Cyclosporine: a new immunosuppressive agent for organ transplantation.
ABSTRACT Cyclosporine, a cyclic endecapeptide of fungal origin, has recently been released for use in clinical transplantation. Trials in kidney, heart, liver and bone marrow recipients were encouraging: 1-year graft survival rates were 70% to 80% for kidney and heart recipients, and 60% to 65% for liver allograft recipients. Cyclosporine is also effective in treating bone marrow recipients with acute graft-versus-host disease. The drug selectively inhibits T-helper cell production of growth factors essential for B cell and cytotoxic T-cell differentiation and proliferation, while allowing expansion of suppressor T-cell populations. Drug absorption varies greatly, necessitating monitoring of drug level and individualization of therapy. Nephrotoxicity is the most frequent side effect of cyclosporine. An increased incidence of B-cell lymphomas seen when cyclosporine was used in conjunction with cytotoxic agents or anti-lymphocyte globulin has very rarely been observed when concomitant immunosuppression has been limited to low-dose corticosteroids. Lower initial doses of cyclosporine, followed by more rapid tapering may reduce the incidence of nephrotoxicity without compromising improved graft outcome.
- [show abstract] [hide abstract]
ABSTRACT: Hydrogens connected to α-carbon (α-C) of amino acid residues are usually resistant to hydrogen-deuterium exchange (HDX) unless reaction conditions promote racemization. Although N-methylglycine (sarcosine) residue has been found in biologically active peptide such as cyclosporine, to the best of our knowledge, the HDX of α-C protons of this residue was not explored yet. Here, we presented a new and efficient methodology of α-C deuteration in sarcosine residues under basic aqueous conditions. The deuterons, introduced at α-C atom, do not undergo back-exchange in acidic aqueous solution. The electrospray ionization-MS and MS/MS experiments on proposed model peptides confirmed the HDX at α-C and revealed the unexpected hydrogen scrambling in sarcosine-containing peptides. Although the observed HDX of α-C protons is only successful in N-acylglycine when the amide possesses a certain degree of alkylation, it offers a new approach to the analysis of sarcosine-containing peptides such as cyclosporine. Copyright © 2014 John Wiley & Sons, Ltd.Biological Mass Spectrometry 01/2014; 49(1):43-9. · 3.41 Impact Factor
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ABSTRACT: End-stage organ disease affects millions of people around the world, to whom organ transplantation is the only definitive cure available. However, persistent organ shortage and the resulting widespread transplant backlog are part of a disturbing reality and a common burden felt by thousands of patients on waiting lists in almost every country where organ transplants are performed. Several alternatives and potential solutions to this problem have been sought in past decades, but 1 seems particularly promising now: whole-organ bioengineering. This review describes briefly the evolution of organ transplantation and the development of decellularized organ scaffolds and their application to organ bioengineering. This modern alchemy of generating whole-organ scaffolds and recellularizing them with multiple cell types in perfusion bioreactors is paving the way for a new revolution in transplantation medicine. Furthermore, although the first generation of bioengineered organs still lacks true clinical value, it has created a number of novel tissue and organ model platforms with direct application in other areas of science (eg, developmental biology and stem cell biology, drug discovery, physiology and metabolism). In this review, we describe the current status and numerous applications of whole-organ bioengineering, focusing also on the multiple challenges that researchers have to overcome to translate these novel technologies fully into transplantation medicine.Translational research : the journal of laboratory and clinical medicine. 01/2014;
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ABSTRACT: We report that one 18-year-old female patient with no epilepsia history developed severe epileptiform seizures while she was receiving "ciclosporin A (CsA)-mycophenolate-methylprednisolone" antirejection therapy after combining one week's voriconazole administration following allogeneic hematopoietic stem cell transplantation (allo-HSCT) for myelodysplastic syndromes (MDS). Her blood concentration of CsA was 378 ng/ml (elevated ↑64%, contrasted with the level before the addition of voriconazole) on the second day of admission, and the MRI of head showed leukoencephalopathy in bilateral occipital and left frontal lobe on the 4(th) day of admission. The most likely mechanism is that because of voriconazole's enzyme inhibition and CsA as the substrate of hepatic enzymes, voriconazole elevated the blood concentration of CsA and enhanced its toxicity. This case highlights the importance of clinical pharmacists joining the medical team and optimizing the patients' treatment protocols by performing a systematic literature research, accumulating the knowledge of the potential drug interaction and examining prescriptions.Journal of pharmacology & pharmacotherapeutics. 10/2013; 4(4):294-7.
Cyclosporine: A New Immunosuppressive Agent for Organ Transplantation
DAVID J. COHEN, M.D.; ROLF LOERTSCHER, M.D.; MARIO F. RUBIN, M.D.; NICHOLAS L. TILNEY,
M.D.; CHARLES B. CARPENTER, M.D.; and TERRY B. STROM, M.D.; Boston, Massachusetts
Cyclosporine, a cyclic endecapeptide of fungal origin, has
recently been released for use in clinical transplantation.
Trials in kidney, heart, liver and bone marrow recipients
were encouraging: 1-year graft survival rates were 70% to
80% for kidney and heart recipients, and 60% to 65% for
liver allograft recipients. Cyclosporine is also effective in
treating bone marrow recipients with acute graft-versus-
host disease. The drug selectively inhibits T-helper cell
production of growth factors essential for B cell and
cytotoxic T-cell differentiation and proliferation, while
allowing expansion of suppressor T-cell populations. Drug
absorption varies greatly, necessitating monitoring of
drug level and individualization of therapy. Nephrotoxicity
is the most frequent side effect of cyclosporine. An
increased incidence of B-cell lymphomas seen when
cyclosporine was used in conjunction with cytotoxic
agents or anti-lymphocyte globulin has very rarely been
observed when concomitant immunosuppression has
been limited to low-dose corticosteroids. Lower initial
doses of cyclosporine followed by more rapid tapering
may reduce the incidence of nephrotoxicity without
compromising improved graft outcome.
IN THE EARLY 1960S, azathioprine was introduced for
maintenance immunosuppression in clinical renal trans-
plantation. Shortly thereafter, with the addition of high-
dose corticosteroid anti-rejection therapy and lower dose
steroid adjunctive therapy, an acceptable regimen for use
in cardiac, renal, and hepatic transplantation was estab-
lished that has undergone little change until the present.
The use of anti-lymphocyte globulin, either as anti-rejec-
tion therapy or as prophylactic immunosuppression im-
mediately after engraftment, has remained a contentious
issue. The salubrious effects of previous blood transfu-
sions on kidney graft survival, recognized in the 1970s,
led to their widespread use for pre-transplant condition-
Immunosuppressive protocols have undergone a major
change with the introduction of cyclosporine in renal,
cardiac, hepatic, pancreatic, and bone marrow transplan-
tation. This agent is a potent immunosuppressant, more
effective than standard drug therapies in preventing rejec-
A metabolite of the soil fungi Cylindrocarpum lucidurn
Booth and Tolypocladium inHatum Gams, cyclosporine
is a cyclic endecapeptide with a molecular weight of
1203. It includes several A'-methylated amino acids and
one new amino acid (Figure 1). Cyclosporine exerts its
• From the Departments of Medicine and Surgery. Laboratory of Immunogenet-
ics and Transplantation. Brigham and Women's Hospital, and the Charles A.
Dana Research Institute, the Harvard.Thorndike Laboratory. Department of
Medicine. Beth Israel Hospital and Harvard Medical School; Boston. Massachu-
Annals of Internal Medicine. 1984;101:667-682.
most well characterized effects on T-lymphocyte helper/
inducer subpopulations; B cell, macrophage, granulocyte
and natural killer cell functions appear unaltered. The
drug is not myelosuppressive, and in-vitro growth of
bone marrow-derived myeloid, erythroid, and B-lym-
phoid cell lines remains unimpaired (1-8). Cyclosporine
is not a panacea, however, as side effects, sometimes seri-
ous, are common, and immunologic graft loss still occurs,
albeit at a reduced rate.
