Cyclosporin a toxicity in children

Cyclosporin A Toxicity in Children ]'ohn F.S. Crocker, Tina Dempsey, Margaret E. Schenk, and Kenneth W. Renton

he discovery of the immunosuppressant Cyclosporin A (CsA) has improved the survival of transplanted kidneys and has made other solid organ transplants a practical reality. Transplant centres were initially reluctant to use CsA in pediatric patients because of a perceived poor-risk benefit ratio of the drug. However, improved transplant survival, largely because of CsA use in adult transplants, made all centres recognize that withholding this drug from children was not warranted. Hirsutism, coarsening of skin, and nephrotoxicity were the major problems associated with its use. However overall pediatric renal survival rates worldwide were below adult survival figures. 1 The need to improve kidney transplant survival has resulted in the widespread use of CsA along with changes in donor profiles and surgical and postoperative care. The change to CsA in pediatric transplantation has become the backbone of most posttransplant immunosuppressant regimes. The previously used myelotoxic drugs such as Imuran (Burroughs Wellcome Inc, Canada) remain in use for triple therapy regimes or for patients in whom CsA toxicity is particularly prominent. We have had a relatively long experience with CsA, and its use in children has been accepted. The question that was originally asked still looms: Do children have any unique toxicity to this drug, and will the dire predictions of centres that first refused to use it in children be borne out with time?

T

Renal Toxicity The most significant clinical side effect of CsA is nephrotoxicity. It is now accepted 2,3that renal changes are in three general pathological patterns (Table 1). The first type of pathology is a form of acute renal failure similar to acute allograft rejection. This form From the Izaak Walton Killam Hoapitalfor (,7~ildren, Halifax, Nova Scotia, Canada. Supported in part by MedicalResearch CbuncilJoint Industry Grant No. UI-OO66with Sandoz Canada Inc. Address reprint requeststoJohn F.S. Crocker,MD, FRCPC, The Izaak Walton Killam Hospitalfor Children, 5850 Universitl,Ave, PO Box 3070, HaliJit,,; Nova Scotia, Canada B3J 3G9. Cbpyr/ght©1993 by W.B. Saunders Company 0955-470X/93/0702)-000255.00/0 72

of CsA cytotoxicity is difficult to distinguish from rejection. <5 Graft function can be demonstrated but there is a decrease in glomerular filtration rate (GFR), impaired urinary osmolarity, and sodium retention. The decrease in GFR has been described 6'7 as consisting of a decrease in renal blood flow and a decreased ultrafiltration coefficient that may be associated with disturbances of eicosanoid metabolism. 7,8 The second pattern is a tubular lesion in the proximal segment of the nephron where tubular endothelial cells show giant mitochondria and vacuolisation. Walker et al 9 noted that renal mixed function oxidases, which play a role in CsA metabolism, occupy the same sites as those damaged by CsA in the renal tubule. This tubular pathology only occurs with levels of CsA that exceed the therapeutic range. The third form of CsA nephrotoxicity has been described as a vascular endothelial nephrotoxicity that is reversible and likely nonprogressive. This latter observation is a difficult one to verify because transplant rejection itself involves vessels of all sizes. However, there are several studies that show a CsA contractile effect on nephroarterioles, resulting in decreased vascular flow. I0'11'12 This effect can be positively modified by calcium channel blockers via afferent arterioles. 13 The interstitial fibrosis seen as chronic CsA toxicity is likely precipitated by a combination of endothelial injury and vasoconstriction, which together may produce renal ischemia. 7 This ischemia is associated with increased synthesis of intracellular matrix proteins. CsA further contributes to the accumulation of matrix proteins by stimulating mediators such as cytokines, peptide growth factors, and thromboxane. 7 Although time intervals needed for fibrosis to occur may vary, at least 12 months of CsA treatment is most clearly associated with a risk for increased fibrosis. 7 Children who receive a renal transplant and CsA treatment have renal function that is reduced below that of a comparable child with a single kidney and no renal transplant. Berg and Bohlin 14 have shown that the GFR reduction was greater than that of the effective renal plasma flow (ERPF) when children were studied at 5 months posttransplant. This suggests that the nephrotoxic effect of CsA is at the glomerular level. After the 5-month period they found that ERPF was more reduced than GFR,

Transplantation Reviews, Vol 7, No 2 (April), 1993:pp 72-81

@cloaporinA To,icity in Children

73

Table 1. Three General Nephrotoxic Effects of CsA No.

