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Toxic effects of immunosuppressive drugs: Mechanisms and strategies for

controlling them

Article  in  Clinical Chemistry · September 1996

DOI: 10.1093/clinchem/42.8.1316 · Source: PubMed

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Clinical
Cbemistiy 42:8(B)
1316-1321 (1996)

Toxic effects of imm U flO5U ppressive drugs:

mechanisms and strategies for controlling them
LESLIE M. Sw,l* BRUCE KAPLAN,2 and DIxoN KAUFMAN2

Since cyclosporine (CsA) was introduced into clinical prac- suppressants, alone and in combination, are now underway at an
tice in late 1983 to prevent rejection in transplant patients, explosive rate [1, 2]. Because of these advances it should be
there has been an almost explosive growth in the number possible to take immunosuppressive therapy to the next level,
and types of transplants and the number of transplant providing the transplant patient an even lower risk of rejection
centers, an increase in the life expectancy of the trans- and also further reducing risk for deleterious side effects.
planted organ, and substantial decreases in rates of acute
rejection and life-threatening infections. Despite these suc- Progress During the CsA Era
cesses, major improvements in immunosuppressive therapy CsA was introduced into clinical practice as a primary immuno-
are needed, especially a reduction in toxic side effects and a suppressant for rejection prophylaxis in transplant patients in
rigorous definition of the relation between drug concentra- late 1983. Thereafter CsA-based immunosuppression rapidly
tion and clinical effects. Such improvements may be achiev- became the standard of practice worldwide. In the summer of
able with the incorporation of new drugs such as tacrolimus 1984, Myers et al. [3] reported on the development of irrevers-
and mycophenolate mofetil into immunosuppression pro- ible kidney damage in several heart transplant patients who
tocols and the development of rigorously defined therapeu- received what now is referred to as “high-dose” CsA-based
tic drug-monitoring programs. immunosuppression. This report led to studies of the mecha-
nism of nephrotoxicity and the development of strategies for
INDEXING TERMS: transplant patients #{149}
therapeutic drug moni-
reducing the risk for its development in transplant patients while
toring randomized
#{149} concentration-controlled trial
retaining effective immunosuppression. It is important to con-
sider this side effect and efforts to curtail it because this led to
The regulation of immunosuppressive therapy is the most
major changes in CsA-based therapy and the search for less toxic
critical aspect of aftercare in transplant patients. Too much
immunosuppression.
immunosuppression increases the risk of side effects unique to
Among the advances made during the past 13 years of
each agent and of “immunotoxic” effects such as opportunistic
GsA-based immunosuppression in transplant patients are [4]: (a)
infections and malignancy. Too little immunosuppression in-
improved patient outcome including (i) decreased intensity and
creases the risk of rejection and graft loss. Here we assess the
rate of rejection, (ii) decreased rate of life-threatening infections,
progress made during the past 13 years, the so-called “cyclospo-
(iii) better control of toxic effects, and (iv) decreased time spent
rime (CsA)era,” as the result of incorporating better immuno-
in the hospital; (b) a substantial increase in the number and type
suppression regimens and CsA therapeutic drug monitoring,
and we discuss the pursuit of improvements in transplant patient of transplants; (c) a substantial increase in the number of
therapy today.3 The discovery and evaluation of new immuno- transplant centers; and (d) the incorporation of a therapeutic
drug-monitoring strategy for optimizing CsA dosing [5-12].
Despite progress in providing optimal immunosuppression
to transplant patients, important improvements or therapeutic
Department of Pathology and Laboratory Medicine, University of Pennsyl-
vania Medical Center, Philadelphia, PA 19104-4283. goals for transplant patients are needed. These suggested im-
2 Division of Organ Transplantation, Department of Surgery, Northwestern
provements reflect the collective thinking of the transplant
University Medical School, Chicago, IL 60201.
* Author for correspondence: Hospital of the University of Pennsylvania, community [13, 14] and are summarized in Table 1. These
7.103 Founders Pavilion, 3400 Spruce Street, Philadelphia, PA 19104-4283. Fax improvements in immunosuppressive therapy should result in
215-662-7529; e-mail les_shaw@pathla.med.upenn.edu. substantially improved patient outcome, decreased costs, and
Nonstandard abbreviations: GsA, cyclosporine; GFR, glomerular filtration
fewer days in the hospital. Thus, in today’s healthcare arena, we
rate; PTLD, posetransplant lymphoproliferative disorder; and RCCT, random-
ized, concentration-controlled trial.
are at a pivotal time for meeting the challenge to provide ever
Received February 22, 1996; accepted May 7, 1996. more cost-effective care for transplant patients.

