Immunosuppressant-induced metabolic toxicities

TRANSPLANTATION REVIEWS VOL

14, NO 2

APRIL

2000

Immunosuppressant-Induced Metabolic Toxicities Gabriel M. Danovitch Efforts to improve long-term allograft survival and quality of life after solid-organ transplantation need to relate to the toxicities of immunosuppressant drugs as a factor in long-term survival that can be addressed by the transplant team. Nephrotoxic, hyperlipidemic, hypertensive, and, to some extent, neurotoxic and hepatotoxic effects of immunosuppressants, are well recognized and well documented in the literature. Others, such as effects on bone metabolism, diabetogenesis, and cosmetic factors, are less well understood or are considered less significant because they do not directly affect the transplanted organ or threaten the survival of the patient. Nevertheless, they may have an important impact on patient compliance and quality of life, and serious consideration should be given to their treatment or, preferably, prevention. This review presents the current understanding of the effects of the immunosuppressants, cyclosporine, tacrolimus, glucocorticoids, mycophenolate mofetil, and sirolimus, on bone, lipid, and glucose metabolism and various cosmetic aspects. Consideration is also given to the development of protocols that could potentially limit the severity and impact of the toxic side effects. Copyright 8 2000 by W. B. Saunders Company

T

he improvement in short-term graft and patient survival rates in solid-organtransplantation that has occurred since the introduction of cyclosporine (GA) into clinical use in the early 1980s’has permitted a shift in the researchfocus of transplant teams from the prevention of early graft loss to the improvement of long-term survival and patient quality of life. There has been somemodest improvement in long-term graft survival, but it remains limited by the high incidence of chronic allograft dysfunction. Until chronic dysfunction of transplanted organs can be ameliorated and the mounting pressure on the available organ pool is relieved, the long-term efftcacy of organ transplantation asa treatment for organ failure will not be’fully realized. From the Division of Nephmio~, UniversQ of Cal#mia at Los Angeler, CA. AaYrw rep’nt reque& to Gabriel M. Danovitch, MD, UCLA Medical Center, Divkion ofNephm&, 7155 Factor Bkig, 108333 Le Conte Ave, Las Angeles, CA 90024-I 738. Cojyight 0 2000 Ly W.B. Saunders Company 0955-470x/00/1402-000.5s10.00/0 doicl O.153hr.2OOO.5377 Transplantation

Revkws,

Vol14,

Our current understandingof the pathophysiological state of chronic allograft dysfunction does not permit its prevention. However, there are several factors that can be manipulated by the transplant team that at least hold somepromise of improving long-term allograft and patient survival rates and patient quality of life. One of these factors is the compositionand doseof posttransplantationimmunosuppressivetherapies. A contradiction of posttransplantation care is that many of the immunosuppressiveagents used to prevent allograft rejection may have serious longterm effects on the transplanted tissue,other organ systems,and the well-being of the transplant recipient (Table 1).2” Moreover, the toxic effects of immunosuppressiveregimens can reduce compliance and lead to allograft rejection or require concomitant medications, which may evoke an additional set of adverseevents. This report reviews the current understanding of the impact of immunosuppressantson bone, lipid, and glucosemetabolism and various cosmetic and dermatologic side effects, together with an overview No 2 (&nil),

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Gabriel M. Danovikh

Table 1. Immunosuppressant

Agents and Their Toxicities

Toxic+

Cyclarlorine

Nephrotoxicity Hypertension Hyperlipidemia Neurotoxicity Diabetes Osteoporosis Acne Gingival hyperplasia Hirsutism Alopecia Gastrointestinal toxicity Hematologic toxicity *Based on current

-

\i J \i d \i d / :;, \i \i

Tacmlimw

Slemidr -

-

; ? \i \i d

\i J \i

4 d

-

; J \i’ 1:

Myophenolate &loj&il

-

Simlinuu

-

\I \i

7 -* -* -* -* -* -* ? \’

&alhioprine

i \i J

clinical experience.

of available treatment options. Toxicities typically have been treated by administering drugs to counter the sequelae of the toxicity and/or by reducing the dose of the immunosuppressive drug, which is associated with the hazard of underimmunosuppression and the subsequent threat of rejection episodes. It is hoped that the enlarging armamentarium of immunosuppressive drugs may permit the development of safe, low-toxicity regimens that can allow a reduction in dose or eventually complete elimination of more toxic agents.

Bone Toxicity Candidates for transplantation often present with risk factors for bone disease, such as reduced mobility (because of inadequate load-bearing exercise), menopause, hepatic cirrhosis, diabetes, hyperparathyroidism, and renal osteodystrophy.“O Moreover, renal transplant candidates are often on a dialysis regimen pretransplantation that consists of continuous treatment with heparin, oral alkali, and acetate, which may further interfere with normal bone.” A study by Floreani et aI6 found that 41% of the candidates for liver transplantation for end-stage liver disease had a bone mineral density already less than the fracture threshold (0.8 g/cm*), and preexisting osteoporosis in lung transplantation candidates has been reported by Shane et al.‘* It is therefore of particular concern that immunosuppressive regimens have detrimental effects on bone metabolism and, ultimately, on the composition and integrity of the skeleton.” A list of immunosup pressants and their effects on bone and mineral metabolism is shown in Table 2.r3

The development of posttransplantation osteopenia has been noted in heart, kidney, liver, lung, and bone marrow transplantation.r3 Kidney transplant recipients, however, appear less susceptible than heart and liver transplant recipients.‘” Typically detected as a reduction in bone mineral density, posttransplantation immunosuppressant-induced or im-

Table 2. Effects of Immunosuppressive and Mineral Metabolism

Drugs on Bone

Cyclosporine and Increased bone resomtion tacrolimus* Increased bone formation and serum osteocalcin levels Marked osteoporosis (resorption > formation) Decreased gonadal steroid synthesis Azathioprine* Increased osteoclast number No change in bone volume Glucocorticoids Reduced net intestinal calcium absorption Increased urinary calcium excretion Increased parathyroid hormone Decreased production of skeletal growth factors Decreased adrenal/gonadal androgen and estrogen synthesis Decreased bone formation by osteoblasts Increased bone resorption Mycophenolate No change in bone volume mofetil* Sirolimus* Increases bone remodeling Inhibits longitudinal growth No short-term effects on bone volume *These observations are based primarily on animal studies. Adapted and reprinted with permission from Excerpta Medica Inc.13

