Myocyte Vacuolization Research Articles

Hamartomas of mature cardiac myocytes: report of 7 new cases and review of literature

Only 8 cases of hamartomas of mature cardiac myocytes have been reported. The aim of the study was to describe 7 new cases and provide clinicopathologic correlation. Our anatomical pathology database was searched for all cases of cardiac hamartoma, of which 7 represented mature myocyte type. Medical records were reviewed for clinical information, and microscopic slides were evaluated for extent of characteristics. Five males and 2 females ranged in age from 6 months to 74 years (mean, 23 years). There were 11 ventricular hamartomas (8 left free wall, 2 right free wall, 1 septum). Death in 3 infants was unrelated to incidental hamartomas discovered at autopsy. A 10- and 16-year-old were asymptomatic but had abnormal electrocardiogram (ECG) results, which led to detection of cardiac masses by imaging studies. Two adult males had only mild coronary disease angiographically. The 57-year-old, who died suddenly, had a 7-year history of abnormal ECG results. The 74-year-old, who died after aortic surgery, had a 3-year history of chest discomfort. Their hamartomas were identified at autopsy and contributed to sudden death in 1. Microscopically, all hamartomas were involved by myocyte hypertrophy and disarray, without inflammation or calcification. Myocyte vacuolization and venular dilatation occurred only in the pediatric cases, and interstitial adipose tissue only affected 1 adult. In conclusion, hamartomas of mature cardiac myocytes may be detected at any age. They primarily affect males, arise predominantly in the left ventricle, are asymptomatic, may have nonspecific ECG findings, and rarely may be associated with sudden death. Microscopic findings in infants differ from older patients.

The Effect of Secretory Leukocyte Protease Inhibitor (SLPI) on Ischemia/Reperfusion Injury in Cardiac Transplantation

We investigated the role of secretory leukocyte protease inhibitor (SLPI) in ischemia/reperfusion injury in cardiac transplantation. SLPI-/- mouse hearts and wild-type (WT) controls were transplanted immediately or after 10 h of cold ischemia (CI). Recombinant SLPI (rSLPI) was added to the preservation solution or given systemically. After evaluation of myocardial performance, grafts were investigated for histology, SLPI, TNF-alpha, TGF-beta, NF-kappaB and protease expression at indicated time points. Early myocardial contraction was profoundly impaired in SLPI-/- hearts exposed to CI and associated with high intra-graft protease expression. Systemic administration of rSLPI had no effect, however, when SLPI was added to the preservation solution, myocardial contraction was restored to normal. At 10 days, inflammation, myocyte vacuolization and necrosis were significantly more severe in SLPI-/- hearts. SLPI gene expression was detected in WT mice at 12 and 24 h and was significantly higher after CI. SLPI protein was observed at 24 h and 10 days. High intra-graft concentrations of SLPI after administration of rSLPI were inversely correlated with protease levels early and TGF-beta expression late after reperfusion. SLPI plays a crucial role in early myocardial performance and postischemic inflammation after cardiac transplantation. A dual inhibitory effect on protease and TGF-beta expression might be the underlying mechanism.

Neurogenic Stunned Myocardium Associated with Status Epileptics and Postictal Catecholamine Surge

A 75-year-old woman developed left ventricular apical ballooning, shortly after recovering from status epileptics. Plasma noradrenaline and adrenaline levels were 2.05 ng/ml and 0.48 ng/ml, respectively. Endomyocardial biopsy disclosed patchy areas of interstitial myocardial fibrosis, atrophy and vacuolization of cardiac myocytes, and some disappearance of myocyte nuclei. Follow-up echocardiography showed that the left ventricular apical ballooning was restored to normal within 25 days. These findings are compatible with neurogenic stunned myocardium. It is important to recognize that patients suffering from intractable seizures may harbor a risk of postictal catecholamine surge and catecholamine-induced myocardial dysfunction.

O020 ENTERAL FEEDING WITH A LACTOSE- COMPARED TO A POLYCOSE-BASED FORMULA IMPROVES NUTRIENT ABSORPTION AND COLITIS RESISTANCE IN PRETERM PIGS

unclear. Osmotic renal charge, amino-acids, aminoside treatment may impair renal function. The aim of this study was to compare retrospectively renal biopsies (RB) in children on LTPN to search similarities suggesting a PN toxicity. Methods: Eleven patients on LTPN for more than 1 year were studied. Median age at RB was 8 years (1 24). Median PN duration was 6.5 years (1 14). Indication for PN was congenital diarrhoea (5 cases), short bowel syndrome (4), Hirschsprung disease (2). Indications for RB were: measured glomerular filtration rate <80ml/min/1.73m2 and tubular impairment (7 cases), proteinuria (2), evaluation before intestinal transplantation (ITx) (2). Lesions observed on RB were classified into: acute and chronic tubulo-interstitial lesions, vascular lesions and glomerular sclerosis with immuno-fluorescence evaluation. Renal ultrasonography (US) at RB was evaluated. Results: Histological anomalies were observed in 6 patients (1 RB before ITx and 5 for renal impairment). One patient presented with acute tubular necrosis after an episode of dehydration. One patient with congenital diarrhoea presented a membranous glomerulonephritis. In the last 4 patients ischemic lesions were observed (arteriolar myocyte vacuolization); 3 of these showed also calcifications and osmotic lesions (tubular microvacuolisation), with interstitial fibrosis in 2. Patients with histological lesions had a greater number of CVC and nephrotoxic treatment. Three of 6 patients with histological lesions showed US anomalies: hyperechogenicity, reduced size and reduced corticomedullary differentiation. No lesions were found in patients with Hirschsprung disease. Conclusion: Tubular microvacuolisation might be of osmotic origin (intravenous immunoglobulins, CT contrast). Hyperosmolar solutions, like PN, could cause such lesion which is not observed in all our patients. No specific lesions were found. Histological lesions are probably of multifactorial origin and they can occur without biological disorders. ITx, the alternative treatment of intestinal failure, shows a high risk of renal side effects. Therefore, a systematic renal histological evaluation in children on LTPN is mandatory, especially at the time of evaluation before ITx, for a correct interpretation of possible lesions after ITx.