1316
 Clinical Chemirty 42, No. 8(B), 1996 1317

increased magnesium excretion [17]. These acute changes in-

Table 1. Therapeuticgoalsafor transplant patients.
crease serum concentrations of creatinine, urea nitrogen, potas-
1. Reduction in the incidence of acute and chronic rejection
sium, and uric acid, and decrease serum concentration of
2. Reduction in the use of antirejection medications and associated
costs magnesium [17]. If these nephrotoxic changes are not checked
3. Reduction in the incidence and severity of debilitating side effects by appropriate GsA dosage reduction, characteristic morpholog-
of immunosuppressive agents ical changes may occur, the most specific of which is hyaliniza-
4. Avoidance of overimmunosuppression tion of afferent arterioles [18].
5. Development of rigorous pharmacokinetic-pharmacodynamic
studies in clinical trials-basis for therapeutic drug monitoring Chronic changes. Patients exposed to high blood concentrations
6. Development of patient-specific measurement of of CsA for sustained periods of time may exhibit the following
immunosuppression
irreversible vascular changes: continued narrowing of afferent
7. Increased compliance
arterioles; damage to the endothelium and smooth muscle;
8. Reduction or elimination of chronic steroid therapy
9. Development of safe and effective therapy for autoimmune arteriolar occlusion; vessel obliteration; glomerular dropout;
disorders tubular atrophy; and striped interstitial fibrosis [19]. These
a All of these involve improved patient outcome, decreased costs, and changes are largely preventable by adjusting GsA dosage early
decreased number of days in the hospital. after transplant surgery to the currently accepted target blood
concentration ranges [19, 20]. These changes were seen in
patients exposed to the high-dose GsA regimens in use when
Side Effects of Immunosuppressive Drugs GsA was first introduced into clinical practice but are less
All immunosuppressants have associated side effects. The most frequently seen in patients receiving the current low-dose
important or the most widely studied side effects of immuno- GsA-based immunosuppression regimens with dosage guided by
suppressive drugs in current use are summarized in Table 2. As therapeutic drug monitoring [19]. Tubular changes in patients
noted, the nephrotoxic effects of GsA played a major role in the exposed to high GsA doses chronically are single cell necrosis,
development of subsequent immunosuppression protocols, and giant mitochondna, and vacuolization [19]. These changes can
tacrolimus is also nephrotoxic [15]. Thus, a consideration of the be reversed by reducing the GsA dose to achieve therapeutic
mechanisms of GsA nephrotoxicity and successful strategies for blood concentrations [21].
minimizing this side effect should provide a basis for the more Although far fewer studies of the detailed renal function
efficient development of tacrolimus-based immunosuppression changes caused by tacrolimus have been done, Steinmuller [22]
and the successful incorporation of other new immunosuppres- and Jusko et al. [23] concluded that these are essentially the same
sive drugs into clinical practice. as the changes produced by GsA and that their occurrence
should be minimized by a therapeutic drug-monitoring strategy.
CsA and Tacrolimus Nephrotoxicity
RENAL FUNCTION AND MORPHOLOGY CHANGES MECHANISMS OF GSA NEPHROTOXICITY
Acute changes. The hallmark acute renal hemodynamic changes The overall mechanism responsible for the development of
caused by GsA include reduced renal blood flow, afferent chronic changes in kidney structure and, consequently, function
arteriolar vasoconstriction, a decreased glomerular filtration rate is incompletely understood. GsA administration almost imme-
(GFR), and increased renal vascular resistance [16]. The major diately reduces renal blood flow and GFR [16], as observed in
acute renal tubular abnormalities attributable to GsA are de- animal models, in transplant patients, and in patients with
creased potassium secretion, decreased uric acid excretion, and autoimmune disorders [17]. In psoriasis patients, the biochem-
ical changes described above correlated well with blood concen-
trations of GsA measured specifically [17]. The latter study is of
Table 2. SIde effects of Immunosuppressivedrugs. special interest in that the observed effects can more directly be
All immunosuppressant drugs have associated significant side attributed to GsA because there were fewer confounding factors
effects. The following are the most important or the most widely
studied side effects caused by the immunosuppressant drugs now such as prior impaired kidney function and other medications
commonly used. that might alter kidney function; the investigators also used a
CsA and tacrolimus Nephrotoxicity, hypertension, and parent-drug-specific method (HPLC) for drug measurement
(FK-506) neurotoxicity [17]. Hemodynamically, the hallmark event causing the reduced
Azathioprine (Immuran) Bone marrow depression renal blood flow and GFR is believed to be the constriction of
hepatotoxicity; posttransplant
afferent arterioles to a greater extent than efferent arterioles
lymphoproliferative disorder (PTLD)
[16]. Of the many reported biochemical changes associated with
Steroids Osteonecrosis and osteoporosis, CNS8
effects, growth suppression, glucose this acutely altered GFR, which ones are ultimately responsible
intolerance, hypertension for the hemodynamic changes is unclear. Possible mediators
OKT3, ATGAM Flu-like symptoms, PTLD include increased thromboxanes and endothelin; enhanced sym-
Mycophenolate mofetil Gastrointestinal toxicity, occasional pathetic activity, platelet-activating factor, and angiotensin II;
leukopenia impaired nitric oxide production; and decreased vasodilating
a CNS, central nervous system; OKT3, orthoclone 0KT3, muromonab CD3;
prostanoids [24]. It is not clear whether the acute hemodynamic
ATGAM,antithymocyte globulin.
effects of GsA cause chronic structural changes [25]. Chronic
1318 Shaw et al.: Immunosuppressive drugs