Immunosu~ptzsan! Toxicities

munosuppressant-exacerbated bonelossisconsidered responsible,at least in part, for fractures in organ recipients.The incidenceof fracture can vary from as low as 7% in kidney transplant recipients without diabetes to as high as65% in female liver transplant recipients.i5J6Perhapsthe most commonand debilitating orthopedic side effects are vertebral compression fractures, resulting in chronic back pain and avascularnecrosisof the weight-bearingjoints, often necessitatingjoint replacement.i7Clinical effects of posttransplantation osteopeniaattributed to immunosuppressanttoxicity from steroids, concomitant immunosuppressives,and mild, residual hyperparathyroidism have been documented in 44 renal allograft patients, 2 of whom experienced spontaneous fractures; aseptic bone necrosis, especially of the femoral head,wasnoted in 7 allograft recipients.” Steroids

Steroids are the immunosuppressantsmost clearly associatedwith osteopenia and osteoporosis.The mechanismsby which they are believed to exert a deleteriouseffect on boneare listed in Table 2.i3In a retrospective review of 160 studies published since 1970,osteoporosiswasfound to occur in at least 50% of the personsadministeredlong-term glucocorticoid therapy.‘s In transplantation specifically, many studies have implicated steroidsas risk factors for posttransplantation osteopenia and osteoporosis.Both cumulative and daily steroid dose levels can be related to the incidenceof demineralization. A multivariate analysis of data from a crosssectional study of 65 renal transplant recipients on immunosuppressant regimens (various combinations of CsA, azathioprine [AZA], and steroids) indicated that cumulative steroid dose is a major predictor of low vertebral bone density.ig Twentythree percent of the patients had vertebral bone densities less than the fracture threshold. The 3-month cumulative steroid dosewaspositively correlated with early femoral neck bone lossin a prospective 3-year study of 70 heart transplant recipients, which also showeda relationship between the daily steroid doseand rate of bone lossduring the second half of the first year.*ORelationshipsbetween both cumulative and daily steroid dosesand bone mineral density were alsoshown in kidney transplant recipients in a cross-sectionaland longitudinal study of 70 transplant recipientsby Pichette et al.*’ In a prospective study of 20 patients administeredAZA, CsA, and steroids,the lossof vertebral bone was histologically attributed to the toxic effects of the glucocorticoids.*

67

A constant feature of studies analyzing bone loss after transplantation is the finding that bone lossis most significant in the first year.2o22Within this period, most bone loss occurs within the first few months. A prospectiveclinical trial to study bone demineralization in heart transplant recipients showed not only that trabecular bone losswas limited to the first 3 months, but that bone density had already signiticantly decreased within as few as 3 weeks from transplantationz3 Furthermore, the greatest rate of demineralization correlated with the greatest dosage of maintenance and pulsed steroids. The implications of this for new low-toxicity regimens are discussedlater. CsA and Tacrolimus

With the introduction of CsA and later of tacrolimus (FK506), glucocorticoid dosesin immunosuppressive regimens were reduced, and it was expected that bone losswould decreasedramatically.i3 However, the persistenceof posttransplantation osteopeniain the post-&A era suggeststhat CsA and FK506 cause or contribute to this condition. Mechanismsby which these calcineurin inhibitors cause bone loss, elucidated from animal studies, are listed in Table 2. Experiments on rats have shown that CsA and FK506 disrupt the balance between bone formation and bone resorption, resulting in a significant degree of bone loss, more marked with FK506.2‘rDespite these findings, detecting this effect in the clinical setting has proven problematic becauseof steroid coadministration and preexisting bonedisease. Accelerated bone turnover causedby stimulation of osteoblastshas been reported in women in a cross-sectionalstudy of 23 allogeneic bone marrow recipients, none of whom received steroids. It was shownthat the disturbance in bone metabolismwas causedby CsA and wasenhancedin women with low estrogenlevels.25It may be concluded that bone loss in postmenopausaltransplant recipientswill be accelerated by CsA. In a prospective,longitudinal study of 24 heart transplant recipients with bone densitometry and biochemical measurementsperformed every 2 months, Thiebaud et alz6noted that changesin serum parathyroid hormone and osteocalcinlevels from pretransplantation to 18months posttransplantation differed from those of glucocorticoid-induced osteoporosis.Immunosuppressionin this study consisted of CsA and prednisonein a tapering dosage. Bone loss,occurring mostly in the hip, wasattributed to either a secondary,unrecognizedhyperparathyroid-

68

Gabriel M. Danouitch

ism or CsA. However, in a randomized trial of 53 first-time renal transplant recipients, bone loss occurred in patients administered Cs.4 and steroids, but those administered CsA alone showed an increase in lumbar bone mineral density during 18 months of follow-up.27 In support of this, a long-term study of bone loss after renal transplantation** concluded that bone loss did not correlate with CsA dosage. Evidence for an overt osteopenic effect of FK506 in the clinical setting is also controversial. In a study of bone metabolism in liver transplantation, 37 patients were randomized to treatment with either CsA, AZA, and steroids or FK506 and steroids. The steroid dose in the FK506 group was half that in the CsA group. Both groups showed significant bone loss, and at l-year follow-up, there was no significant difference in lumbar spine bone mineral density between the two groups. Although these data appear to implicate FK506 in the bone loss that continued even in the presence of a reduced steroid dose, the investigators decided that the trial was too small to make firm conclusions because of the uncertainties surrounding steroid use and other causes of osteopenia?s AZA, Sirolimus,

and Mycophenolate

Mofetil

Clinical data on the adverse effects of AZA on bone are conflicting. A study of rats showed that it does not have a deleterious effect on bone volume?g A clinical study suggested it may correlate with a greater incidence of avascular bone necrosis than CsA.3o There are no clinical data on sirolimus, but there is evidence in rats that it increases bone remodeling and decreases growth rates.31 Mycophenolate mofetil (MMF) did not cause osteopenia in a short-term study using a rat mode1.32 However, biochemical evidence of a decrease in osteoblastic activity was noted. The use of MMF in clinical trials has not been associated with an increase in the incidence of osteopenia or disturbances in calcium or phosphate metabolism.33-35 Treatment of Pretransplantation Posttransplantation Osteopenia Osteoporosis