Mechanism of Action
Initial studies by Borel and coworkers (1, 9) showed a
suppressive effect of cyclosporine on antibody production
in a mouse model. This effect was subsequently shown in
this and in other systems to be mediated by inhibition of
the T-cell help required for B-cell activation (9, 10). The
polyclonal B-cell response to Escherichia coli lipopoly-
saccharide—a direct stimulator of B cells—was not
blunted by the presence of cyclosporine in the culture
medium, nor was the activation of B cells by mitogenic
T-independent antigens such as Epstein-Barr virus (10-
12). In fact, the growth of Epstein-Barr virus-infected B
lymphoblastoid cell lines was favored by cyclosporine
(13). Time course studies clearly showed that although
administration of cyclosporine at the time of antigenic
challenge suppressed antibody production, on-going anti-
body responses were not impaired (9). In fact, cyclospo-
rine did not interrupt primary antibody responses unless
introduced during the early steps of B-cell activation, be-
fore acquisition of responsiveness to B-cell growth factor
(13). A direct effect of cyclosporine on B-cell function
was discerned, however, in studies using anti-immuno-
globulin as a surrogate to antigen. Here, cyclosporine in-
terrupted an early, premitotic phase of B-cell activation
In contrast, direct inhibitory effects on T-cell responses
were easily shown in several in-vitro systems (15-21). As
with antibody production, suppression only occurred
when the drug was present at initiation or in the early
stages of test cultures. The effector functions of previous-
ly activated cytolytic or suppressor T-cells were not al-
tered (15, 16). Similarly, pretreatment of T lymphocytes
followed by removal of the drug before antigen or lectin
exposure was without effect on subsequent responsiveness
The currently accepted model of the T-cell activation
sequence requires expression and recognition of two
types of signals: antigen or mitogen, and cell-derived
"growth factors." (Figure 2). Antigen is presented by
©1984 American College of Physicians 6 6 7
H CH3 CH2 CH3
L I L il I '
Figure 1. Chemical structure of
accessory cells to T-inducer cells, which are thereby trig-
gered to release a factor (or factors) that target the mac-
rophage. The macrophage is induced to release interleu-
kin-1, previously termed lymphocyte activating factor.
This monokine stimulates release of interleukin-2, previ-
ously termed T-cell growth factor, from antigen primed
T-helper cells. Interleukin-2 acts on antigen-primed cyto-
lytic T-cell precursors, other T-helper cells, and perhaps
on T-suppressor cells, and is essential for their continued
growth and proliferation (22). In the absence of interleu-
kin-2, blastogenesis may occur, but cells are unable to
enter the S-phase of their growth cycle (23). The manner
in which cyclosporine interrupts this cascade of T-T-
macrophage interactions, thus preventing T-cell activa-
tion, differentiation and proliferation, has been studied in
vitro by many workers.
Cyclosporine was convincingly shown to impair inter-
leukin-2 production by naive as well as activated T-help-
er populations in several different models. Hess and co-
workers (17-19) extensively studied the effects of this
agent on the human mixed lymphocyte culture. Suppres-
sion of proliferation and cytotoxic T-lymphocyte genera-
tion by cyclosporine in primary and secondary mixed
lymphocyte cultures was associated with a dramatic inhi-
bition of interleukin-2 production. Similar results were
obtained in murine and guinea pig cultures (20-25).
Bunjes and associates (25) showed that the conconava-
lin-A-induced release of interleukin-1 by some, but not
all, macrophages was also impaired, presumably second-
ary to an effect on the T-cell help required for this func-
tion, because T-independent induction of macrophage in-
terleukin- 1 release by lipopolysaccharide was resistant to
the effects of cyclosporine. These results were confirmed
by Palacios (21).
Conflicting results have been noted in attempts to as-
certain whether cells activated in cyclosporine-treated
cultures acquire the ability to respond to interleukin-2 or
whether the drug prevents expression of the interleukin-2
receptor. Larsson (20) found that the lectin-induced ex-
pression of interleukin-2 responsiveness was inhibited in
murine lymphocytes, such that even when cells were
washed free of cyclosporine, they failed to proliferate in
response to interleukin-2. Palacios (21) provided evi-
dence to support this concept. These studies, however,
did not discriminate between a decrease in interleukin-2
receptor expression and post-receptor defects. More re-
cently, direct evidence showing that cyclosporine does
not prevent expression of interleukin-2 receptors on acti-
vated T cells has been obtained by use of an anti-interleu-
kin-2 receptor monoclonal antibody (26). Orosz and as-
sociates (27, 28) provided indirect confirmation with
cloned murine T lymphocytes. Furthermore, addition of
exogenous interleukin-2 to human allogeneic mixed lym-
phocyte cultures treated with cyclosporine restored pro-
liferation, although those cultures still failed to generate
cytolytic T cells (18, 19). We found full restoration of
allogeneic responsiveness with the addition of lympho-
kines rich in interleukin-2 to cells cultured in the pres-
ence of cyclosporine (29, 30), as did Bunjes and associ-
ates (25). Although cyclosporine inhibited the release of
various lymphokines, including cytotoxic differentiation
factor (31), and gamma interferon (32, 33), macrophage
responsiveness to lymphokine was not impaired (3).
Coincident with the depression of T-helper/inducer
cell function, inhibition of interleukin-2 production, and
the subsequent abrogation of proliferation and cytotoxic
T-cell development, there appeared to be relative sparing
of T-suppressor subpopulations by cyclosporine. Studies
by Hess and associates (34) showed the emergence of
suppressor cells in primary human mixed lymphocyte
cultures treated with cyclosporine, despite the virtual ab-
sence of proliferation. Similar results were seen in murine
cultures (30, 35). The drug itself did not induce suppres-
sor cells in the absence of antigen or lectin stimulation,
and at sufficiently high doses inhibited suppressor cell
development (17, 34). Doses of cyclosporine that
markedly suppressed the induction of cytolytic T cells
allowed the differentiation of potent alloantigen-activated
November 1984 • Annals of Internal Medicine • Volume 101 • Number 5
suppressor cells. With the increasing evidence that the
generation of alloreactive T-suppressor cells depends on
the availability of specific differentiation factors distinct
from interleukin-1 and interleukin-2, it would appear
that the environment created by cyclosporine uniquely
favors production of T-suppressor cell-inducing lympho-
kines (36, 37). An analysis of the inhibitory effects of
cyclosporine in guinea pig mixed lymphocyte culture
showed that release of a genetically restricted suppressor
factor by T cells was not impaired (38). Recently Moha-
gheghpour and associates (39) showed activation of sup-
pressor-inducer T cells in cyclosporine-treated human
cultures, whereas cytolytic T cell-inducer cell generation
Considerable experience has accumulated with the use
of cyclosporine in experimental transplantation, where
remarkable successes have been achieved. Initial studies
in a rat heart transplant model showed that indefinite
allograft survival could be readily induced by short-term
treatment with cyclosporine (40-42). A permanent state
of unresponsiveness was established after 7 to 14 days of
immunosuppression. Prolonged acceptance of cardiac al-
lografts was also induced in pigs, for the first time, and
primates, although continued drug administration was
necessary (43-46). Results with renal transplant models
were comparable: tolerance to fully histoincompatible
kidneys was seen in rats and rabbits, whereas rejection
followed discontinuation of drug treatment in the dog
and in primates (47-60). Mixed but generally favorable
results have also been reported with pancreatic islet cell
and segmental pancreatic allografts in dogs, rats, and ba-
boons, although very high doses of cyclosporine were fre-
quently required, and rejection of pancreatic tissue was
seen whereas simultaneously allografted kidneys or
hearts remained unaffected (61-69). Studies on the im-
munosuppressive effects of cyclosporine have also exam-
ined lung (70), skin (71-73), liver (74), small intestine
(75, 76), muscle (77), nerve (78), ovary (79), and cor-
nea (80) transplant models. Deeg and coworkers (81)
and Tutschka and coworkers (82) have reported facilita-
tion of bone marrow transplant engraftment and induc-
tion of tolerance (graft to host) in the dog and rat, re-
spectively. Tolerance induction was achieved in rats
across major histocompatibility barriers, but not in any
other species (81, 82). In the canine model, until recent-
ly, only minor histocompatibility differences could be
The observation that a prolonged state of tolerance was
created after only limited periods of drug treatment led
investigators to probe its immunologic basis. Strong evi-
dence has emerged showing that suppressor cells may be
important in maintaining this unresponsive state.