Type

1

Acute renal failure

2

Proximal tubular lesion

3

Vascular endothelial pathology

Characteristics

Decreased GFR Low urine osmolarity Sodium retention Giant mitochondria and vacuolization in endothelial cells Decreased renal blood flow

indicating a nephrotoxic effect related to plasma flOW.

There is no evidence documented in the medical literature that children have a higher incidence of nephrotoxicity than adults. In fact, there have been allusions to the opposite, that children tolerate higher doses of CsA without demonstrating CsA toxicity.15 The mechanism by which CsA is nephrotoxic has recently been studied at the molecular level. Skorecki et aP 6 divided CsA nephrotoxicity into a reversible acute form in which GFR and blood flow are reduced, and a second more chronic form in which nephron attrition occurs. Their work indicates that the former type is "a prototype for a renal transmembrane signalling disorder." CsA augments calcium signalling responses while inhibiting (by a different mechanism) the "counterbalancing release of vasodilatory eicosanoids in contractile cells of the glomerular microcirculation and in vascular smooth muscle cells." However, clinically, three primary effects of CsA have been suggested, (1) increased intraproximal tubular pressure activating glomerular tubular feedback, (2) a decreased glomerular filtration coefficient, and (3) reduced renal blood flow primarily through its effect on the afferent arteriole.

Hypertension Hypertension, induced by CsA, is more common in pediatric transplant recipients than in adult recipients. Hoyer et aP 5 reported CsA-induced hypertension in up to 80% of children with transplants. Porter et aP 7 noted that only 50% of adults with transplants exhibited CsA-induced hypertension. Several mechanisms whereby CsA might induce hypertension can be postulated. CsA can inhibit prostaglandin E9 release from vascular smooth muscle cells. ~8 CsA is also reported to increase the production of thromboxane A9.19Blocking the thromboxane receptors causes a partial reversal of CsA-

ProposedMechanism

Eicosanoid metabolism disturbance Mixed function oxidase disturbance Contractile effect of CsA on nephroarterioles Augmented Ca ~+ transmembrane signalling

mediated renal vasoconstriction2 °,21 The possibility that CsA may have a direct effect on atrial resistance has been supported by experimental data in hypertensive rats. 22 The treatment of choice for hypertension associated with long-term CsA use has been calcium channel blocking drugs.

CsA-Evoked Facial Dysmorphism In children CsA induces evident facial changes, eyebrows become prominent, skin coarsens, lips thicken, and often there is gingival hypertrophy. ~3 More subtle have been the bony changes in the jaw bone structure reported by Resnik et al. 94 The dramatic changes that can be seen are illustrated in Figs 1, 2, and 3. In the photographs, the changes that occur in a single individual before and after CsA therapy are readily evident. Many investigators feel that these changes are insignificant in the adult population, and are rarely, if ever, seen in children. This latter statement is often caused by the difficulty distinguishing CsA toxicity from prednisone toxicity. Resnik et aF 3 reported that patients receiving Imuran and prednisone did not show the facial changes seen with CsA. The extent to which prednisone aggravates the situation is currently unknown. However, with improvement in drug therapy of transplant recipients, prednisone is used to a lesser degree and, in most cases, is discontinued after the first 3 months of therapy. There is little doubt that CsA alone can induce major changes to the facial structure of children. Children with chronic renal failure who are either dialysis- or nondialysis-dependent see themselves as having a normal self body image, even though they may not always seem normal to their parents and physicians. Transplantation rejection prophylaxis often changes a child's facial configuration for the worse. This is the main thrust of ongoing work at The