and and

It has been recommended that all candidates for transplantation be assessed preoperatively for osteopenia and osteoporosis by spine radiographs, bone densitometry, and tests for thyroid function, serum calcium, vitamin D, parathyroid hormone, and testosterone levels (in men). If the presence of bone disease

is confirmed, treatment should ideally begin before transplantation.‘3J” Physicians may select from a number of treatments, including the administration of calcium and vitamin D and sex hormone replacement therapy. Another strategy is to prescribe antiresorptive agents, such as calcitonin, bisphosphonates, and fluoride.14J63’ The treatments have been successful in at least slowing the rate of bone loss. For example, in cardiac transplant recipients, prophylactic administration of calcium carbonate and alphacalcidol after transplantation reduced bone loss and osteoporotic complications.3s Load-bearing exercise has been shown to be osteogenic and to reverse bone loss. A prospective, randomized, controlled study determined the effect of resistance exercise training on bone metabolism in heart transplant recipients. After 6 months of resistance training consisting of low-back exercise coupled with variable-resistance exercises, bone mineral density was restored toward pretransplantation levels.3g In a time of increasing healthcare costs, the expenses associated with monitoring bone density, bone metabolism, and treatment of immunosuppressant-induced osteopenia, osteoporosis, and fractures represent an unwelcome burden in transplantation medicine. The estimated incidence and lo-year cost of treating steroid side effects have recently been reported for a cohort of 50 patients. The lo-year cost for treating peripheral fractures was $4,300, and for osteonecrosis of the hip, it was $61,700.‘W Protocols that safely permit steroid withdrawal or, preferably, avoidance would have a potentially positive economic impact, in addition to clinical benefit.

Diabetogenic Actions of Immunosuppressive

Drugs

Several of the currently used immunosuppressants have been shown to be diabetogenic and can induce diabetes in nondiabetic patients. This further complicates pretransplantation and posttransplantation care. In addition, patients with posttransplant diabetes mellitus (PTDMJ are at greater risk for serious infections and have decreased rates of patient and graft survival .41*42The 12-year graft survival rate in patients with diabetes developed posttransplantation was 48% versus 70% in control patients (P = .04). Furthermore, complications similar to those in nontransplant-associated diabetes (neuropathy, nephropathy, hyperosmolar or ketoacidotic coma, or precoma) may occur in PTDM.42

Immurwsupzssant Toxicities

Steroids The development of glucoseintolerance and F’TDM has long been regarded as one of the major side effects of high-dosesteroid regimens.43Recent data continue to implicate steroidsin the development of PTDM. Glucoseintolerance wasprospectively examined in 173 consecutivekidney transplant recipients by oral glucose tolerance tests or the diagnosisof diabetesmellitus at 10weeksafter transplantation.# It wasfound that the risk for developingFTDM was 5% per 0.01 mg/kg/d of prednisolone.The investigators concludedthat increasedsteroid doseand older age are strongly associatedwith the development of posttransplant glucoseintolerance. Another study of 1,325 renal transplant recipients found that pulsed steroid therapy might be the critical factor in the onset of PTDM and that the risk was increasedin older patients.45 The diabetogenic side effects of steroids are probably more severein black patients, who have been shown to metabolize steroid doses more slowly, thus increasingdrug exposure.* IX!506 and CsA The associationbetween FK506, CsA, and PTDM has been confirmed in both laboratory and clinical trials. Very clear indicationsof potential diabetogenicity have been obtained in animal and in vitro studies. In human cell lines, FK506 reversibly inhibited insulin gene transcription, leading to a decline in insulin messengerRNA levels, insulin synthesis, and ultimately, insulin secretion.47A study of rats administered either 5 or 10 mg/kg/d showed a reversible decreasein insulin content of the pancreas and a decreasein plasma insulin levels.48Similarly, CsA was shown to depress glucose-stimulated insulin release from perfused human isletspg and when administered to rats for 12 weeks at a dose of 1.25 mg/kg of body weight, CsA causedglucoseintoleranceand a decreasein pancreatic insulin content.50 In the clinical setting, CsA and FK506 are often usedin combination with steroids;therefore, separating the steroid effect from that of the calcineurin inhibitors becomesdifficult. Nonetheless,their contribution to the disturbance of glucosemetabolismcan be detected. From the outset, it was expected that the introduction of CsA into immunosuppressant regimens with a concomitant reduction in steroid dosagewould lead to a reduction in the incidence of new-onsetPTDM. Unfortunately, new-onsetPTDM continues to be a problem, possiblybecauseof the diabetogenicity of CsA and perhaps becauseit in-

69

creasesthe plasma half-life of steroids, leading to increasedsteroid activity.51 In a study of 314 kidney transplant recipients previously without diabetes, the incidence of PTDM in patients administered AZA and methylprednisolone was 9.1% compared with 18.6% (P < .05) in patients administered C&A,AZA, and the samedose of methylprednisolone.PTDM occurred rapidly and required insulin treatment in the majority of patients.52Another study comparing the incidence of diabetes in kidney transplant recipients previously without diabeteswho were maintained on two different regimens showed a similar pattern. The incidence of new-onsetdiabetes was 6 of 20 patients administered CsA and low-dosemethylprednisolone (30%; P < .05) and 4 of 53 patients administered AZA and methylprednisolone (7.5%).53The worsening of the metabolic statusof heart transplant recipients who previously had diabetesand were administered CsA but not steroidshasbeen attributed to the diabetogenicity of CsA or the surgical procedure itself.%An evaluation of 1,325renal transplant recipients found that diabetes occurred mdre rapidly in patients administeredboth CsA and steroidsthan in patients administeredsolelysteroids.+5This suggests that CsA may exert a greater diabetogenic effect when combined with other immunosuppressants. However, a prospective study comparing renal transplant recipien,tsadministeredCsA monotherapy,CsA and prednisone or AZA and prednisone concluded that despitein vitro data, normal dosesof CsA do not have a clinically important effect on beta-cell function, and instead, the effect is causedby concurrently administered steroids.55Perhaps partly confirming this, a recent light- and electron-midroscopicstudy of pancreatic biopsy specimensfrom kidney-pancreas transplant recipients showedstructural damage to beta cells similar to morphological and functional abnormalities previously documentedin experimental animalswhen exposedto CsA and FK506. When islet anatomy was correlated with serum levels of CsA and FK506, corticosteroid administration, and glycemia, the results showed that the diabetogenic effects of toxic levels of CsA or FK506 are potentiated when high-dosesteroids are administered, but that toxic levelsof CsA or FK506 are rarely diabetogenieon their 0wn.5~ In this regard, it is interesting that a 2-year, randomized, double-blind,placebo-controlledtrial of 514 patients examining the efficacy and toxicity of CsA in chronic, progressivemultiple sclerosisfound no statistical differences in serum glucoselevels at