Tutschka and colleagues (84) have shown the presence
of splenocytes capable of suppressing the donor T-cell
responses to host antigens. Similarly, lymphocytes from
cyclosporine-treated rats showing tolerance to cardiac al-
lografts prevented the generation of cytotoxic T-cells in
mixed lymphocyte culture. Cyclosporine treatment alone
did not induce suppressor cells in unprimed animals but
bone marrow chimeras,
Cytotoxic T Cell
of B Lymphocytes
Figure 2. Effects of cyclosporine on T-cell activation. Adapted from
Strom and Carpenter (248) (drawing by Bunji Tagawa), with per-
mission of Hospital Practice.
appeared to have a selective premissive effect on alloanti-
gen-induced suppressor cell generation in vivo, thus cor-
roborating in-vitro studies cited earlier. Adoptive transfer
experiments confirmed the in-vivo activity of these cells
(85-88). In this model, cyclosporine-treated hosts
showed a grossly impaired capacity to elaborate interleu-
kin-2, and a less marked defect in interleukin-1 produc-
tion. Release of interleukin-3, a factor that may be linked
to suppressor cell activation, was actually increased (89).
In agreement with in-vitro studies, the timing of cyc-
losporine administration in relation to antigen exposure
(allografting) was shown to be extremely important. Pre-
vious treatment of recipients for up to 2 weeks preceding
transplantation had no beneficial effects on allograft sur-
vival, whereas delay in administration for several days
resulted in rejection. Maximal benefit was generally seen
with initiation of treatment at the time of primary anti-
gen exposure (46, 90). Although Homan and associates
(91, 92) suggested that cyclosporine was only marginally
effective in prolonging allograft survival in presensitized
animals, more recent studies have challenged this con-
cept. Deeg and associates (57), in a dog model, and Shu-
lak and colleagues (93) and Marquet and coworkers
(94), in the rat, showed effective inhibition of second set
Cohen etal. • Cyclosporine 6 6 9
rejection with cyclosporine treatment.
The immunosuppressive effects of cyclosporine have,
thus, differed considerably between species, limiting any
direct inference that may be made regarding use in hu-
man organ transplantation, and precluding formulation
of a unifying concept explaining the observed diversity of
actions. Nonetheless, both in-vitro and in-vivo studies
have shown inhibition of lymphokine production with
blockade of the T-cell help required for B-cell activation,
cytolytic T-cell generation and further expansion T-help-
er/inducer subpopulations. At the same time, there is se-
lective expansion of T-suppressor cell populations. The
persistence of suppressor cells in vivo, suggests they play
a central role in allograft tolerance. In-vitro models and
experimental transplantation also show that cyclosporine
may permit successful allografting even where presensiti-
zation to donor alloantigen has occurred.
Cyclosporine is extremely hydrophobic and must be
dissolved in lipids or organic solvents before administra-
tion. For oral use, cyclosporine is dissolved in an olive
oil-based solution, and for intravenous use, in a polyoxy-
ethylated castor oil and alcohol solution. Although in
experimental models, oral and intramuscular routes have
proved equally effective, intramuscular administration
should be avoided in humans: poor absorption has been
shown which may result in inadequate immunosuppres-
sion (95-97). For patients unable to tolerate oral medica-
tion, cyclosporine may be given by intravenous infusion
over 4 to 12 hours, at approximately one third the oral
Oral administration in humans results in highly vari-
able rates and degrees of absorption (98). After a single
600-mg oral dose, peak drug levels ranged from 242 ng/
mL to 1246 ng/mL. Mean bioavailability in steady state
was 34%, ranging from 20% to 50% (99). Peak plasma
or whole blood levels occurred anywhere from 1 to 8
hours after oral administration, but were generally
reached at 3 to 4 hours. The alpha half-life was approxi-
mately 1 hour, whereas the terminal half-life was 25 to 30
hours (95, 96, 100). Distribution in whole blood and
plasma protein binding have been evaluated in vitro. In
the concentration range 25 to 500 ng/mL (at 21 °C)
binding to or uptake by erythrocytes represents 50% to
60% of total cyclosporine found in whole blood. Ten per-
cent is bound to granulocytes and lymphocytes, with the
remaining 30% to 40% found in plasma. Ninety percent
of plasma cyclosporine is protein bound, in large part to
the lipoprotein fraction (99, 101-103). The distribution
of cyclosporine in whole blood shows a strong tempera-
ture dependence for concentrations in the therapeutic
range. When the temperature is lowered from 37 °C to
21 °C, the drug diffuses into erythrocytes, with a new
equilibrium reached within 2 hours, at which time the
plasma cyclosporine concentration has decreased to ap-
proximately 50% of its initial value (102, 104). Due to
the lipophilic nature of the molecule, it is widely dis-
persed among body organs. Chronic administration re-
sults in accumulation of tissue stores in skin and fat, in
particular, with high levels also seen in the liver, kidney,
lymphoid organs, and endocrine glands (101, 104, 105).
However, saturation of the peripheral compartment, or
an increase in absorption, eventually results in decreased
dosage requirement with long-term usage, and mainte-
nance of serum levels (106-108).
Cyclosporine is extensively metabolized by the liver
and excreted via the bile into the feces (99). Immunosup-
pressive effects of metabolites remain poorly delineated.
Enterohepatic recirculation has been reported (108). The
cumulative urinary excretion of native cyclosporine is
0.1% after a single dose, whereas approximately 10% of
total drug metabolites are excreted into the urine (99).
Hepatobiliary dysfunction markedly slows elimination of
the drug (100). Thus, patients with altered liver function
require particularly careful monitoring. Renal insufficien-
cy, however, does not significantly alter serum level.
Many factors may influence cyclosporine absorption
and metabolism. Proximity of oral drug intake to meals
delays absorption and results in lowered drug levels
(100). Similarly, patients with clinical gastrointestinal
dysfunction of any cause may show poor or minimal ab-
sorption of orally administered cyclosporine (109, 110).
Clinically important effects on cyclosporine pharmacoki-
netics from concomitantly administered drugs have been
seen with diphenylhydantoin (100, 107), rifampin (111),
and intravenous trimethoprim-suffadimidine (112), all of
which caused marked reduction of cyclosporine blood
and serum levels. Ketoconazole, cimetidine, and high-
dose methylprednisolone administration have been asso-
ciated with elevated cyclosporine levels (99, 113-115).
Because of the marked variability in absorption, con-
siderable effort has been devoted to measurement of cy-
closporine levels in patient blood as a means of monitor-
ing adequacy of treatment and avoiding drug toxicity.
Reproducible serum and whole blood cyclosporine con-
centrations can be assayed both by high performance liq-
uid chromatography and radioimmunoassay (95, 98,
116). High performance liquid chromatography mea-
sures parent drug only, whereas the radioimmunoassay
detects both cyclosporine and its metabolites, resulting in
trough levels which may be two to three times higher.