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Crocker et al

Figure 1. Photograph taken 10 months after kidney transplantation of a 7-year-old child on CsA therapy. Note the prominant eyebrows and gum hypertrophy. Marks on the face are for morphometric comparison. Izaak Walton Killam Hospital for Children. The importance of the lips and chin in influencing the quality of facial features as seen by others was recognized in the Renaissance period, and has become the focus of much of the orthodontic work performed in past decades. Patients who are placed on CsA therapy are also often given prednisone. It is difficult for a clinician who is not experienced with renal transplant patients to distinguish between the changes in physiognomy caused by prednisone and those caused by CsA. De Camargo 25 reported gingival hyperplasia in pediatric transplant recipients being treated with CsA. This investigator showed that a minimal dosage is required for gingival enlargement, but once over-

growth develops, there is no correlation between increases in the dose and the severity of the lesions. Many pediatric recipients have no gingival hyperplasia and low equivalent serum concentrations of CsA. However, higher salivary concentrations of CsA were found in those children with gum overgrowth. Gingival hyperplasia is an age-related toxicity, because this overgrowth was seen in only 30% of children over 15 years of age but in 100% of those under 15 years. 26 This phenomenon may represent an enhancement of the fibroblast growth response by CsA. This hypothesis is further supported by histological evidence that shows cells of the overgrowth to be modified myofibroblasts.27 The degree or volume of gingival hypertrophy,

QvdosporinA To,~city in Children

75

F i g u r e 2. Photograph of a nondialysis-depende nt 10-yearold child before kidney transplantation. usually plateaus after 1 year of treatment. The syndrome may present from 1 to several months after the initiation of the drug and tends to begin in the anterior region of the mouth. Measurement of the soft tissue of the face has been performed directly by Smythe and Young 28and other investigators. However, the results of direct measurements are confounded by the small size of the parameters, complexity of facial form, soft nature of the facial tissue, and difficulties in assessing interracial differences. Photography is the most convenient indirect mea-

surement and one that has standards established by Farkas. 29 Tanner and Weiner 3° have had difficulty accepting the validity of measurement of the growing face, although they felt that photographic measurements were satisfactory for trunk and limb assessment. A widely used method to study facial soft tissue growth uses cephalometric radiographs. ~,32 However, the risks of serial radiographs of the face for research purposes are difficult to justify. Another method used to study facial changes in children is that of a contour map as described by Zeller. 33 This technique is similar to axial surveys of terrain using

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Crockeret al

Figure 3. Photograph of the child in Fig 2 4 months after renal transplantation in whom CsA is the sole immunosuppressive agent. Note the lowered hair line on the forehead and the change in the eyebrows. Bony changes are not apparent by visual examination but are present when measured morphometrically or by radiographic inspection. stereometric cameras and has been used to study various facial syndromes. More recently, several computer software programs have been developed to study the three-dimensional structure of soft and bone tissue by computed axial tomography scan and nuclear magnetic resonance. Reconstructive work can then be demonstrated to the patient, indicating how he/she will look after plastic surgical repair. These techniques may be applicable to facial morphometrics caused by drugs, but to our knowledge this has not been pursued. The precise developmental pattern of the face has been studied in detail by several investigators, and bony growth changes have been the subject of most of these studies. For instance, Nanda 34 reported the presence of an adoles-

cent growth spurt in certain bony facial parameters. A growth spurt has also been reported for soft facial tissue. 35 The association between the pattern of facial growth and general somatic growth is not precise. The methods used in our own study, which is described below, have limitations primarily because invasive techniques are no longer possible for research purposes. However, noninvasive techniques can help to define what we call a "cyclosporin facies." Is it a definable entity, or simply a clinical impression that is actually caused by the myriad of drugs to which a child with a transplanted organ is exposed? Objective morphometric data to determine the exact amount of facial change, whether it is age- or sex-