Gabriel M. Dam&h

entry or exit between the treatment groups. The median CsA trough level was maintained at 310 to 430ng/mL.57 On balance, the accumulated clinical data on FE506 and CsA suggest that FE506 is more diabetogenie; however, one study has shown that they are equivalent in this regard.58 Again, it must be remembered that coadministered steroids complicate the analysis. Patient race is also a factor; black patients are more susceptible to the diabetogenic effect of FE.506 than white patients, in whom the condition is more easily reversed.5g The effect of FE506 on glucose metabolism was reported in the l-year safety data of phase II trialsW It was shown that 12 of 92 patients who previously did not have diabetes (13%) required insulin at l-year posttransplantation, but the investigators claimed that concomitant steroid use may have contributed to this development. A clearer picture of the greater diabetogenicity of FE506 emerged from a multicenter randomized trial comparing FE506 and CsA in the prevention of renal allograft rejection.61 In this trial, the maintenance oral prednisone dose for both groups was 5 mg/d from day 43 onward. The incidence of diabetes mellitus in FK506-treated versus GA-treated patients was 11.6% versus 3% (P = .OOl), and the incidence of hyperglycemia was 16.2% versus 6.9% (P = .Ol). New-onset insulin-dependent diabetes mellitus was diagnosed in 8.3% of the FK506-treated patients and 2.2% of the GA-treated patients. A multivariate analysis showed that the development of PTDM was associated with increasing whole-blood concentrations of FK506. A randomized, open-label study comparing the efficacy and safety of FK506-based and CsA-based immunosuppression in renal transplantation found that the incidence of new-onset PTDM after 1 year was 19.9% and 4%, respectively. Covariate analysis showed that trough levels of FE506 were a significant predictor of the development of the disease.@ However, it also showed that steroid dose was a factor, and 75% of the patients who developed PTDM had maximum total daily steroid doses of 25 mg/d or greater during the 30 days before PTDM onset. The 3-year data of this trial showed that only 33% of the patients with new-onset diabetes were off insulin therapy by year 3 .63The greater diabetogenicity of FE506 was also reported in the US multicenter trial of its use in liver transplantation.M Hyperglycemia was reported more frequently in the FE506 group than the CsA group (steroid dose was the same in both groups), with decreasing incidence after trans-

plantation. Of those in whom diabetes developed, 11 patients administered FE506 and 5 patients administered CsA continued to require insulin by day 360. Even a lowdose FK.506-based regimen was found to be more diabetogenic than a GA-based regimen. The incidence of new-onset diabetes with FE506 versus CsA was 27.8% versus 17.1%. The affected patients required insulin treatment for 5 months.65 The reports of its diabetogenicity understandably discouraged experimentation with FK506 in pancreatic transplantation; however, the latest outcomes are encouraging. A single-center study has reported the results of pancreas and pancreas-kidney transplantation in patients administered baseline immunosuppression with FE506 and steroids (the majority also received AZA) without antilymphocyte induction. Mean follow-up was 35.1 2 5.9 months. Mean fasting glucose level was 91.6 2 13.8 mg/dL, and the dose of FE506 was gradually reduced to maintain blood levels of 5 to 10 ng/mL after 6 months. Transient hyperglycemic episodes (blood glucose > 180 mg/dL) occurred in 26 patients at a mean of 45.2 2 118 days posttransplantation, and the mean blood level of FE506 during these episodes was 19.2 2 9.1 ng/mL. Sixty-two percent of these cases were associated with the treatment of rejection, but none resulted in graft loss or diminished long-term pancreatic function. All transplant recipients have normal glucose metabolism beyond 2 years.66

MMFandSirolimus Experiments with diabetes-prone BB rats have shown that continuous treatment with MMF at a dose of 20 mg/kg/d prevented the development of both insulitis and diabetes. When MMF was withdrawn, the animals developed diabetes.67 MMF, however, has been found to exert an unfavorable effect on pancreatic function in other in vitro and in vivo animal models. Long-term exposure of cultured rat pancreatic islets impaired beta-cell function, possibly because of an inhibition of the formation of guanosine metabolites. In vivo experiments on rats and mice showed that at a dose of 70 mg/kg of body weight, minor impairments were noted during glucose tolerance tests. The investigators concluded that MMF is potentially harmful to beta cells, but this has never been clinically evident, and MMF currently is regarded as not having clinically significant diabetogenic effects.68 Sirolimus doses of 10 to 50 times the effective immunosuppressive dose have an adverse impact on glucose homeostasis in murine islet transplantation.‘jg It is unclear at present if this finding has

Immunosu@ressant

relevance to the clinical setting. A recent randomized trial comparing a sirolimus-based regimen with a GA-based regimen reported that hyperglycemia occurred more frequently in the sirolimus group. The incidence of insulin-dependent diabetes, however, was the same for both arms.7o

allograft survival. *2@ In addition to their deleterious effects on bone and glucose metabolism, steroids have long been known to affect serum lipid levels, and this side effect has been discussed in many reviews.71s78 Cd,

Management

of PTDM

Monitoring blood glucose levels to detect the onset of F’TDM should be a routine part of posttransplantation care. Dietary control for diabetes has not been successful in heart transplant recipients.7i Dose reduction of the immunosuppressants may reverse the diabetogenic effects but may expose the patients to the additional hazard of underimmunosuppression. Alternatively, F’TDM has been reported to reverse on switching from FK506-based to GA-based immunosuppression.62*72 Most patients require the administration, at least transiently, of oral hypoglycemic agents or insulin. Either option will control the F’TDM but can expose patients to adverse drug interactions and exacerbate compliance issues. In particular, oral hypoglycemic agents have been reported to change serum CsA levels. Seven patients administered troglitazone experienced a decrease in serum CsA levels, and an acute rejection episode subsequently developed in one of these patients. 73 In another small study, glibenclamide was found to increase serum levels of CsA.74 These reports emphasize the importance of monitoring CsA levels in patients who receive oral hypoglycemic agents for F’TDM. It has also been reported that the condition can be rectified by substituting prednisone for deflazacort, which has fewer side effects. However, this was investigated in a small trial and must be tested more rigorously.75 A Markov cost model has been constructed to estimate the lo-year cost of treating PTDM in a group of 50 kidney transplant recipients. The cost amounted to $89,700, a figure that reflects the high incidence of this complication and stresses the need to reduce its incidence.W