Whole blood levels generally run three to five times great-
er than plasma levels (117, 118). Unfortunately no uni-
formly safe trough drug concentration range (in serum
or whole blood), which avoids toxicity while assuring
immunosuppression, has been established. Desirable drug
level and dose may differ considerably between patients,
and in any given patient over time. Serial determinations
of trough levels appear to afford the simplest, albeit im-
perfect, guide to treatment. The most frequently used as-
say employs the radioimmunoassay, utilizing the kit pro-
vided by Sandoz Pharmaceuticals (East Hanover, New
Jersey), the manufacturer of cyclosporine. Optimum
trough serum cyclosporine levels by radioimmunoassay
appear to be in the 50 to 200 ng/mL range during chron-
ic administration (96, 98). This statement assumes that
blood samples have been allowed to equilibrate and clot
at room temperature for 2 hours before separation. If
specimens are fractionated immediately, or after standing
November 1984 • Annals of Internal Medicine • Volume 101 • Number 5
for longer than 2 to 3 hours at room temperature, plasma
or serum levels will be higher.
Pilot Studies begun in 1978 by Calne and coworkers
(119, 120) showed that cyclosporine could be an ex-
tremely effective immunosuppressive agent in preventing
rejection of renal allografts. One-year graft survival of
poorly matched kidneys was 86%. Starzl and associates
(121) achieved an overall graft-survival rate of nearly
80% in 66 consecutive cadaver kidney recipients during a
follow-up period of 9 to 18 months. These early promis-
ing results have been confirmed. Further experience has
elucidated problem areas and defined approaches to opti-
mize effective use of the drug and minimize associated
Several prospective randomized trials compared cy-
closporine, either alone or in combination with low-dose
prednisone, to conventional immunosuppressive therapy
with azathioprine plus prednisone and, in some cases, to
anti-lymphocyte globulin. Although not all centers
showed a statistically significant improvement in 1-year
allograft survival in cyclosporine-treated patients, overall
results were favorable, despite differences in treatment
protocols. In both the European and the Canadian multi-
center trials, significantly higher 1-year graft survival
rates were noted in patients receiving cyclosporine: 72%
versus 52% and 80.4% versus 64% respectively (122,
123). Similar graft survival rates with cyclosporine—
85% 2-year success for first cadaver kidney transplants—
were achieved in our own series (124) and at the Univer-
sity of Texas (125). Starzl and colleagues (126) had even
more impressive results: a 1-year graft survival rate of
89.5% compared with a 50% rate for patients treated
with azathioprine and prednisone. However, trials con-
ducted at the University of Minnesota, in Australia, and
elsewhere failed to show any beneficial effect of cyclospo-
rine on graft survival (127-130). One-year graft survival
was 80% or greater in the control groups, however, fig-
ures superior to those generally achieved in recipients of
cadaveric kidneys. Virtually all conventionally treated
patients in these trials received prophylactic anti-lympho-
cyte globulin. Overall, graft survival rates with cyclospo-
rine have consistently been as good as and frequently
better than the best achievable results with conventional
immunosuppressive therapies. Nonrandomized studies in
pediatric patients were equally encouraging (131).
Selected subgroups of high-risk patients have also had
significant improvement in outcome, including recipients
over 55 years of age, recipients of second or third allo-
grafts, "strong immune responders," and minimally or
untransfused recipients of kidneys from living related do-
nors who display a positive donor-directed mixed lym-
phocyte response (126, 132-134).
In association with the improvement in allograft sur-
vival, some centers reported a marked reduction in the
frequency and severity of rejection episodes (127, 132,
135). In other carefully controlled prospective trials,
however, the rate of rejection was the same in the two
treatment groups (122, 123). Reliable estimates of rejec-
tion frequency have not been readily available: the dis-
tinction between rejection and nephrotoxicity may not
always be evident. Najarian and associates (136), who
were the most aggressive in lowering cyclosporine dosage
in response to rises in serum creatinine, found a signifi-
cantly decreased incidence of acute rejection episodes in
cyclosporine-treated patients (31% versus 58% for con-
trols). Seventy to eighty percent of acute elevations in
serum creatinine in the first several months after trans-
plant were not due to acute rejection, but responded to
diminution of cyclosporine dose (136, 137). Rejections
occurring in patients treated with cyclosporine have been
clinically less morbid, easier to abort, and often occur
later in the course. It is uncommon for rejection to pres-
ent with the classic signs and symptoms of fever, graft
tenderness and swelling, oliguria, and a rapid rise in se-
rum creatinine level.
Repeated rejection episodes or prolonged primary
oligo-anuria have led to conversion to azathioprine and
prednisone in 15% to 20% of patients treated with cy-
closporine alone or with cyclosporine and extremely low
doses of corticosteroids (122, 123, 127, 138-140). In
most centers, 50% to 60% of these kidneys were salvaged
after conversion. Clinically stable patients have also been
switched to azathioprine and prednisone under protocol;
15% to 20% had acute rejection episodes within the first
2 to 3 weeks, generally easily reversible, although poor
outcomes were also seen (140). In our own patients
converted at 4 months after transplantation, 12% had
rejection episodes, generally responsive to antirejection
Data comparing the incidence and number of infec-
tious complications occurring in renal allograft recipients
treated with cyclosporine or azathioprine remain incon-
sistent. Although many workers have observed a reduc-
tion in the total number of infections or in the percent of
patients with clinically significant infectious complica-
tions, some report a decrease in viral infections, whereas
others report a decrease in bacterial infections with no
change or an increase in viral infections (127-129, 132,
141, 142). The European Multicentre Trial (122) found
no difference in frequency of infection or in the nature of
the infectious agents between treatment groups. The inci-
dence of Pneumocystis carinii pneumonia has been re-
ported to be slightly increased (143).
In theory, cyclosporine (which blocks interleukin-2
release) and prednisone (which blocks interleukin-1
release) should be a synergistic immunosuppressive com-
bination. Nonetheless, routine use of low-dose oral corti-
costeroids in conjunction with cyclosporine has remained
controversial. Calne and associates (144) found that of
39 patients on cyclosporine alone, 12 never required ster-
oids, and 17 who received steroid pulses for rejection epi-
sodes did not need maintenance administration. This
group thus advocated cyclosporine monotherapy. Starzl
and associates (121) noted early acute rejection episodes
in 70% of patients on cyclosporine monotherapy and
subsequently standardized treatment to include continu-
ous low-dose prednisone. Most North American trials
Cohen etal. • Cyclosporine
have used prednisone therapy from the time of transplan-
tation, without any increase in short-term complications.
Addition of maintenance prednisone to cyclosporine low-
ered serum creatinine in the Oxford study (139). The
preliminary report from a trial comparing cyclosporine
alone with cyclosporine and prednisone suggests better
graft function during the first 30 days in the prednisone-
treated patients (145). Our initial attempts at using a
one-drug protocol were unsuccessful (146). At present,
dual-drug treatment would appear to be preferable, al-
though long-term follow-up has established that cyclo-
sporine alone may be adequate treatment in some pa-
tients (147, 148).
Available data do not permit a firm conclusion regard-
ing the interaction between cyclosporine and other fac-
tors known to influence graft outcome. Kahan and asso-
ciates (132) found no significant benefit to HLA-A, B or
HLA-DR matching in cyclosporine-treated recipients of
cadaver renal allografts. The European Multicentre Trial
(122) also concluded that there was no beneficial effect
of HLA-DR matching in cyclosporine-treated patients,
and, in fact, patients receiving better matched HLA-A, B
allografts had reduced 1-year survival compared with
those receiving poor HLA-AB-matched kidneys. Similar-
ly, multiply transfused patients had a lower graft survival
rate. Morris and colleagues (149) on the other hand,
found that greater than five transfusions conveyed a sig-
nificant benefit in cyclosporine-treated patients. As yet
unpublished data from the Canadian Multicentre Trial
confirm the beneficial effects of blood transfusion on 1-
year graft survival in patients treated with cyclosporine.