CyclosporinA Toxicit~ in Children

related, and whether the bony changes are variable and reversible all need to be addressed. We and other investigators 36 believe that technical simplicity, cost effectiveness, and the availability of an extensive data base of normal variability (including Farkas' Standards) as the basis to interpret specific data, make craniofacial morphometric techniques very useful. Photogrammetry has recently become an acceptable method for measuring facial features. The method is low in cost, noninvasive, and requires a minimum of cooperation from the patient. A comparative study by Farkas and Klotz~7 showed that specific measurements of the photographed face can be obtained with as much accuracy as direct anthropomorphic measurements. Defining dysmorphic facial changes may allow us to identify susceptible children so that appropriate counselling may be initiated. Aggravating drugs can also be avoided in these children. For instance, nifedipine and certain anticonvulsants that also cause gingival h~-pertrophy may potentiate any CsA effect. A data base including the therapeutic history, blood levels of CsA, data from the actual transplant, several pharmacokinetic assessments, and morphometrics to study facial dysmorphism are all now established in our laboratory. The methods involve both photogrammetry and anthropometric techniques for the study of drug-induced facial dysmorphism. Data are collected pretransplant and posttransplant. Features of CsA that can be defined are: 1. Cephalic indices measure basic head proportions, eg, high, square forehead. 2. Facial indices determine upper and lower facial heights. 3. Mandibular changes, prognathia versus retrognathia. 4. Orbital measurements, eg, intercanthal indices, eye fissure length. 5. Nasal indices describe general nose shape. 6. Mouth and lip measurements. 7. Ear measurements determine the general shape of the ear. Preliminary analysis on children receiving CsA shows an abnormal increase in the mandibular width with an abnormally wide face. There is a indication (not yet statistically significant because of the small sampie size) that mandibular body length decreases, as do both maxillary and mandibular depth, which results in retrognathia. There also seems to be a suggestion that both the nose and lips become fuller.

77

The increase in the lip size may be caused by gingival hyperplasia, and studies are underway to try to determine ifCsA influences lip fullness in some other way. Facial height shows no significant increase. These preliminary data should also be considered with the perspective that the nonvariable features of eyebrow changes, hair growth, and gum hypertrophy all are additive to the above picture.

Psychosocial Effects The psychosocial aspects of transplantation are very complex. Approximately one third of children presenting for treatment of renal failure have various degrees of congenital anomalies. Does a blind child deserve an organ any less than a sighted child? Should a child with limited capacity for self-care both physically and intellectually have the same priority as a bright child blessed with the social graces? Death of the treatable child with whatever degree of impediment is now felt to be unacceptable in North American society. The only children for whom transplantation is contraindicated are those to whom transplantation would give only a brief reprieve from death balanced against the necessary trauma of the transplant operation. A child's emotional vulnerability and the stress to the family are often placed in the equation of transplant surgery. Empirical data do not support delaying transplant surgery. Korsch et al3~ studied 35 children with transplants and found that they had returned to preillness equilibrium within 1 year posttransplant. However, there was doubt as to whether they had attained levels of self-esteem equivalent to their peers. Khan et a139 treated the emotional problems of 14 children posttransplant and found feelings of social isolation, excessive dependency on parents, and depression. Bernstein, 4° in a large study of 100 children posttransplant in Minnesota, noted that parents found increased physical vigour and improved appetite as the two major changes in their children after transplant. Negative effects included the appearance of Cushingoid facial features when steroids were prescribed and protuberant abdomens. These effects are usually transient. Psychologically, younger children had a "striking" development of personality traits together with cognitive growth. Preadolescent children also showed psychological growth. Adolescents' perceptions of growth were often philosophical because transplantation sharpened their outlook on their current and future life. Bernstein found that 9% of pediatric