Dyslipidemic

Effects

Dyslipidemia, often encountered after transplantation, occurs in more than 80% of heart transplant recipients, 60% to 70% of renal transplant recipients, and 45% of liver transplant recipients administered immunosuppressant therapy.7m’ Several analyses have shown that elevated cholesterol and triglyceride levels correlated with shorter

71

Toxicities

FK!506, Sirolimus,

and MMF

The adverse effect of CsA on serum lipid levels was highlighted when CsA was used as monotherapy to treat patients with amyotrophic lateral sclerosis. Elevated serum lowdensity lipoprotein (LDL) cholesterol levels developed in these patients.& The mechanism for this is not known, but it has been hypothesized that CsA binds to the LDL receptor in association with LDL particles.*5 An abnormality in this interaction caused by the presence of CsA may be responsible for ensuing hypercholesterolemia, discussed by Markell et al.71 When FK506, another calcineurin inhibitor, became available, it was expected to exert a similarly potent hyperlipidemic effect. Although it certainly affects blood lipid levels, the effect is apparently not as severe as with CsA or steroids. A study of liver transplant recipients reported that serum levels of cholesterol and triglycerides increased significantly in patients administered FE506 and CsA5* The retrospective study by Satterthwaite et ala6 compared cholesterol levels during the first year after renal transplantation in FK506- and CsAtreated patients matched for cumulative fust-year steroid dose and hypercholesterolemia risk factors. None of the patients were hypercholesterolemic before transplantation. At the end of the first year, 26% of FK506-treated versus 67% of CsA-treated patients were hypercholesterolemic (P < .05). The hypercholesterolemia was not associated with greater steroid doses in either treatment group. A study comparing the effects of CsA and FE506 on lipid levels 1 year after liver transplantation also found that the incidence of hypercholesterolemia and increased triglyceride levels was greater in the group administered CsA. The cumulative posttransplantation steroid dose was not related to the changes in either groups7 The difference in hyperlipidemic potency between CsA and IX506 was shown in a study by McCune et al,ss in which there was a significant reduction in serum cholesterol, LDL cholesterol, and apolipoprotein B levels when FE506 replaced CsA in regimens administered to renal transplant recipients with established hyperlipidemia. Steroid doses were maintained at the same levels after the change to FK506. This is in contrast to the study by Steinmuller et al,5s

72

Gabriel M. Danovitch

which did not find evidence that FK506 had a cholesterol-reducingeffect in patients, noneofwhom had abnormal serum lipid levels before transplantation. The limited clinical data available on the newest immunosuppressiveagent, sirolimus, show that it causeshyperlipidemia, and the effect is dosedependent. In a dose-controlledstudy of 11renal transplant recipients, 9 patients were administeredCsA, prednisone,and sirolimusand 2 patients were administered placeboinstead of sirolimus.By 2 to 4 months after transplantation, serum triglyceride levels significantly increasedto 11.7 to 42 mmol/L in 4 of the 9 patients administered sirolimus. Serum triglyceride levels remained at less than 5.0 mmol/L in the 2 control patients. There was a significant correlation betweenelevated serumtriglyceride levelsandwholeblood trough levels of sirolimus. Serum cholesterol levels also increased. The sirolimus dose was decreasedin 3 of the patients and discontinued in 1 patient. Serum triglyceride levels then decreased over 1 to 2 months for all 4 patients.*gConfirming these findings, another open-label, single-center, phaseI/II doseescalationstudy of sirolimus/CsAand tapered prednisone(prednisonewaswithdrawn completely in selectedpatients) in renal transplant recipients alsoshowedthat sirolimusdisturbed serum lipid levels.At 1 year, sirolimussignificantly increasedthe changefrom baselinevaluesof serumcholesteroland triglycerides and the meanlevel observed.W A study of kidney transplant recipients hasshown that MMF hasbeneficial effects on serumlipid levels. This prospective study compared two groups of patients, one group administered MMF, CsA, and steroids and the other group administered CsA and steroids alone.g1At 2 years, although the serum cholesterol and serum triglyceride levels had increasedin both groups,the gain waslesspronounced in the MMF group (cholesterol, 253 v 285 mg/Q triglyceride, 194 v 228 mg/dL). This was accompanied by slightly greater serum glucoselevels in the MMF group, both at the beginning and throughout follow-up (MMF, 87 mg/& control, 84 mg/dL). MMF has not been reported to adversely affect serum lipid levelsin its major clinical trials.33~g2~g3 Treatment Dietary treatment of posttransplantation hyperlipidemia is often ineffective.% Reducing the doseof an immunosuppressant,such assteroidsor CsA, may be attempted, but it may expose the patient to the danger of underimmunosuppression.Methylpredni-

sonehasbeen successfullyreplacedwith deflazacort in pediatric renal transplantation to ameliorate dyslipoproteinemia. Another strategy, steroid sparing in the presence of powerful immunosuppression,is discussedlater.95 The statins are the preferred lipid-reducing therapy in transplant recipients.78A prospective, randomized pilot study of the useof pravastatin after renal transplantation showed that it successfully controlled total cholesterol, LDL, and triglyceride levels in addition to reducing mean natural-killercell cytotoxicity. g6 The statins are generally more cost-effective than other treatments.g7