Clearly, cyclosporine and low-dose prednisone repre-
sent an attractive alternative to azathioprine and predni-
sone for renal transplantation. Although a significant im-
provement in allograft survival has not always been
shown, and mean serum creatinine levels are higher, the
convalescent period has been marked by fewer overall
complications, with less clinical morbidity, fewer rejec-
tion episodes, no greater frequency of infectious compli-
cations, and shorter hospital stays. Those patients with
recurrent rejection may be switched to azathioprine with
good salvage rates. Optimum treatment regimens and
subgroups of cadaveric kidney recipients who may derive
particular benefit or suffer undue harm from cyclosporine
therapy have not yet been defined. The frequent problem
of nephrotoxicity associated with cyclosporine adminis-
tration warrants caution in interpreting these favorable
The advent of cyclosporine dramatically transformed
clinical liver transplantation. Orthotopic liver transplan-
tation is now an option for increasing numbers of patients
with severe irreversible progressive hepatic insufficiency.
Before the use of cyclosporine, graft (and hence patient)
1-year survival rates remained in the 30% to 35% range
despite combinations of azathioprine, cyclosphospham-
ide, prednisone, antilymphocyte globulin, and thoracic
duct drainage (150). First used by Calne and associates
(120), then by Starzl and coworkers (151) and
Pichlmayr and coworkers (152), cyclosporine therapy
immediately doubled 1-year graft survival rate to approx-
imately 65%. Starzl and coworkers (151) reported the
largest series, including 67 patients receiving cyclospo-
rine and low-dose prednisone with a minimum 1-year fol-
low-up; the 1-year survival rate was 63%. There was no
change in candidacy criteria or in the spectrum of diseas-
es for which transplantation was done to explain the
superior outcome. Mortality has remained largely periop-
erative, with early deaths due to preexisting anatomic
conditions, rendering adequate revascularization of the
graft extremely difficult, or to technical problems with
graft preservation or biliary tract reconstruction. Results
with virtually all diseases were improved.
Pichlmayr and colleagues (152) examined two consec-
utive groups of hepatic allograft recipients, the first treat-
ed with conventional immunosuppression, the latter with
cyclosporine. The difference in frequency of acute rejec-
tion episodes was striking, with only 25% of cyclospo-
rine-treated patients having episodes of rejection, com-
pared with 66% of the azathioprine-prednisone-allograft
Survival rates for pediatric liver transplantation were
equally impressive, with 63% overall patient survival.
Some patients resumed normal growth patterns, probably
related to improved hepatic function and lower-dose ster-
oids. Infarction, rejection, vascular accidents, and infec-
tion were the most important causes of graft failure
(152). Thirty percent of the pediatric patients required
retransplantation, and only 38% of these survived (153).
Many patients, especially those under 6 years of age, tol-
erated high doses of cyclosporine without any nephrotox-
icity, although changes in renal function were the most
frequent reason for lowering cyclosporine dosage (154).
Recurrent malignancy has become a problem as longer
survival times have been achieved with cyclosporine. Par-
ticular difficulty with altered absorption and metabolism
of orally administered cyclosporine was seen by Wonigeit
and associates (155). They recommended continued
high-dose intravenous administration (5 to 10 mg/kg
body weight • d) for several weeks, until an adequate
absorption of the oral drug could be shown. Careful mon-
itoring of drug level was deemed essential after transplan-
tation to avoid inadequate immunosuppression. As seen
in patients receiving renal transplants, the dosage re-
quired to maintain therapeutic blood levels markedly de-
creased with time and the long-term dosage of 5 to 8 mg/
kg body weight . d was similar in both groups.
The impact of cyclosporine on this field is perhaps best
reflected in the rapidly increasing numbers of patients
and centers participating in liver transplantation.
BONE MARROW TRANSPLANTATION
The treatment of severe aplastic anemia, acute and
chronic leukemia, and immunodeficiency diseases in chil-
dren with bone marrow grafts poses a number of specific
problems not seen in solid organ transplantation. In addi-
tion to graft rejection, acute and chronic graft-versus-
host disease and interstitial pneumonitis must be consid-
November 1984 • Annals of Internal Medicine • Volume 101 * Number 5
Fifteen to thirty percent of patients with severe aplastic
anemia reject marrow grafts from HLA-identical donors
(156), and most of these patients subsequently die from
overwhelming infection. Approximately 35% of patients
treated with methotrexate become long-term survivors
(157, 158). Cyclosporine has improved these results
mainly through a reduced frequency of rejected grafts.
Seventy-five percent of patients with severe aplastic ane-
mia can now be expected to become long-term survivors.
In some, a stable hematopoietic chimerism with the pres-
ence of donor and recipient marrow cells was seen (157,
158). The results obtained with combined transfusion of
donor bone marrow and donor buffy coat cells were simi-
lar to those seen with cyclosporine therapy (159) and
have made it difficult to assign the improved results to
the effect of cyclosporine alone. Controlled studies are
needed comparing groups of similarly sensitized and
treated patients, including or excluding the use of donor
buffy coat cells, to assess the real benefit of cyclosporine
therapy for bone marrow recipients with severe aplastic
Leukemic patients are less prone to graft rejection,
which occurs only in approximately 1%. It remains diffi-
cult to compare results from different reports, because
patients frequently differed in type and stage of leukemia.
Bone marrow transplantation was initially associated
with a disappointing patient survival rate of 15% (160).
Transplantation attempts in patients with acute myelo-
blastic leukemia in first or second remission and in those
with chronic myelogenous leukemia in chronic phase
have yielded improved long-term survival rates, which
can be expected to plateau at 50% to 60% (161-163). In
considering the long-term survival of marrow-grafted
leukemic patients, it has been speculated that a reduced
incidence of graft-versus-host disease may increase the
relapse rate, as a graft-versus-leukemia effect may be pro-
tective (164). Trials to date do not support this notion.
The Seattle group (165) has conducted a controlled
trial comparing the immunosuppressive efficacy of cy-
closporine and methotrexate in two homogeneous patient
groups with acute nonlymphoblastic leukemia in first re-
mission and chronic myelogenous leukemia in chronic
phase. The actuarial survival rates did not differ in the
respective groups, nor did the incidence of acute or
chronic graft-versus-host disease.
The major benefit of cyclosporine in bone marrow
transplantation has been in the treatment of established
acute graft-versus-host disease. Cyclosporine was initially
used to treat five patients with acute graft-versus-host
disease; the lesions resolved in all five, as reported by
Powles and coworkers (166). More recently, Tutschka
and associates (167) confirmed that intravenous cyclos-
porine at a dose of 5 mg/kg body weight • d cured acute
lesions in 13 of 15 patients. It was hoped that cyclospo-
rine might also successfully prevent the occurrence of
graft-versus-host disease. Preliminary results of two on-
going controlled trials comparing the prophylactic effects
of cyclosporine versus methotrexate and cyclophospham-
ide, however, did not show significant improvement in
lowering the incidence of graft-versus-host disease (165,
167). Disease grades II to IV were seen in about 40% of
patients (165). Data from three uncontrolled studies sug-
gested an unaltered frequency of graft-versus-host disease
in patients with severe aplastic anemia (158, 168, 169).
The mortality from severe graft-versus-host reaction ap-
peared to be reduced. However, controlled trials have not
confirmed this observation (165, 167).