78

Crockeret al

patients (who received transplants at 6 weeks to 1 1 years of age) and 12% of adolescents (12 to 18 years of age) had significant emotional problems 1 year after transplantation. These problems included anxiety and depressive, compulsive, and phobic reactions. Suicidal thinking was observed almost exclusively in the adolescent group. Anxiety about rejection of their kidney was often vocalized. Suicide attempts were usually in reaction to some event in their lives. Levels of self-esteem, self-consciousness, happiness, openess of their true feelings, estimates of popularity, and levels of anxiety were equivalent to agematched controls in this Minnesota study. Some children find that their visible change in appearance makes their medical handicap apparent to the world. Children with transplants who are dissatisfied with their appearance are particularly vulnerable. They have lower self-esteem, feel distinctive, and are self-conscious. Teenagers may also focus specifically on their abdominal surgical scars as evidence of their altered body image. CsA facies are often seen as a reason for a child to be noncompliant about medications and diet. Some centres have noticed noncompliance in about 30% of adolescents with transplants. 4j Lowering CsA doses permits some reversal of the facial changes and,

certainly, removing medications, such as steriods, calcium channel blockers, and anticonvulsants, that can alter the appearance of gums and face is the aim of the medical team. Steriods can only be tapered after a successful transplant. Other drugs may be substituted if there is an additive effect to dysmorphic features. It is important to realize that altered body self-image, particularly in adolescents, adds to a child's vulnerability. We have had a native Indian child weep because her appearance in school was greeted with the remark "wolf girl." The children were mimicking a movie they had seen. The CsA face was devastating to this little girl and she withdrew temporarily from school. She wrote poems centered around Indian folklore but virtually all featured death as their theme.

Metabolism It is important to establish the part taken by some CsA metabolites (Fig 4) in the immunosuppressant activity and toxic side effects of the drug. 42,43 Efforts to discover a different profile of CsA metabolites in children than in adults have been unsuccessful in our laboratory (eg, by using high-pressure liquid chromatography).

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CyclosporinA To~citf in Children

Watkins et a144 demonstrated that enterocytes have cytochrome p450 IIIA activity, the isoenzyme that is responsible for the major pathway of CsA metabolism. Webber et a145 demonstrated that in vitro human gastrointestinal mucosa is capable of CsA metabolism. At least 20 CsA metabolites have been described. 42,46All metabolites still possess the undecapeptide structure of the parent c o m p o u n d s Several of the metabolites result from p450 activity,47 and therefore the elimination of CsA can be inhibited by pretreatment with erythromycin4a,49 and enhanced by phenobarbital. 5°

Dosage The oral absorption of CsA is incomplete and highly variable for the following reasons. (1) Only 20% to 30% of CsA administered orally is available as active drug to children after renal transplantation. 51,5~ (2) Whitington et a153 and Hoppu et a154 investigated prehepatic CsA metabolism and found that the bowel seems to be the site of CsA metabolism. (3) Other posttransplant drugs, such as calcium channel blockers and certain antibiotics and foods, may interfere with CsA absorption and metabolism. 55,56 The list of drug interactions with CsA is lengthy and includes everything from antihypertensives to other nephrotoxic drugs. 57 A partial list of these drugs includes aminoglycoside antibiotics, amphotericin B, ciprofloxacin, and colchicine. However, most transplant units are aware of the many interactions and closely monitor drug levels and the patient's overall state when these drugs are necessary. (4) Whitington et a153 studied the small bowel length in children receiving CsA for liver transplants. They found that the length of the small bowel was the "chief determinant of the required dose of orally administered CsA in children after liver transplantation." Other investigators have questioned these results because they have been unable to find a correlation to bowel length. Children's risk of CsA toxicity in the early phases of transplantation has led to routine performance of pharmacokinetic studies pretransplant to predict the necessary dosage of the immunosuppressant drug. 5~,59 Continuous intravenous infusion eliminates the bowel metabolism factor to a certain degree and allows smoother drug levels. 6°Whether this actually changes any of the other renal side effects has yet to be explored. Over the time frame that CsA has been available