Cosmetic Effects of Immunosuppressants The drug regimensprescribed for transplant recipients are complex and require a high level of patient compliance to maintain adequate immunosuppression. The average patient will not be aware of such invisible adverseeventsasnephrotoxicity, hyperlipidemia, and hypertension until they require substantial clinical intervention. Patients will, however, become very consciousof visible, or cosmetic,adverseeffects. It must be remembered that transplant recipients are eager to reenter and function normally in society, and in some patients, notably women and adolescents, compliance with drug regimens is compromised if a drug is perceived to induce socially unacceptable cosmeticsideeffects. Hirsutism and Alopecia Hirsutism is a well-known, dosedependent pharmacologicaleffect of CsA therapy, occurring in approximately 40% of the patients.g8In a follow-up of 402 kidney transplant recipients, hypertrichosis developed in almost half the patients by the third month, with hair growth concentrated on the upper trunk and face. Children were the most severely affected.W In a more recent study, hypertrichosis was still a problem at lower initial dosesof CsA, with a reported incidence of 9.7%.‘j’ The incidence of hirsutism was 31% in patients administered CsA and 7% in those administered FK506 in a recent trial comparing the two drugs for use in liver transplantation.” In another trial comparing FK506 and CsA in cadaveric renal transplantation, the incidenceof hirsutism was 0.5% and 8.7% (P < .OOl), respectively.s2 The potent nature of this sideeffect of CsA is such that it has been used successfullyto treat alopecia areata and male-pattern alopecia.icc’ The mechanism

ImmunacuppresantToxiciti

responsible for hirsutism is not known, but it has been suggested that CsA induces hypertrichosis by increasing 5ol-reductase activity in peripheral tissues.‘O’ In animal studies, FK506 has shown hair-growthstimulating properties, lo2but there are very few data on this side effect in the setting of transplantation. The converse appears to be the case, and the drug is associated with alopecia. 64 In the trial comparing FK506 and CsA in cadaveric renal transplantation, the incidence of alopecia was 10.7% and 1% (P < .OOl), respectively.6* MMF has in one instance been reported to cause a moderate, diffuse alopecia when used as monotherapy. There have been no other reports of this side effect with MMF when used in other clinical trials, and in this instance, the alopecia developed without a firm correlation with mycophenolic acid trough levels. lo3 No clinical data on hair growth are available for sirolimus. Gingival

Hyperplasia

Gingival hyperplasiais another recognizedsideeffect of CsA therapy. Fibrous hyperplasiaof the gums has been reported in up to 33%of the patients by McGaw et al’” and 22%of the renal transplant recipients by Ring et aLlo There are no reports that MMF or sirolimus is associatedwith this side effect. In a recent randomized, multicenter trial comparing IX506 with CsA for the prevention of renal allograft rejection, the incidenceof gingival hyperplasiawas6.2%in patients administeredCsA and 1.3%in patients administered FK506.6’Another trial of FK506 versusCsA for renal transplantation showed an incidence of 1% versus 5.3%.62 Gingival hyperplasia is particularly serious and distressing for pediatric transplant recipients becauseit may delay the eruption of teeth and hamper speech development.‘06Recently, a correlation has been found betweengingival overgrowth and changes in renal function in pediatric renal transplant recipients.‘07This suggeststhat the fibrosisseenin gingival overgrowth and C&induced nephrotoxicity may be related, andit is tempting to speculatethat transforming growth factor-beta (TGF-l3) may be involved in the mechanism.Cell culture studieshave shownthat at immunosuppressiveconcentrations, CsA, but not FK506, will upregulate the production of biologically active TGF-13.‘OB However, there are alsoreports that IX506 upregulatesthe production of TGF-p, in both cell culture and animal models.lOg-‘llGiven that FK506 is not consideredto induce gingival hyperpla-

73

sia, it may be that TGF-l3 is not or is only partly responsible.The incidence of the condition in relation to CsA dose, however, has not proven easy to determine.“2-“4 In 21 pediatric patients who underwent liver transplantation, no correlation was found between serum CsA levels and dental indices.1’3A doserelationship has been reported for renal transplant recipients, however. Patients with gingival hyperplasiawere administered significantly more CsA than those without (P = .001).‘05More recently, a cross-sectionalstudy of 39 heart transplant recipients suggested a cumulative, time-dependent relationship,’‘5 and another study showedthat gingival enlargement will resolvein responseto a reduction in CsA dosage.]I6 Gingival overgrowth correlated with plaque and gingivitis scores in one study of renal transplant recipients’” and with the pattern of localization of plaque in heart transplant recipients in another study.‘I7 These data support the relation between plaque development and gingival overgrowth. Hypertension and nephrotoxicity, alsosideeffects of CsA, are often treated with such calcium channel blockers as nifedipine. Unfortunately, gingival overgrowth is increasedby the combination of CsA and nifedipine, probably becauseof a reduction in the collagenolytic activity of fibroblasts, subject to individual patient susceptibility.‘1* Treatment

of Cosmetic

Side Effects

Hirsutism and alopecia The hirsutism associated with CsA use can be quite vigorous, and depilatory creams often cannot adequately counter the problem,Wleaving shaving and electrolysisasthe unsatisfactory alternatives for women. Counselingis often required for women and adolescents to prevent noncompliancewith the drug regimen.% Gingiualhyperplask Opinion is divided about the role of dental hygiene in the prevention of gingival hyperplasia. Montebugnoli et a.l1l5found that the degree of oral hygiene was not related to gin&al overgrowth, but McGaw et allo found a linear correlation between gingival overgrowth and plaque index. Another study by Somacarreraet al’ I7confirmed that the removal of plaque is an important preventive measurefor C&induced gingival overgrowth. A study of gingival parameters in 106 pediatric renal transplant recipients recommended that calcium channel blockers should not be coprescribed with CsA and can be replaced in the majority of patients by hydralazine.‘I9 The prescription of medicationsis alsoadvisedfor the treatment of this side effect. The

74

Gabriel M. Danouitch

macrolide antibiotic, azithromycin, and metronidazole have been effective in resolving gingival hyperplasia, but the mechanism of action of these drugs in this setting is probably not related to an antimicrobial action.‘20J2’ In some cases, periodontal surgery is required.‘06 It has been reported that up to 67% of patients treated with azithromycin for gingival hyperplasia experience significant improvement.‘20 Failing this, the alternative strategy is to correct the condition by oral surgery. The cost of a 5day treatment with azithromycin is approximately $48 compared with $850 for a gingivectomy. In terms of effectiveness, one gingivectomy is equivalent to 18 treatments with azithromycin. Most patients seem to believe that the morbidity associated with the drug is preferable to the trauma of oral surgery, and azithromycin may be prescribed as a first treatment.‘*O