renal histopathological changes include hyalinization of afferent calcium channel-blocking antihypertensive agents is another
arterioles, damaged endothelium and smooth muscle of afferent strategy to decrease nephrotoxic risk. These agents attenuate
arterioles, tubular atrophy, glomerular sclerosis, and striped some of the GsA-mediated renal hemodynamic changes but may
interstitial fibrosis. Burdmann et al. [25] found in recent animal not affect the more chronic histological changes [38]. (c) A risk
model studies that these chronic changes may be dependent on factor for GsA nephrotoxicity is the underlying condition of the
angiotensin II but independent of the renal hemodynamic kidney itself [21]. Thus, the condition of the kidney before
changes. transplant surgery, the concomitant use of nephrotoxic agents,
and the number and intensity of rejection episodes are examples
CSA METABOLITES AND NEPHROTOXICITY of risk factors that predispose this organ to GsA nephrotoxicity.
Christians and Sewing [26] detected >30 metabolites of GsA. (d)Introducing new drugs, such as mycophenolate mofetil and
The structures of 15 of these have been characterized. Some rapamycin, with fewer overt side effects such as nephrotoxicity,
metabolites appear in appreciable concentrations in tissues and can allow further reduction of GsA dosage but could also prompt
blood in transplant patients, especially during episodes of liver a tendency to give more immunosuppressive drug than neces-
dysfunction [27]. Ghristians et al. [27] reported an association of sary. Thus, defining an upper window for reduced risk for
high concentrations of metabolites AMlc9 and AM19 with immunotoxic effects is critical to providing optimal therapy and
nephrotoxicity in the early postoperative period in some liver to rigorously defining relationships between drug concentration
transplant patients but could not distinguish between cause and and risk for side effects.
effect for the metabolites. Several consensus groups have con-
cluded that the clinical importance of GsA metabolites is immunotoxicity
controversial and that in most clinical situations monitoring Adjusting immunosuppressive drug dosage to achieve narrow
metabolite concentrations in patients’ blood, in addition to that target concentration ranges can also reduce the risk for immu-
of the parent drug, is not warranted [7, 9, JO]. Nevertheless, the notoxicity. Besides drug-specific side effects, all immunosup-
possible role of GsA metabolites remains under investigation pressive agents are immunotoxic, increasing risk for infections
[26]. Christians and Sewing [26] provide details of most studies and cancers. The risk for infections has been successfully
conducted in this area to date. reduced by a combination of prophylactic antiinfective agents
and tight control of GsA and tacrolimus dosing. All immuno-
TACROLIMUS METABOLITES suppressive agents put patients at increased risk for cancer.
Tacrolimus is converted to at least 15 metabolites by several PTLD is one of the most common cancers associated with
members of the cytochrome P-450 family [23, 28]. Less than 1% immunosuppression [39, 40]. The incidence of PTLD is a
of the parent drug is excreted unchanged in urine [23, 28]. In function of the intensity of immunosuppression (Fable 3). The
single dose studies, tacrolimus metabolites do not accumulate mechanism responsible for the development of PTLD is postu-
appreciably; but in chronically dosed patients, five main metab- lated to be the loss of normal T cell surveillance secondary to
olites, measured by HPLG-mass spectrometry, accumulated in immunosuppression. The risk for development of PTLD in-
blood as high as 145% and 152% of the tacrolimus concentra- creases with increased intensity of immunosuppression and
tion in liver and kidney transplant patients, respectively [29]. appears to be highest in transplant recipients with negative
Jusko et al. [23] characterized the immunological activity of nine Epstein-Barr virus titers at the time of transplant surgery [41].
metabolites and measured cross-reactivity with the monoclonal The pediatric patient population has a particularly high risk for
antibody used in the commercially available tacrolimus immu- this complication.
noassays. However, nothing has been published regarding the
possible toxicity of tacrolimus metabolites. Strategies for ReducingPTLD Risk
Azathioprine and OKT3 subject transplant patients to the
Strategies to Reduce the Risk for Developing greatest risk for PTLD according to epidemiological studies
Nephrotoxicity [39]. Two important outcomes of the multicenter clinical trials
Effective strategies for reducing the risk of acute and chronic for tacrolimus and mycophenolate mofetil were the reduction of
nephrotoxicity are: (a) GsA dosage adjustment to maintain blood OKT3-based full-course antirejection therapy by twofold and
concentrations of the parent drug within a narrow target range.
In three studies overt acute nephrotoxicity was reduced to an
Table 3. incidence of PTLD as a function of
incidence of 4-8% by maintenance of parent-drug blood con-
immunosuppressionintensity f39J.
centrations within a tight concentration range in renal trans-
Immunosuppresslon PhD Incidence (%)
plant patients [8, 30, 31]. This contrasts sharply with the inci-
Pre-1983, *conventional* immunosuppression 1-4.9
dence of acute nephrotoxicity of 70% [32] and 370% [33] in
Early high-dose CsA 9-13
renal transplant patients whose GsA dosing was based on serum
C5A, low-dose, guided by TDM8 Up to 1.5
creatinine changes alone. Although prolonged exposure to con-
Triple therapy (C5A + steroid + azathioprine) Up to 5
trolled-dose GsA causes some loss of renal function [34], renal
OKT3 Up to 11
function is stable and graft loss due to the chronic nephrotoxic TDM therapeutic drug monitoring; OKT3, orthoclone OKT3, muromonab
sequelae, suggested by Myers et al. [3] under high dose GsA
CD3.
regimens, is avoided [35-37]. (b) Goncomitant therapy with
 Clinical
Chemistry 42, No. 8(B), 1996 1319

