimus
based immunosuppression.
Sirolimus is an immunophilin-binding agent that is
structurally similar to tacrolimus and binds to
FK-binding protein. Contrary to Csa and FK506,
sirolimus blocks IL-2 dependant proliferation and
the activation of the Il-2 signal by CD-28 cross linkage.
Sirolimus also is felt to have antiproliferative effects and
thus represents a new class of immunosuppression.30
The side effects profile includes no nephrotoxicity but
hyperlipidemia, transient thrombocytopenia, and
leukopenia have been reported. The incidence of herpes
simplex infections and pneumonia were higher
in sirolimus-treated patients. In a large, randomized,
controlled, blinded, multicenter trial, sirolimus
decreased the incidence of biopsy-proven rejection in
non-black kidney transplant recipients. The use of
sirolimus demonstrated the feasibility of withdrawing
corticosteroids and lowering Csa dosages in this
same group.31,32
Newer agents such as FTY720, soluble MHC class 1
proteins, and antisense-oligonucleotides (Oligos) are
currently in trials.33-35 Each of these agents represents
a novel mechanism of action. Oligos set a new standard
for specificity by targeting the mRNA product of a gene
thereby interrupting a single pathway. Soluble donor
specific proteins can interfere with allograft recognition
and have been shown to improve graft survival in
animal models. FTY720 (FTY) has an unclear
mechanism of action but it appears to alter signal
transduction and apoptosis and thereby gives naïve
T-cells a signal to home to specialized lymphoid area,
separating them from recognizing an allograft. FTY is
currently in early clinical trials.
Chronic rejection
Chronic rejection (CR) in kidney allografts is
characterized by an indolent and variable loss of
function, which mostly occurs in combination with
proteinuria and hypertension. Since many of the
pathophysiologic and immunologic features of CR
were first recognized in kidney allografts, it remains
the most widely studied organ for evaluation of CR.
CR is also known as chronic allograft nephropathy
(CAN), a term which acknowledges the important
contribution of non-immunologic factors such as
hypertension, hyperfiltration injury, and other
insults, to the progressive decline of renal structure
and function.
As in other organs, risk factors for CAN are divided
into immunologic and non-immunologic, although the
latter assumes a greater importance in kidney
allografts because they are frequent causes of disease
in native kidneys. Immunologic factors are repeated
acute rejection episodes, vascular rejection episodes,
rejections that occur late after transplantation, MHC
mismatching, donor and recipient gender differences,
and recipient race.36-38 Non-immunologic factors that
augment the immunologic injury or contribute to the
architectural or vascular pathology of CR include
advanced donor age, delayed graft function, donor
source (living-related and living-unrelated versus
cadaveric), cold ischemia time, delayed graft function,
size mismatching or insufficient nephron mass,
hyperlipidemia, and hypertension.
The histopathology of CR in the kidney is not
thought to be specific, because similar histopathologic
changes can be seen in other disorders such as
hypertension, diabetes, and hyperlipidemia. However,
transplant glomerulopathy and multilayering of the
peritubular capillaries are highly characteristic features
of CAN.39,40 Even though the histopathologic findings
are not specific, biopsy findings can provide important
information for patient management. Early-protocol
biopsies of stable, well-functioning kidney allografts
reveal a high prevalence of clinically unsuspected acute
and chronic pathology, including rejection, which is
predictive of long-term allograft outcome.41
The most popular therapeutic approach in patients
with early CR is to increase or change baseline
immunosuppression. The goal is to limit or stop the
ongoing immunologic injury and allow the graft
to recover before completely irreversible damage
has occurred. An additional advantage can be realized
if the new immunosuppressive drug does not
contribute to the development of allograft fibrosis
such as sirolimus. In addition to changes in
immunosuppression, medical management of
cardiovascular risk factors has been shown to slow
progression. Options include the addition of calcium
channel blocker (diltiazem), angiotensin converting
enzyme agents (ramipril), and lipid lowering agents
(pravastatin).36
The introduction of a new immunosuppressive
agent is often heralded by claims of laboratory
evidence of decreased chronic rejection. While these
may in fact be real, the true benefit requires long term,
randomized trials that incorporate biopsy protocols, and
stratify for cardiovascular risk factors. The most
important factors for the development of CR are acute
rejection, delayed graft function and histoincompatibility.