79

for pediatric transplants, the overall survival of organs in data from the United States and Europe has been significantly below adult survival. 61 The reasons for this are complex but, when addressed with improved clinical protocols, can result in better survival. CsA blood levels in pediatrics have been an area of concern because a child requires larger doses of CsA per kilogram of body weight in the initial phases of the drug use to attain the same blood levels as adults. As Hoyer et a162first noted, the levels could be achieved by using amounts of CsA that would have been nephrotoxic in adults. The dosage of CsA in children is calculated in reference to body surface area. Pediatric dosage starts at 500 mg CsA/m 2 daily, decreasing weekly by 50 m g / m 2 until a maintenance dose of 300 m g / m 2 is reached. 62 Adult dosage is calculated by body weight and averages 5 to 20 mg/kg body weight. Blood level monitoring of CsA is performed on all children to avoid toxic levels but, again, children have much more labile blood levels than adults. The original enthusiasm to achieve better survival of pediatric kidney transplants by rapidly infusing larger doses of the drug has been replaced, in virtually all centres, by a desire to achieve a gradual smooth steady-state CsA levels. 63,~aInitial CsA toxicity in a kidney at risk by prolonged cooling or warming time is avoided by adding other drugs such as OKT3, antilympholyte globulin, or Imuran. This approach seems to reduce some of the early nephrotoxicity of CsA in pediatric transplants and then, hopefully, the risk. Mean elimination half-life of CsA in children is 7.3 hours compared with adults in whom it varies between 10 and 27 hours. 65 This increased clearance of CsA in pediatric recipients necessitates shorter dosing intervals or, alternatively, administering a drug that would interfere with CsA breakdown. More frequent dosing of CsA is based on the concept that the hepatic clearance differs in the child. The fat distribution in many children is different from adults. CsA (which is lipid soluble) must saturate these sites before steady-state kinetics can occur, 65 Figure 5 shows the variation in the half-life from one child to another when receiving intravenous CsA. This illustrates why pharmokinetic data is helpful for children as we try to reduce the drug toxicity and maximize its immunosuppressant effect.

Conclusion CsA has altered the field of solid organ transplantation to the point where this treatment has become

80

Crocker et al

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5. Bar graph indicating the variation in half-life from one child to another in intravenous pharmokinetics of CsA in pediatric patients. This variation complicates dosage calculations to achieve immunosuppression and yet avoid unnecessal T drug toxicity in children.

t h e t r e a t m e n t o f choice for m a n y c o m p l e t e o r g a n failures. D e s p i t e its toxicities, C s A still h a s p l a c e d transplantation above other modalities of treatment for c h r o n i c r e n a l failure. T h e p a t i e n t a n d t h e m e d i c a l t e a m h a v e l e a r n e d to b a l a n c e t h e risk o f toxicity w i t h t h e c r e a t i o n o f a m o r e active p a t i e n t life. T h e p a t i e n t is o f t e n e n t h u s e d a b o u t this n e w life, a n d it gives t h e m a n e w p h i l o s o p h i c a l f r e e d o m . C s A is a d r u g t h a t h a s p a s s e d t h e s c r u t i n y o f science in t h e t h o u s a n d s o f r e p o r t s p u b l i s h e d o n its actions; it is t h e s t a n d a r d a g a i n s t w h i c h all f u t u r e a n t i r e j e c t i o n d r u g s will b e j u d g e d .

References 1. Kahan BD, Conley S, Portman R, et ah Parent-to-child transplantation with cyclosporine immunosuppression.J Pediatr 1987, 111:I012 2. Myers BD: Cyclosporine nephrotoxicity. Kidney Int 1986, 30:964 3. Dieperink H: Cyclosporin A nephrotoxicity. Dan Med Bull I989, 36:235 4. Chan GLC, Hodge EE, Chang HHH: The use of routinely available clinical data in differentiating renal allograft rejection from cyclosporine nephrotoxicity. Transplantation 1989, 48:1075 5. Alexopoulos E, Leontsisi M, Daniilidis M, et al: Differentiation