Chronic graft-versus-host disease may develop either
as an extension of the acute reaction or de novo. The
disease is associated with impaired immune function fre-
quently responsible for late deaths. It has continued to be
seen in about 30% to 60% of patients, but has usually
been mild in those treated with cyclosporine (157, 165,
After marrow grafting, interstitial pneumonitis is a se-
vere problem whose pathogenesis remains incompletely
defined. Radiation effect, graft-versus-host reaction, and
infection may play important roles. Some groups have
seen a greatly reduced death rate attributable to this com-
plication in recipients immunosuppressed with cyclo-
sporine (158, 171). In a controlled study, the Seattle
group could not confirm this observation, however
(165). In this series, patients with both acute nonlym-
phocytic and chronic myelogenous leukemia died from
interstitial pneumonitis with similar frequencies, irrespec-
tive of the immunosuppressive regimen. Cyclosporine has
been associated with a particular epithelial and endotheli-
al leak syndrome localized to the lungs. Twelve of thirty-
five recipients of one haplotype-mismatched bond mar-
row allograft died from pulmonary edema (172). This
complication was also observed in HLA-identical recipi-
ents (170). Data remain insufficient to establish a causa-
tive link between this endothelial defect and cyclosporine
Prevention of graft-versus-host disease has not corre-
lated with cyclosporine plasma trough or peak levels as
measured by radioimmunoassay. Reliance on monitoring
serum creatinine and urea levels has been recommended
as a guide to cyclosporine dosage (162, 170, 173). A
comparison of plasma levels in patients with and without
graft-versus-host disease involving the intestine clearly
showed poor absorption of orally administered cyclospo-
rine in patients with gut dysfunction (174). In this clini-
cal setting, measurement of peak and trough levels may
be useful to document adequate drug absorption. Some of
the observed drug interactions occur preferentially in
bone marrow recipients. Melphalan may potentiate the
nephrotoxic effect of cyclosporine leading to acute renal
failure (170, 175). The frequent use of amphotericin B
and ketoconazole in bone marrow transplantation leads
to a high incidence of an enhanced nephrotoxic effect of
cyclosporine in these patients.
HEART, HEART AND LUNG, AND LUNG
Cyclosporine was first introduced in human cardiac
transplantation in December, 1980, and is now the stan-
dard immunosuppressant in heart transplant recipients.
The largest series have been reported from Stanford Uni-
versity (176), the University of Pittsburgh (177), and
Cohen etal. * Cyclosporine
the United Kingdom Trial (178). No randomized pro-
spective trials comparing the efficacy of cyclosporine and
prednisone with conventional immunosuppressive regi-
mens have been reported. However, the results of retro-
spective comparisons showed a marked improvement in
outcome when patients were treated with cyclosporine.
At Stanford, where cyclosporine was used as the primary
immunosuppressant in 69 consecutive recipients of ortho-
topic cardiac transplants, the 1- and 2-year survival rates
were approximately 80%, and 70% to 75%, respectively.
These rates were significantly better than the 60% 1-year
and 55% 2-year survival formerly noted with azathio-
prine (176). Results reported by the University of Pitts-
burgh and in the United Kingdom Trial were quite com-
parable, with 79% and 76% overall survivals noted,
A major difference in treatment protocols between
these centers involved the use of antithymocyte globulin.
In the Stanford experience (176), a short course of pro-
phylactic rabbit antithymocyte globulin was associated
with an increased incidence of early lymphoproliferative
disorders that led to reserving the use of this agent for the
treatment of steroid-resistant rejection episodes, or those
characterized by rapid progression or unusual severity. A
similar policy of selective use of rabbit antithymocyte
globulin has been recommended by the Pittsburgh group.
In the United Kingdom Trial (178), however, early re-
jection episodes, occasionally severe and in one case fatal,
prompted the addition of a 10-day course of prophylactic
horse antithymocyte globulin. In the reported follow-up
period of up to 14 months, no lymphomas or lympho-
proliferative disorders were noted.
Although the incidence of rejection was somewhat
lower among patients treated with cyclosporine, this dif-
ference did not achieve statistical significance (176, 179).
However, the clinical presentation and apparent outcome
of biopsy-proven allograft rejection was surprisingly dif-
ferent in this group. Cardiac allograft rejection in cyclo-
sporine-treated patients has become recognized, as is the
case in kidney transplantation, as a smoldering process.
The heralding electrocardiographic signs and early con-
gestive heart failure were not present in cyclosporine-
treated patients. This lack of signs may have been due, in
part, to the absence of interstitial edema, so prominent in
the conventionally treated group. Endomyocardial biopsy
is regarded as the only reliable way of diagnosing rejec-
tion (176-179). These clinically silent, biopsy-proven re-
jection episodes have occurred more than 1 year after
transplantation, and thus myocardial biopsy to continue
surveillance appears obligatory. Fortunately, in contrast
to conventionally treated patients, even histologically se-
vere rejection has not been associated with clinically seri-
ous cardiac dysfunction, and thus, the Stanford group
(176) has recommended less intense initial anti-rejection
therapy, and consequently lower cumulative doses of
steroids. No adverse effects on outcome with this regi-
ment have been seen (179). They have also recommend-
ed twice daily dosing of cyclosporine, to maintain serum
trough levels of approximately 200 ng/mL (180).
A peculiar form of myocardial fibrosis, not seen in con-
ventionally treated patients, has been seen in biopsy sam-
ples from most patients receiving cyclosporine. Sequen-
tial biopsies, including postmortem examinations of two
patients, suggested that the fibrosis was not progressive,
nor did it appear to have hemodynamic significance (176,
178). Long-term follow-up will be required to confirm
these observations. As in the case of rejection, the overall
incidence of infectious complications was modestly but
not significantly reduced in comparison with convention-
ally treated patients. Viral infections appeared to be
increased in frequency (141, 179). However, clinical
morbidity and mortality from infection were markedly
reduced, as was the duration and cost of hospitalization
(176, 178), perhaps due to the steroid-sparing effect of
Adverse effects of cyclosporine in heart transplant re-
cipients included nephroxicity, hypertension, and lym-
phoproliferative disorders. The advent of cyclosporine
has had a major impact on cardiac transplantation, with
improved patient survival and an easier course after
transplant. Optimal regimens and long-term effectiveness
in light of myocardial fibrosis and hypertension remain
The first human heart-lung transplant was done in
1968, followed by one in 1969 and one in 1971. Patient
survivals were 11 hours, 8 days, and 23 days respectively.
No further transplants were done until March 1981. In
1983 the Stanford group reported its experience with six
recipients of heart-lung transplants. Four of the six sur-
vived to hospital discharge and remained clinically stable
for 8 to 17 months after surgery (181). Treatment in the
first 2 weeks included azathioprine, cyclosporine and rab-
bit antithymocyte globulin, with prednisone substituted
for azathioprine after 2 weeks. There were six episodes of
rejection, based on endomyocardial biopsy, with minimal
or no apparent clinically significant pulmonary effects. A
self-limited syndrome of early pulmonary interstitial ede-
ma ("reimplantation response") was recognized. Further
trials are anticipated.
Two cases of single lung transplantation treated with
cyclosporine were reported by Kamholz and associates
(182). Neither patient survived more than 7 weeks.
Seventy-six recipients of segmental pancreatic allo-
grafts, most also receiving renal transplants, have been
treated with cyclosporine. To date no advantage in graft
survival has been discerned when compared with conven-
tional immunosuppression. The proportion of function-
ing grafts at the time of review was somewhat higher for
the cyclosporine-treated group (24% versus 13%), but
follow-up time was much shorter (183). The group at
Lyon (184) found a similar rate of early failure in both
treatment groups. In the Minnesota series (185), graft
survival rates remained low regardless of immunosup-
pressive therapy and, overall, better in azathioprine-treat-
ed patients (53% versus 26% of all technically successful
transplants). All centers have seen failure of pancreas
transplants coincident with continued survival of simul-
November 1984 • Annals of Internal Medicine • Volume 101 • Number 5
taneously transplanted kidneys from the same donor.
Nephrotoxicity: Nephrotoxicity represents the most
frequent and clinically important complication associated
with cyclosporine use, and may ultimately define the lim-
its of clinical utility of the drug for long-term immuno-
suppression. Cyclosporine-induced renal dysfunction,
manifest in experimental animals only at extremely high
dosages (186, 187), was evident from the first clinical
trial in humans, and may present as acute or chronic
renal insufficiency. Hyperkalemia and hypertension may
also be due to nephrotoxic effects.