Low-Toxicity

Regimens

In the 199Os, the number of immunosuppressive agents grew to include FK506, MMF, sirolimus, daclizumab, and basiliximab. Newer, low-toxicity regimens are emerging as centers modify the classic tripartite regimen of C&A, AZA, and steroids by the judicious addition of the newer agents and reduction or removal of the older ones. The approach to the widespread use of low-toxicity regimens is understandably cautious because the maintenance of effective immunosuppression and avoidance of rejection are of paramount concern. Steroids are constantly singled out as responsible for a number of serious morbidities in the transplant population, as discussed here. Many studies using steroid withdrawal from regimens using CsA, AZA, and steroids show that bone mineral density, blood glucose and lipid levels, and hypertension improve after withdrawal (Table 3).‘22-‘3’ This maneuver, however, is often associated with increases in the incidence of acute rejection episodes and a decline in graft function to such an extent that it has occasionally been censured despite potential metabolic advantages for the patient.‘24*‘25J32Two reports in particular, by Sinclair’33 and Ratclilfe et al,lz5 delivered warnings of possible adverse, long-term consequences of steroid withdrawal in the presence of CsA, AZA, or a combination of the two. In the Canadian steroid-withdrawal study, 133the graft survival curves started to dissociate after 1.5 to 2 years, and at 5 years, patients who continued with prednisone had a better graft survival rate. The study is not without

criticism. When risk factors were included in the Cox proportional hazards model, there was no statistically significant diflerence between the two groups in terms of graft survival. ‘33 The steroid-withdrawal study by Ratcliffe et al, lz5however, did little to dispel doubts. Although the incidence of acute rejection was very low, a large proportion of the patients experienced a decline in graft function, and the investigators concluded that withdrawal may have adverse long-term complications. It must be noted that there were patients on these studies for whom steroid withdrawal worked; unfortunately, we cannot yet identify such patients until after the maneuver. An analysis of trial data by Ponticelli et al’34 concluded that the best candidates for steroid withdrawal and maintenance with CsA monotherapy were those without immune-mediated renal diseases who had good graft function in the early posttransplantation period. The Collaborative Transplant Study found that 5-year graft survival was significantly greater in patients switched from tripledrug therapy to steroid-free maintenance with CsA or CsA and AZA.‘35 The best survival rates were found in patients administered relatively high doses of CsA. Although this finding may be flawed because of selection bias, it raises the possibility that to be successful, steroid withdrawal has to be performed in the presence of intensilied immunosuppression. The removal of steroids after 1 week has been shown to be feasible with maintenance immunosuppression with FK506 and MMF in a prospective trial with a mean follow-up of over 7 months. Rejections occurred in 7 patients (26%), 3 of them before steroid withdrawal.’ Steroid withdrawal from a regimen of CsA and sirolimus has also been attempted, with a success rate of 70% to 78% at 12 months.s’-’ In an open pilot study, MMF facilitated the safe removal of steroids from a tripledrug regimen of CsA, MMF, and steroids in renal allograft recipients.13’ Steroid-free immunosuppression in renal transplantation has been reported in a retrospective consecutive clinical study of 68 patients with historical controls.‘3s Patients were administered steroid-free immunosuppression with an initial IO-day antithymocyte globulin induction and CsA and MMP as maintenance therapy. After a median follow-up of 488 days, 15% experienced acute rejection. All rejections occurred in the first few months, and there were no late rejections. Acute rejection occurred in 37.4% of the historical controls who had the same protocol but without MMF. The availability of the interleukin-II

Immunosufiprrercant

75

To.ricities

Table 3. Sparing Regimens Follow-up Period AJer Withdrawal/ Reduction (mon)

Spared Aulhor

h.c

Regimen

Steroids

Lebranchu’**

CNMMF in low-dose steroid group; steroids withdrawn by 3 mon

9

Steroids

Matas et a1’23

6

Steroids

Hollander

CsA/MMF, steroid withdrawal begun at 3 mon posttransplant (terminated early) &A/m steroids withdrawn at I year

Steroids

Ratcliffe et al125

CsA/AZA withdrawal CsA/AZA/Pred

CSA

Weir et a1126

CsA reduced 50%, MMF replaced AZA (mean steroid dose reduced)

GSA

Ducloux et al’27

Convert from CsAIAZA/ Pred to MMF/Pred

GSA

Schrama et al’*s

Convert from CsA/Pred to MMF/Pred

CsA

Hueso et alus

CsA reduced after MMF added to CsA/Pred regimen

Abbreviations:

HDL,

high-density

et al’24

lipoprotein;

Pred, prednisone;

v

I2 8 7.2 + 0.2

12t2

NA

6

Rt3Ult.C Impact on Adverse Euents

Significant improvement in serum cholesterol, triglycerides, blood pressure, and hone mineral density Lower cholesterol (not significant) Decrease in serum cholesterol; also decrease in HDL cholesterol Decrease in serum cholesterol; no decrease in triglycerides Improved renal function, significant reduction in serum cholesterol and trend to decrease arterial blood pressure Improved renal function, improved hyperlipidemia and blood pressure Improved renal hemodynamics, improved gingival hyperplasia and hirsutism Significant reduction in serum creatinine and TGF-S levels, systolic and diastolic blood pressures; significant increase in glomerular fdtratidn rate and renal plasma flow

NA, not available.

receptor-blocking antibodies, daclizumab and basiliximab, widens the ppportunities to reduce toxicities in immunosuppressive regimens, possibly allowing the reduction of steroid dosages. In a recent doubleblind, placebo-controlled trial of renal transplant recipients, patients administered daclizumab with CsA and steroids versus placebo, CsA, and steroids had significantly less biopsy-proven rejection and significantly lower cumulative doses of prednisone.‘3g Recently, a multicenter, prospective, randomized, double-blind trial in Europe and a prospective, randomized study in the United States have examined the feasibility of steroid dose reduction and withdrawal in the presence of MMF and CsA. The

European

trial of 500 patients

compared

two cortico-

steroid regimensin combination with CsA and MMF in renal transplantation. tz2 Patients were divided into two groups, one group maintained throughout on full-dose steroids with CsA and MMF

and the other

group administered 50% of that dosewith CsA and MMF. In this group, the steroids were gradually tapered and withdrawn by 3 months posttransplantation. At the 6-month (posttransplantation) primary end point, the incidenceof biopsy-provenacute rejection was 14% versus 23% in the low-dose/withdrawal group (P = .008). At 12 months posttransplantation, the incidence of biopsy-proven acute rejection was