the elimination of azathioprine from triple therapy regimens for developed through single-center retrospective review of concen-
liver and renal transplant patients, respectively [15,42].The risk tration-effect data. The RGCT approach differs in that it is a
for PTLD could be lessened further by reducing or eliminating prospective study design in which study patients are randomly
these two risk factors in the immunosuppression regimen and by assigned to one of several predetermined cohorts. The dosage is
further optimizing the new immunosuppression regimens titrated for each patient cohort within a study to achieve a
guided by careful therapeutic drug monitoring strategies. An- certain active drug steady-state concentration range for a sus-
other important benefit of the reduction in acute rejection rate tained period. Hard outcome variables are measured throughout
with new immunosuppression regimens is the decrease in num- the study. For transplant patients, the outcome measures include
ber of hospital days and costs [42, 43]. acute rejection, toxic side effects, and infections. Drug concen-
trations in the appropriate biological fluid are measured at
New immunosuppressive Drugs predetermined times during the study period. An example of this
The development of new immunosuppressive agents led to the strategy is a double-blinded RCCT involving 120 renal trans-
recent introduction of tacrolimus and mycophenolate mofetil plant patients receiving mycophenolate mofetil together with
into clinical practice. Rapamycin is under clinical evaluation in GsA and prednisone. CsA dosage was regulated according to a
renal transplant patients [44]. Leflunomide analogs, which in- trough concentration strategy, and prednisone was given ac-
hibit the lymphocyte proliferative response primarily by inter- cording to an empirical dosing strategy. The basis for this study
ruption of de novo pyrimidine nucleotide biosynthesis [45] and was the observation of a strong inverse correlation between the
humanized monoclonal antibodies such as CTLA4-Ig [46], 12-h mycophenolic acid area under the concentration cuve and
which act by blocking the CD2 8-mediated costimulatory signal, risk for acute rejection [50-52]. The latter observation was
are under intense investigation in animal transplant models. originally made in a group of Japanese renal transplant patients
New agents and combinations of new and established immuno- and confirmed in a group of patients enrolled in the American
suppressive drugs will likely be used clinically in the near future. multicenter trial [50]. In the RCGT study, the patients were
Thus, it might be possible to reduce further the risk for toxic assigned to one of three study groups, one receiving low doses of
effects of such drugs as CsA and tacrolimus if lower doses and mycophenolate mofetil to achieve a low mycophenolic acid
concentrations will provide at least equivalent efficacy when concentration range, the second a mid-target range, and the
combined with the newer agents, providing both a challenge and third a high target range. We hope that the results of these
an opportunity to the laboratorian. In this scenario, it is studies will provide a more rational basis on which to develop a
important to develop well-founded therapeutic drug-monitor- therapeutic drug-monitoring strategy in individual patients. The
ing strategies at the earliest possible time during drug develop- clinical laboratorian can affect the development of such strate-
ment. Table 4 gives a summary of proposed therapeutic drug- gies by providing laboratory support and participating in the
monitoring goals for immunosuppressive drugs, based on the development of immunosuppression protocols.
accumulated experience with monitoring GsA and tacrolimus. Tests for the inhibition of the target pathways of immuno-
Continuing experience with GsA and tacrolimus clearly indicate suppressants are being developed to provide new laboratory
the value of developing well-validated analytical methods for evaluation approaches to the assessment of the immunosuppres-
measuring active drug that meet stringent but realistic criteria sion status of the patient. New approaches to pharmacodynamic
[7, 9, 10, 47, 48]. monitoring currently under evaluation in transplant patients
Peck et al. [49] proposed that the randomized, concentration- include calcineurin phosphatase inhibition [53] as an assessment
controlled clinical trial (RGCT) can be an efficient way to of GsA immunosuppression and inosine monophosphate dehy-
acquire drug concentration vs clinical effect information for drogenase inhibition in whole blood as an assessment of myco-
specific cohorts of study patients. In the discipline of therapeutic phenolic acid immunosuppression in the individual patient [54].
drug monitoring, most of the guidelines for how to use drug
concentration in the appropriate biological fluid have been Analytical Goals for Immunosuppressive Drug Measurement
For routine therapeutic drug-monitoring purposes, monoclonal
antibody immunoassays are most commonly used for CsA
Table 4. Therapeutic drug monitoringgoals for measurement, although a substantial number of laboratories are
immunosuppressive drugs. using validated HPLC methods that provide for specific mea-
1. Develop specific, well-validated methods for measurement of drug surement of the parent drug [10]. In a review of the performance
and active metabolites, if any, at the earliest time during drug characteristics of immunoassays, Oellerich et al. [JO] pointed out
development. that because of differences in specificity of the monoclonal
2. Select the most appropriate biological fluid for drug
antibodies and between-method differences in calibration, GsA
measurement.
3. Study the relationship between drug concentration and clinical measured in the same patient’s blood sample by the three
outcome as early as possible during clinical trials. available immunoassays (Abbott TDx, Incstar radioimmunoas-
4. Establish a threshold concentration for effective say, and Syva-Behring enzyme-multiplied immunoassay tech-
immunosuppression. nique) can differ by as much as 100%. This degree of discrep-
5. Establish an upper limit concentration for reduction of risk for the ancy is especially likely in samples containing high
development of immunotoxicity.
concentrations of cross-reacting GsA metabolites relative to the
6. Participate in an appropriate quality-assessment program.
parent drug. Because GsA metabolites contribute little to overall
1320 Shaw et al.: Immunosuppressive drugs