Calne and associates (119, 120), on the basis of early
experience with several cases of primary and secondary
oliguria in renal allografts, presumably due to cyclospo-
rine, recommended withholding the drug until a diuresis
of 50 to 100 mL/h was established immediately after
transplant. However, others initiated cyclosporine thera-
py at the time of transplantation and continued regard-
less of initial function. No difference was seen in the inci-
dence of acute renal failure or ultimate allograft survival
(123, 125, 188, 189), although the mean number of days
from transplantation to last hemodialysis was longer than
in azathioprine-treated patients. A deleterious effect of
cyclosporine on intial function of renal allografts subject
to prolonged machine perfusions was reported in two
centers (123, 125). It is likely that prolonged renal ische-
mia potentiates drug-induced toxicity. Shell and associ-
ates (128) and Rocher and colleagues (190) saw a small
number of patients with extended periods of initial non-
function rapidly reverse on discontinuation of cyclospo-
rine. A transient period of oliguria, lasting several days,
characterized by avid renal sodium retention and low
urine osmolarity, was reported in heart (191, 192), bone
marrow (193), and liver (194) recipients after initiation
Although irreversible acute renal dysfunction may un-
commonly occur immediately after transplant in patients
on cyclosporine, reversible, chronically impaired renal
function has been frequent among recipients of renal
(122, 123, 127, 149), cardiac (176, 178, 179), pancreatic
(184), bone marrow (195), and liver (196) allografts
treated with long-term cyclosporine. The rise in serum
creatinine has generally been modest (to approximately
2.0 to 2.5 mg/dL), occurring within a few weeks of ini-
tiation of treatment, and not progressive (127, 189). In-
vestigation of associated morphologic changes has largely
been limited to renal allografts, in which a mild tubulo-
interstitial nephritis was sometimes found, accompanied
by nonspecific vacuolization and giant mitochondria in
proximal tubular cells (121, 197-199). Renal interstitial
inflammation has not been reported in non-renal trans-
plant patients, despite similar increases in serum creati-
nine (200), nor in experimental animals, with the possi-
ble exception of a single rat study (201). The mecha-
nisms responsible for the decrease in glomerular filtration
rate have not been elucidated. Fortunately this form of
nephrotoxicity appears reversible. Reduction of cyclospo-
rine dose in patients with acute rises in serum creatinine
due to nephrotoxicity, or conversion to azathioprine in
stable renal allograft recipients on low maintenance doses
has consistently resulted in an improvement in renal
function (139, 140, 202). More marked elevation in se-
rum creatinine prompted discontinuation of cyclosporine
in 4% to 17% of patients. Virtually all patients had sig-
nificant decreases in serum creatinine (122, 123, 139,
140, 196, 203-205). There is no serum or whole blood
cyclosporine level below which this mild form of revers-
ible chronic renal dysfunction can be uniformly avoided.
The severity of this dysfunction correlates poorly with
cyclosporine level and dosage.
More worrisome forms of nephrotoxicity have been
seen in bone marrow transplant recipients, where a he-
molytic-uremic syndrome developed, accompanied by
glomerular thrombosis (162, 193, 206) and arteriolar
hyaline deposition. Mihatsch and associates (197) found
similar lesions in renal allografts. This arteriolar hyalino-
sis and mucoid intimal thickening, distinct in distribution
from the pattern of vascular rejection, correlated with
progressive interstitial fibrosis on repeat biopsy. Exten-
sive interstitial fibrosis has also been seen in hypertensive
heart transplant recipients (207).
Clinically and experimentally, synergistic nephrotoxic-
ity is seen with simultaneous administration of cyclospo-
rine and aminoglycoside (208), amphotericin B (209),
melphalan (175), and trimethoprim (210) and in the
presence of severe hypertension (207, 211) and renal
A major difficulty in renal transplant recipients has
involved differentiating nephrotoxicity from acute rejec-
tion episodes. Several clinical and morphologic features
have been suggested as helpful in establishing the cause of
acute deteriorations in renal function. Rejection episodes
were more likely in the first 30 to 60 days after trans-
plant, and were characterized by a fall in urine output
and a more rapid rise in serum creatinine. Trough serum
cyclosporine levels under 200 ng/mL lessened the likeli-
hood, but did not exclude nephrotoxicity (96, 98, 205).
Morphologically, interstitial edema, vasculitis, and glo-
merulitis, with diffuse interstitial mononuclear cells infil-
trates were strongly predictive of rejection, as were ele-
vated T8/T4 ratios of T cells infiltrating grafts (212,
213). The histoiogic pattern of acute cellular rejection of
renal allografts, if it occurs, is not altered by cyclospo-
rine. In the absence of signs of rejection on biopsy sam-
ples, and of other factors that may impair renal function,
acute rises in serum creatinine should be assumed to be
due to cyclosporine. The response to lowered cyclospo-
rine dosage, as shown by the Minnesota group, was a
most valuable diagnostic maneuver. Uncertain cases were
best managed by empiric decreases of cyclosporine dos-
age by approximately 1 mg/kg body weight • d and ob-
servation of renal function. Maintenance doses as low as
6 mg/kg body weight on alternate days provided appar-
ently adequate immunosuppresion, with reduced nephro-
toxicity (202). Rejection and nephrotoxicity may occur
Positive immunofluorescent staining for the presence
of cyclosporine deposits in cells obtained from renal
Cohen etal. * Cyclosporine
allografts by fine needle aspiration, and low renal subcap-
sular hydrostatic pressure were also evaluated in this con-
text, and both suggested nephrotoxicity rather than rejec-
tion (214, 215).
Persistent elevation of blood pressure, requiring inten-
sive combination antihypertensive regimens, developed
within the first several weeks after transplant in 60% to
95% of cardiac allograft recipients (176, 179, 216). An
increased incidence of hypertension has also been seen in
bone marrow transplant patients (202). Anywhere from
28% to 75% of renal transplant recipients on cyclospo-
rine have been reported to be hypertensive, but only the
Canadian Multicentre Trial saw a significant increase in
the frequency of hypertension in patients treated with
cyclosporine (217). The cause of the hypertension re-
mains unknown. Thompson and associates (216) saw a
positive correlation between the mean systolic and dias-
tolic blood pressures and mean serum creatinine levels,
suggesting an interrelationship between nephrotoxicity
and hypertension. Experimental studies in the dog and
rat have provided some evidence for cyclosporine-in-
duced stimulation of the renin-angiotensin-aldosterone
axis. In humans, however, no abnormality was detectable
in sympathetic nervous system function or in plasma re-
nin activity in hypertensive cardiac transplant patients
(211, 216, 218). Mean serum potassium levels are higher
in many renal transplant recipients treated with cyclospo-
rine, with occasional patients developing unexplained
frank hyperkalemia (128, 219, 220). No mechanism has
been defined as yet, although intrinsic tubular dysfunc-
tion is most likely.
Monitoring of drug level remains a useful, albeit im-
perfect, guide to therapy. Despite the lack of a clear-cut
correlation between serum trough levels and nephrotoxic
effects, close following of the cyclosporine level aids in
minimizing drug dosage and selecting those patients with
unexpectedly poor absorption, at risk of under-immuno-
suppression (221), as well as identifying patients with
grossly elevated levels. Long-term effects on kidney func-
tion—either native or allografted—are unknown, and
routine conversion to alternate immunosuppressive treat-
ments after an initial inductive period remains an option,
although no data indicate that this is beneficial for most
Hepatotoxicity: Preliminary animal studies with cy-
closporine showed hepatotoxic effects, which were imme-
diately confirmed in pilot studies of renal transplantation
in humans (119, 121). A transient rise in serum bilirubin
occurred, generally in the first month after transplant, in
up to 20% of renal transplant recipients seen in the Euro-
pean Multicentre Trial (122) and by Klintmalm and as-
sociates (222). Mild elevations in transaminases were
less frequent, and appeared, as did the hyperbilirubine-
mia, to be associated with serum trough levels in excess
of 500 ng/mL and oral dosages of 17 mg/kg body
weight . d or greater. All abnormalities corrected quickly
with dosage reduction, although mean serum bilirubin
and transaminase levels remained higher in patients re-
ceiving cyclosporine compared with those receiving aza-
thioprine (122, 223). A cholestatic pattern of hepatic en-
zyme elevation was reported in cardiac transplant recipi-
ents and attributed to cyclosporine therapy (224). Atkin-
son and associates (225) identified drug induced hepato-
toxicity as the single most frequent cause of hyperbiliru-
binemia in bone marrow transplant recipients, although
other contributory factors could be defined in half of
Several centers reported a persistent elevation of serum
alkaline phosphatase levels in renal transplant patients,
not consistently responding to a reduction of cyclospo-
rine dosage (122, 223, 226). In most patients, alkaline
phosphatase levels rose within the first 3 weeks, whereas
in others a delay of 3 to 6 months was seen. However,
isoenzyme determinations suggested the serum enzyme
was derived from bone, perhaps an expression of a repa-
rative process in patients with pre-existing renal osteo-
dystrophy, as this picture has not been seen with bone
marrow, heart, or liver allograft recipients. The patho-
physiology of hepatotoxicity remains unknown and ade-
quate human biopsy data are not available. Cholestasis is
a possible mechanism. Clinically, hepatotoxicity has been
of little significance, and is frequently reported with the
lower initial doses of cyclosporine currently used.