Thus, newer potent immunosuppressives and
improved donor and recipient management will play a
key role in the future rate of graft deterioration.
Currently, it is important to minimize the risk
factors listed above and maximize medical manage
in patients so that toxicity is minimal and long-term
graft survival increases.
Conclusions
The limitation of transplantation has historically
been the prevention of acute rejection. Progress
during the last 10 years has had a dramatic impact in
this area. The most important boundaries of the
21 st century will be the development of specific
therapies that can be altered according to patient
co-morbidities and other factors influencing outcome,
circumventing CR, minimizing drug toxicity, and
increasing organ procurement.
Since episodes of acute rejection are less frequent,
we will require a more sensitive measure of new
combinations of immunosuppression. Renal transplant
biopsy protocols can detect sub-clinical acute rejection
and have been demonstrated histological to respond
to anti-rejection therapy. Biopsy protocols have been
adapted by many pediatric transplantation centers and
a few adult programs as well.
As the number of new therapies increase, so do
the possible combinations of immunosuppressants.
Current wisdom predicts that the optimal therapy
will consist of multiple specific agents that can be
chosen according to co-morbidities and patient
characteristics. However, just as we thought that it is
time to move on to newer and better drugs as standard
immunosuppression, concepts of maximizing drug
exposure and predicting individual absorption
patterns highlight the importance of learning how
best to utilize our current therapies. In doing so,
we will gain a greater understanding of how to
improve patient outcomes and better utilize
new therapies.
Improved immunosuppression will translate into
less CR and, until we can induce a drug-free state of
tolerance, efforts to minimize CR will be an active area
of research. Organ donation has received attention at
a national level. Increased donation rates can be
achieved by adopting programs in education, by
developing a national organ procurement agency, or
possibly through legislature.
References
1. Hume DM, Merrill JP, Miller BF, et al. Experiences with renal
homotransplantation in the human: report of nine cases.
J Clin Invest 1955:34:327-382.
2. CORR Report, Canadian Organ Replacement Register
database at the Canadian Institute for Health Information
(CIHI). 1999/2000 CIHI Web site: www.cihi.ca
3. Belitsky P, MacDonald AS, Lawen J, McAlister V,
Bitter-Suermann H, Kiberd B, West K, Sketris I. Kidney
transplantation, the Halifax experience. Clin Transpl 1996:
231-240.
4. Calne RY, White DJG, Thiru S, et al. Cyclosporin A in patients
receiving renal allografts from cadaver donors. Lancet
1978:2:1323-1327.
5. Keown P, Landsberg D, Halloran P, Shoker A, Rush D, Jeffery J,
Russell D, Stiller C, Muirhead N, Cole E, Paul L, Zaltzman J,
Loertscher R, Daloze P, Dandavino R, Boucher A, Handa P,
Lawen J, Belitsky P, Parfrey P. A randomized, prospective
multicenter pharmacoepidemiologic study of cyclosporine
microemulsion in stable renal graft recipients. Report of the
Canadian Neoral Renal Transplantation Study Group.
Transplantation 1996:62(12):1744-52.
6. Kahan BD, Rajagopalan PR, Hall M. Reduction of the occurrence
of acute cellular rejection among renal allograft recipients
treated with basiliximab, a chimeric anti-interleukin-2-receptor
monoclonal antibody. United States Simulect Renal Study
Group. Transplantation 1999:67:276-284.
7. Belitsky P. Neoral use in the renal transplant recipient.
Transplant Proc 2000:32:S10-S19.