between renal allograft rejection and cyclosporine toxicity: A clinicopathological study. AmJ Kidney Dis 1991, 18:108 6. Kiberd BA: Cyclosporine-induced renal dysfunction in human renal allograft recipients. Transplantation I989, 48:965 7. KoppJB, Klotman PE: Cellular and molecular mechanisms of Cyclosporin nephrotoxicity.J Am Soc Nephrol 1990, 1:162 8. Erman A, Chen-Gal B, RosenfeldJ: The role of eieosanoids in cyclosporine nephrotoxicity in the rat. Biochem Pharmac 1989, 38:2153 9. Walker RJ, Lazzaro VA, Duggin GG: Renal metabolism of Cyclosporin A (CsA) may contribute to nephrotoxicity. Kidney Int 1989, 36:1173 (abstr) 10. Curtis JJ, Luke RG, Dubovsky E, et al: Cyclosporin in therapeutic doses increases renal allograft vascular resistance. Lancet 1986, 2:477 11. Murray BM, Paller MS, Ferris TF: Effect of cyclosporine administration on renal hemodynamics in conscious rats. Kidney Int 1985, 28:767 12. Garr MD, Paller MS: Cyclosporine augments renal but not systemic vascular reactivity. Am J Physiol 1990, 258:F211 (abstr) 13. Dawidson I, Rooth P, Fry WR, et al: Prevention of acute cyclosporine-induced renal blood flow inhibition and improved immunosuppression with verapamil. Transplantation 1989, 48:575 14. Berg UB, Bohlin A-B: Renal function tbllowing kidney transplantation in children treated with cyclosporine. Pediatr Ncphrol 1992, 6:339 15. Hoyer PF, Oflher G, Oemar BS, et ah Four years' experience with Cyclosporin A in pediatric kidney transplantation. Acta Paediatr Scand I990, 79:622 16. Skorecki KL, Rutledge WP, Schrier RW: Acute cyclosporine nephrotoxicit~Prototype for a renal membrane signalling disorder. Kidney Int 1992, 42:1 17. Porter GA, Bennett WM, Sheldon GS: Cyclosporine-associated hypertension. Arch Intern Med 1990, 150:280 18. Kurtz A, PfeilschifterJ, Ktihn K, et al: Cyclosporin A inhibits PGE2 release from vascular smooth nmscle cells. Biochem Biophys Res Commun 1987, 147:542 19. Cohen DJ, Loertscher R, Rubin M, et ah Cyclosporin: Renal effects and prostacyclin. Ann Intern Med 1984, 102:420 20. Perico N, Benigna A, Zoja C, et ah Functional significance of exaggerated renal thromboxane A2 synthesis induced by cyclosporine A. AmJ Physiol 1986, 251 :F581 21. Elzinga L, Kelly V, Houghton DC, et al: Fish oil modifies experimental cyclopsorine nephrotoxicity and decreased renal prostaglandins. Transplantation 1987, 43:271 22. Golub MS, Berger ME: Direct augmentation by cyclosporine A of vascular contractile response to nerve stimulation. Hypertension 1987, 9:96 (suppl 3) 23. Reznik VM, Jones KL, Durham BL, et al: Changes in facial appearance during cyclosporin treatment. Lancet 1987, 2:I405 24. Reznik VM, BergerJS, Jones KL, et al: Cyclosporine induces abnormal facial bone growth in children: A preliminary study. Pediatr Nephrol 1989, 3:296 25. De Camargo PM: Cyclosporin- and nifedipine-induced gingival enlargement: An oveIview.J Western Soc Periodont 1989, 37:57 26. Stiller CR, Dupr6 J, Gent M, et al: Effects of cyclosporin immunosuppression in insulin-dependent diabetes mellitus of recent onset. Science 1984, 223:1362 27. Yamasaki A, Rose G, Pinero G, et al: Ultrastructure of

Cyclosporin A Toxicity in CTdldren

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46. 47.

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48.

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50.

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53.

54.

55.

56.

57. 58.

59.

60.

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64.

65.

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