15%versus 25% (P < .Ol), and 4% in the full-dose

76

Gabriel M. Danovifch

tial asa calcineurin-sparingagent. In a smallstudy of versus5%in the low-dose/withdrawalgroup lost their I9 patients with a follow-up ranging from 2 to 14 grafts. Patient survival was 97% versus 98%. The months, sirolimus was used successfullyto replace majority of the acute rejection episodeswere mild CsA or IX506 to alleviate nephrotoxicity, hirsutism, (BantI grade I), easily controlled by steroids, and or severe gingival hyperplasia. The change resulted occurred within the first month posttransplantation. in improved renal function in 12 patients and a There were significant improvements in blood lipid lessening of facial dysmorphism in 2 patients.14i levels, blood pressure,and bone density (IL? and L3) Another study by Schramaet al’** successfullysubstiin the lowdose/withdrawalgroup.Mean serumcreatituted MMF for CsA in 15 of 17 stable renal transnine level was similar in both groups at 12 months. plant recipients. They noted that gingival hyperplaThis trial concludedthat in the presenceof MMF and sia and hirsutism improved when CsA was removed CsA, tapering of low-dosesteroids to cessationat 3 and replacedwith MMF in the drug regimen.Finally, months is safe and doesnot lead to an increasein the preliminary resultsof a multicenter, randomized, serum creatinine level by 9 months after steroid controlled trial of the withdrawal of CsA from a withdrawal’22 regimen of CsA, MMF, and steroids have recently The US trial also assessed steroid withdrawal in been presented.14* At 6 months after complete withthe presenceof MMF and CsA, but had a different drawal of CM, there was an improvement in renal design.*23It tapered and withdrew steroids from function consistentwith the small studiespreviously patients who were free from acute rejection at 90 mentioned. This trial hasa 5-year follow-up and will days posttransplantation. The study recruited 266 of permit the rigorous assessmentof the long-term its 500 patients before it was terminated early beoutcome of this therapeutic strategy that is essential causeof a greater incidenceof acute rejection in the before its widespreadadoption. steroid-withdrawal group (24 v 6 patients; P = .OOl). Graft losses,however,were similar in the two groups. There were more acute rejection episodesin black Summary and Conclusion than nonblack patients (42% v 12%;P < .OOl). At both 6 months and 1 year, steroid-withdrawal paThe aim of transplantation is to return the patient to tients had lower cholesterol levels, less need for a state of health, maintain this state long term, and antihypertensives, and significantly greater serum allow normal social functioning. This ideally would creatinine levels. Overall, 78% of the steroid-withrequire a minimum of medical intervention. The drawal group remain free from acute and chronic development of powerful immunosuppressiveregirejection at 1year posttransplantation.’ It is known menshas largely achieved this goal, although issues that the timing of steroid withdrawal and black race remain concerning the long-term adverse effects of are predictors of steroid-withdrawal failure.‘40 The immunosuppressionon the transplanted organ and US steroid-withdrawaltrial providesfurther evidence the transplant recipient’s other body systems. of the greater immunologic responsiveness of black Although this review hasdocumentedsomeof the patients and suggests that in nonblack patients, toxicities of currently used immunosuppressives,it steroidwithdrawal in the presenceof MMF and CsA has also pointed out that the toxicities can have a can be achieved safely in the great majority. Once greater impact depending on patient profile. Black again, however, long-term data will determine the patients are more susceptible to the toxicities of successof steroid sparing, regardlessof whether it is IX506 and steroids,462g particularly with regard to performed in the presenceof the newer agents. diabetes.Preexisting cardiovascular diseasemay be CsA dose has been successfullyreduced in the exacerbatedby steroids,C&A, sirolimus,and, possibly presenceof or replaced completely by sirolimus or to. a lesserdegree, FK506. Menopausal women and MMF in several small studies, all with short-term transplant candidateswith reducedmobility or preexfollow-up (Table 3). These conversionswere peristing bone diseasewill be more vulnerable to the formed principally becauseof CsA nephrotoxicity, osteopenic effects of the drugs. Reflecting on the and s&&cant improvementsin renal function, blood likely early onset of steroid-induced bone loss,23it pressure,and/or lipid profiles were noted.103J*6J2gJ41would seem prudent to avoid steroid dosing altoMost importantly, there were no increasesin rejecgether rather than having to withdraw it. It is hoped tion episodes.In view of the reported link between that specificcombinationsof the newer immunosup renal toxicity and gingival hyperplasia, these results pressiveswill achieve this. Thus, a drug regimen are very encouraging.lo7Sirolimus has shownpotenshould be tailored according to patient characteris-

Immunosuppw.sant Toxicitizs

tics. We are now seeingexperimentation with drug regimens designed to reduce toxicities in patients. These are a recent development, and although there are a few randomized, controlled trials, there are no long-term data to rigorously test the benefits. These newer regimenscan now take advantage of sirolimus or h4MF, which are not nephrotoxic, to replace or reduce the dosageof CsA or FK506 in casesof nephrotoxicity. 126~127~141 In the caseof MMF, sucha substitution alsotakesadvantageof the lack of cardiovascular toxicity of MMF, and improvements in blood pressure and lipid profiles are often seen (Table 3). Sirolimus may alsorepresent an alternative to calcineurin inhibitors when nephrotoxicity is suspectedif the early clinical results are maintained over the long term. Unfortunately, it increasesblood lipid levels, a factor likely to limit its long-term use, certainly in patients with preexisting cardiovascular disease.8g*143 Although it remainsa very controversial subject, the total withdrawal of steroidsfrom immunosuppressivedrug regimensmay now be possiblein the presence of the newer agents,122JMalthough steroid avoidancemay be the bestcourseto pursue. To maintain the health of transplant recipients, it is important to monitor and manage the toxicities that, if left untreated, may have a profound effect on compliancewith immunosuppressiveregimens,quality of life, and long-term health. Various treatment modalities are available to alleviate the impact of these immunosuppressant-inducedtoxicities. However, the recent introduction of new low-toxicity immunosuppressants providesclinicianswith a more attractive option; prevention of toxicity rather than treatment of its consequences.

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Immunosu~~tccsant Toxicities

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