Lymphoma: The occurrence of six cases of non-T-cell
lymphoma in the first pilot studies using cyclosporine in
clinical transplantation led to grave concern (120, 227-
229) and raised the question as to whether the already
elevated risk of lymphoreticular malignancies in trans-
plant patients receiving conventional immunosuppression
would be further increased by cyclosporine. In each case,
cyclosporine was administered in combination with high-
dose corticosteroids and a cyclophosphamide derivative
(229), azathioprine (227), or thoracic duct drainage
(120). Subsequent experience has shown an association
in heart and kidney transplant recipients between the in-
duction of lymphoproliferative disorders and administra-
tion of both anti-lymphocyte sera and cyclosporine (176,
Cyclosporine is not directly mutagenic as assessed by
the Ames test using five different strains of Salmonella
typhi (231). Recently, however, two lymphomas were
documented in five non-transplanted monkeys treated
with cyclosporine (232). Although lymphomas have
been documented in experimental allografted animals
treated with cyclosporine alone, and in human allograft
recipients treated with cyclosporine alone or in combina-
tion with low-dose prednisone (233-235), these cases rep-
resent a small fraction of those reported. In virtually all
patients who developed lymphoproliferative disorders,
previous Epstein-Barr virus infections were shown. The
presence of Epstein-Barr virus nuclear antigen on tumor
cells and Epstein-Barr viral genomes incorporated into
tumor cell DNA strongly suggest a causative role for this
virus in these B-cell tumors (236, 237). The combination
of immunosuppressive agents used may have favored an
escape from T-cell surveillance normally exerted over
proliferation of Epstein-Barr virus-infected B cells, as
shown in vitro (13). Cleary and associates (234) showed
that five of five lymphoproliferative lesions occurring in
cyclosporine-treated heart transplant recipients repre-
November 1984 • Annals of Internal Medicine • Volume 101 • Numbers
sented true B-cell neoplasms, containing notable mono-
clonal cell populations, rather than benign polyclonal B-
As of early 1984, more than 5550 patients had been
treated with cyclosporine. Thirty-three lymphomas and
seven other lymphoproliferative lesions have been report-
ed, representing an overall incidence of 0.7% (0.6% for
renal, 2.0% for liver, 3.7% for cardiac, and 0.2% for
bone marrow grafts) (238). Although individual series
had higher incidence rates, these pooled data did not
show any increased risk compared with data from con-
ventionally treated patients. In contrast with the lympho-
mas seen in this latter population, those in cyclosporine-
treated patients appeared earlier (average 5.6 months
after transplantation versus 24 months) and rarely
involved the central nervous system (239). Treatment
has included surgical resection, decreased cyclosporine,
acyclovir, radiotherapy, and chemotherapy. Appropriate
treatment may depend on the extent of disease and poly-
clonality versus monoclonality of proliferating cells (230,
234, 235). Starzl and coworkers (237) provided evidence
that reduction or discontinuation of immunosuppression
was sufficient to cause regression of most lesions, and that
chemotherapy and radiotherapy were not beneficial and
Since the early trials, dosages of cyclosporine used
have generally decreased, with concommitant immuno-
suppression largely restricted to low-dose corticosteroids.
Under these circumstances, the increased risk of neopla-
sia appears to represent the risk of broad immunosup-
pression rather than a unique attribute of cyclosporine
Miscellaneous: Gingival hyperplasia, clinically similar
to that seen with diphenylhydantoin, occurred in 2% of
bone marrow and in 8% to 26% of kidney allografted
patients (122, 217, 240). It was seen most frequently in
children, but was rarely severe enough to require gingi-
vectomy. Resolution 1 to 2 months after discontinuation
of the drug was common.
Several young bone marrow recipients treated with
cyclosporine had seizures (241-243). Concomitant hy-
pertension or high-dose methylprednisolone treatment
was suspected to have played a permissive role. In bone
marrow transplant patients, central nervous infection
may have been involved. Seizures have also been reported
in renal transplant patients (121, 217, 244) and heart
transplant patients (177). Transient tremors and par-
esthesias have been common, reported in 10% to 39%
and 10% of patients respectively. Both appeared readily
responsive to lowered drug dosage (122, 217). A mild
form of depression was seen in several bone marrow
transplant recipients (157, 171, 245).
Hirsutism is a frequent side effect of cyclosporine ther-
apy, occurring in 30% to 44% of patients (122, 217).
Hirsutism has been mild in most cases, developing within
2 weeks to 1 month after transplant, involving predomi-
nantly the face, arms, eyebrows, and back. No endocrino-
logic cause has been found. Hirsutism resolves 1 to 2
months after discontinuation of he drug. Transient gas-
trointestinal symptoms have also occurred quite com-
monly, generally in the first several weeks of treatment
when doses are highest. These, symptoms have included
anorexia, nausea, and ileus, all of which respond to low-
ered dosage (122, 177, 238). Breast fibroadenomas, he-
molytic anemia, renal vascular throrhbosis, and recur-
rence of the hemolytic uremic syndrome, have also been
reported in cyclosporine-treated patients (216, 246, 247).
In clinical practice, cyclosporine has proved to be ef-
fective in supporting engraftment of kidney, heart, liver,
and bone marrow transplants. As follow-up periods in
these patients have been relatively short, a final assess-
ment of the role of cyclosporine in clinical transplanta-
tion cannot be made. Although the drug is unquestiona-
bly potent, and does not appear to have a higher rate of
infectious complications than standard therapy, other
side effects are disturbing. In particular, the high inci-
dence of nephrotoxicity, occasionally associated with ar-
teriolopathy and interstitial fibrosis, warrants careful
scrutiny. As universal improvements in renal function
have been seen in kidney transplant patients converted
from cyclosporine to azathioprine, and renal function has
remained stable, albeit abnormal, for several years on
continuous daily cyclosporine, it seems unlikely that ne-
phrotoxicity will preclude use of the agent. Rapidly ta-
pering protocols that use lower doses of cyclosporine
(which blocks interleukin-2 production), in concert with
corticosteroids (which block interleiikin-l production),
may provide a classic example of drug synergy by inhibit-
ing T-cell proliferation at two successive steps of the acti-
vation pathway, thus promoting graft acceptance while
minimizing nephrotoxicity. Analysis of structure-activity
relationships may allow development non-nephrotoxic
analogues. The excellent clinical results that have been
obtained during a learning phase are encouraging. More
judicious use of cyclosporine in the future should give
rise to improved results.
• Requests for reprints should be addressed to David J. Cohen, M.D.; De-
partment of Medicine, Renal Division. Columbia-Presbyterian Medical Cen-
ter, 622 W. 168th Street; New York, NY 10032.
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