immunosuppression, using the least-specific assays in patients cyclosporine in renal transplantation. Clin Biochem 1995;28:
with high metabolite concentrations could cause the physician 195-211.
to underdose the patient. There continues to be a pressing need 13. Hunt 5, Billingham M. Long-term results of cardiac transplanta-
tion. Annu Rev Med 1991;42:437-47.
for the development of well-validated analytical methods that
14. Almond PS, Mata A, Gillingham K, Dunn DL, Payne WD, Gores P,
meet stringent but realistic criteria for the accurate and repro-
et al. Risk factors for chronic rejection in renal allograft recipients.
ducible measurement of active drug for GsA [7, 9, 10, Transplantation 1993;55:752-7.
47, 48, 55], and initial experience with tacrolimus measurement 15. US, Multicenter FK-506 Liver Study Group. A comparison of
shows that this need is as pressing for this immunosuppressive tacrolimus (FK-506) and cyclosporine for immunosuppression in
agent [23]. Well-validated analytical methods are also essential liver transplantation. N Engl J Med 1994;331:111O-5.
in pharmacokinetic studies performed during preclinical and 16. English I, Evan A, Houghton DC, Bennett WM. Cyclosporine-
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44:135-41.
scientific and, ultimately, the clinical value of such study data
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CN, Voorhees JJ. Short-term changes in renal function, blood
RCGT design discussed above and the use of validated analytical pressure, and electrolyte levels in patients receiving cyclosporine
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