8. Mahalati K, Belitsky P, Sketris I, West K, Panek R. Neoral
monitoring by simplified sparse sampling area under the
concentration-time curve: its relationship to acute rejection
and cyclosporine nephrotoxicity early after kidney
transplantation. Transplantation 1999:68(1):55-62.
9. Kahan BD, Welsh M, Urbauer DL, et al.Low Intraindividual
Variability of Cyclosporin A Exposure Reduces Chronic
Rejection Incidence and Health Care Costs. J Am Soc Nephrol
2000:11(6):1122-1131.
10. Mahalati K, Lawen J, Kiberd B, Belitsky P. Is 3-hour
cyclosporine blood level superior to trough level in early post-
renal transplantation period? J Urol 2000:163(1):37-41.
11. Mayer AD, Dmitrewski J, Squifflet JP, et al. Multicenter
randomized trial comparing tacrolimus (FK506) and
cyclosporin in the prevention of renal allograft rejection: a
report of the European Tacrolimus Multicenter Study Group.
Transplantation 1997:64:436-443.
12. Shield CF, McGrath MM, Gross TF. Assessment of health-related
quality of life in kidney transplant patients receiving tacrolimus-
based versus cyclosporin based immunosuppression.
Transplantation 1997:64:1738-1743.
13. Vincenti F, laskow DA, Neylan JF, et al. One year follow-up
of an open label trial of FK506 for primary kidney
transplantation. A report of the US Multicenter FK506 Kidney
Transplant group. Transplantation 1996:61:1576-1581.
14. Pirsch JD, Miller J, Deierhoi MH, et al. A comparison of tacrolimus
(FK506) and cyclosporin for immunosuppression after
cadaveric renal transplantation. FK506 Kidney Transplant
Study Group. Transplantation 1997:63:977-983.
15. Natsumeda Y, Ohno S, Kawasaki H, et al. Two distinct cDNAs
for human IMP dehydrogenase. J Biol Chem 1990:256:5292.
16. European Mycophenolate Mofetil Cooperative Study Group.
Placebo-controlled study of mycophenolate mofetil combined
with cyclosporin and corticosteroids for prevention of acute
rejection. Lancet 1995:345:1321-1325.
17. Sollinger HW for the U.S. Renal Transplant Mycophenolate
Mofetil Study Group. Mycophenolate mofetil for the
prevention of acute rejection in primary cadaveric
renal allograft recipients. Transplantation 1995:60:225-232.
18. Wiesel M, Carl S. A placebo controlled study of mycophenolate
mofetil used in combination with cyclosporine and
corticosteroids for the prevention of acute rejection in renal
allograft recipients: 1-year results. The European Mycophenolate
Mofetil Cooperative Study Group. J Urol 1998:159:28-33.
19. Mathew TH. A blinded, long-term, randomized, multicenter
study of mycophenolate mofetil in cadaveric renal
transplantation: results at three years. Tricontinental
Mycophenolate Mofetil Renal Transplant Study Group.
Transplantation 1998:65:1450-1454.
20. Kim YS, Moon JI, Kim SI, et al. Clear benefit of mycophenolate
mofetil-based triple therapy in reducing the incidence of acute
rejection after living donor renal transplantations.
Transplantation 1999:68:578-581.
21. vanGelder T, Hilbrands LB, Vanrenterghem Y, et al.
A randomized, double-blind, multicenter, plasma concentration
controlled study of the safety and efficacy of oral mycophenolate
mofetil for the prevention of acute rejection after kidney
transplantation. Transplantation 1999:68:261-266.
22. Sinclair NR. Low-dose steroid therapy in cyclosporine-treated 40. Peschke B, Scheuermann EH, Geiger H, Bolscher S, Kachel HG,
renal transplant recipients with well-functioning grafts. Can Med Lenz T. Hypertension is associated with hyperlipidemia,
Assoc J 1992:147:645-657. coronary heart disease, and chronic graft failure in kidney
23. Ashan N, Hricik D, Matas A, et al. Prednisone withdrawal transplant recipients. Clin Nephrol 1999:51:290-295.
in kidney transplant recipients on cyclosporine and 41. Al-Awwa IA, Hariharan S, First MR. Importance of allograft
mycophenolate mofetil - a prospective randomized study. biopsy in renal transplant recipients: correlation between clinical
Steroid Withdrawal Study Group. Transplantation and histological diagnosis. Am J Kidney Dis 1998:31:S15-S18.
1999:68:1865-1874.
24. Ratcliffe PJ, Dudley CRK, Higgins RM, et al. Randomised
controlled trial of steroid withdrawal in renal transplant
recipients receiving triple immunosuppression. Lancet
1996:348:643-648.
25. Hollander AAMJ, Hene RJ, Hermans J, et al. Late prednisone
withdrawal in cyclosporine-treated kidney transplant
patients: a randomized study. J Am Soc Nephrol 1997:8:
294-301.
26. Gulanikar AC, Belitsky P, MacDonald AS, et al. Randomized
controlled trial of steroids versus no steroids in stable
cyclosporine-treated renal graft recipients. Transplant Proc
1991:23:990-991.
27. Shapiro R, Jordan ML, Scantlebury VP, et al. Outcome after
steroid withdrawal in renal transplantation patients receiving
tacrolimus-based immunosuppression. Transplant Proc
1998:30:1375-1377.
28. Grewal HP, Thistlethwaite JR Jr, Loss GE, et al. Corticosteroid
cessation 1 week following renal transplantation using
tacrolimus/mycophenolate mofetil based immunosuppression.
Transplant Proc 1998:30:1378-1379.
29. Kupin W, Venkat KK, Goggins M, et al. Improved outcome of
steroid withdrawal in mycophenolate mofetil-treated primary
cadaveric renal transplant recipients. Transplant Proc
1999:31:1131-1132.
30. Watson CJE, Friend PJ, Jamieson NV, et al. Sirolimus: a potent
new immunosuppressant for liver transplantation.
Transplantation 1999:67:505-509.
31. Kahan BD, Julian BA, Pescovitz MD, et al. Sirolimus reduces
the incidence of acute rejection episodes despite lower
cyclosporine doses in caucasian recipients of mismatched
primary renal allografts: a phase II trial. Rapamune Study Group.
Transplantation 1999:68:1526-1532.
32.Nashan B. The interleukin-2 inhibitors and their
role in low-toxicity regimens. Transplant Proc 1999:31:
23S-26S.
33. Kahan, B.D.: New strategies in immunosuppression:
Oligonucleotide therapy and allochimeric transplantation
antigens. BioDrugs 1997:8:19-22.
34. Troncoso P, Stepkowski SM, Wang ME, et al. Prophylaxis of acute
renal allograft rejection using FTY720 in combination with
subtherapeutic doses of cyclosporine. Transplantation
1999:67(1):145-51.
35. Stepkowski SM, Wang ME, Condon TP, et al. Protection against
allograft rejection with intercellular adhesion molecule-1
antisense oligodeoxynucleotides. Transplantation 1998:66(6):
699-707.
36. Paul LC. Chronic allograft nephropathy: An update. Kidney Int
1999:56(3):783-793.
37. Porter KA, Thomson WB, Owen K, et al. Obliterative
vascular changes in four human kidney homotransplants.
BMJ 1963:2:639.
38. Humar A, Kerr S, Gillingham KJ, Matas AJ. Features of acute
rejection that increase risk for chronic rejection. Transplantation
1999:68(8):1200-1203.
39. Delmas S, Picot MC, Vergnes C, Cristol JP, Mourad G. Risk factors
of chronic rejection in kidney transplantation, results of a single
center study. Nephrologie 1999:20(3):153-158.