Unusual etiology of slow colonic transit constipation: visceral hypertophic myopathy

Background: Slow transit constipation (STC) is a disorder of intestinal motility of unknown etiology. Myogenic or neural mechanisms have been implicated in its pathophysiology. Morphological changes seen in intestinal myopathies include fibrosis, hypertrophy or atrophy of muscle fibers, vacuolation of myocytes, and alteration in the immunohistochemical staining patterns of myocyte contractile proteins, abnormal muscle layering, and presence of intracellular inclusion bodies.

Relationship between atrial histopathology and atrial fibrillation after coronary bypass surgery

Postoperative atrial fibrillation is common after coronary surgery. The cellular condition of atrial myocytes might play a part in the postoperative development of atrial fibrillation. Our study aimed to investigate whether patients in whom postoperative atrial fibrillation develops show pre-existent alterations in histopathology of the right atrium and how such changes are expressed in relation to the use of cardiopulmonary bypass. Seventy patients undergoing elective coronary revascularization were prospectively randomized to on-pump conventional surgery (conventional coronary artery bypass grafting, n = 35) or off-pump surgery on the beating heart (off-pump coronary artery bypass grafting, n = 35). Samples from the right atrial appendage were immediately collected after opening the pericardium. In the on-pump group samples were also taken after weaning from cardiopulmonary bypass. Focusing on degenerative alterations, histology was studied by means of light microscopy and for confirmation of particular findings by means of electronic microscopy. Twenty-two (31%) patients had postoperative atrial fibrillation, with the rate not being different between the off-pump coronary artery bypass grafting and conventional coronary artery bypass grafting groups (P = .797). Left atrial enlargement and inotropic requirement were related to atrial fibrillation. Interstitial fibrosis, vacuolization, and nuclear derangement of myocytes were the histologic abnormalities associated with the development of postoperative atrial fibrillation. However, in multivariate analysis fibrosis was confounded by myocyte vacuolization (P = .002) and nuclear derangement (P = .016), representing independent atrial fibrillation predictors. As expected, the conventional coronary artery bypass grafting and off-pump coronary artery bypass grafting groups showed similar histology, but more importantly, no atrial changes were detected in relation to cardiopulmonary bypass exposure in the conventional coronary artery bypass grafting group. Atrial histology showed degenerative changes that correlated with advanced age and left atrial enlargement. Our study supports the contention that atrial fibrillation after coronary surgery is associated with pre-existing histopathologic changes of the right atrium. Patients randomly allocated to off-pump coronary artery bypass grafting procedures showed a similar rate of atrial fibrillation and a similar relationship to atrial histology as did those exposed to cardiopulmonary bypass. Cardiopulmonary bypass did not cause additional changes in tested histology variables.

Structural Heart Disease, SCN5A Gene Mutations, and Brugada Syndrome

The report of the Second Consensus Conference, published in Circulation in 2005, defined the Brugada syndrome as ST-segment elevation in the right precordial ECG leads (so-called type 1 ECG) and a high incidence of sudden death in patients with structurally normal hearts.1 An autosomal dominant disease with incomplete penetrance, Brugada syndrome has been linked to mutations in SCN5A , the gene encoding the alpha subunit of the cardiac sodium channel.2 More than 80 mutations in SCN5A have been linked to this syndrome (references cited in Reference 1). Analysis of several of these mutations has consistently demonstrated a loss of function related to multiple mechanisms, including failure of sodium channel protein expression and changes in the voltage and time dependence of sodium channel current activation, inactivation, or reactivation.1 Still, SCN5A mutations have been reported in only &20% of patients with Brugada syndrome diagnosed on the basis of clinical criteria, suggesting that other genetic defects and/or other disease mechanisms may give rise to this clinical picture. To complicate matters further, SCN5A mutations have also been identified in patients with the long-QT syndrome. These mutations generally lead to a “gain of function” in the sodium channel, which prolongs the QT interval by increasing inward current. In fact, at least 3 human diseases have been linked to defects in this gene: Brugada syndrome, long-QT syndrome, and progressive conduction disturbances.2–4 Furthermore, there is considerable overlap of clinical profiles, so some patients with Brugada syndrome also have atrial fibrillation, conduction defects with sinus node abnormalities, or prolonged QT interval (reviewed in Reference 1). Thus, genotype-phenotype relationships in Brugada syndrome are highly complex and serve to underscore our incomplete knowledge of the pathogenesis of this type of inherited arrhythmogenic disease. Article p 3680 A similar area of increasing complexity and uncertainty has to …

Hydroxychloroquine-induced Cardiotoxicity in a 39-year-old Woman with Systemic Lupus Erythematosus and Systolic Dysfunction

A 39-year-old woman with a history of systemic lupus erythematosus developed chest pain and conduction abnormalities. An echocardiographic examination revealed systolic dysfunction and ventricular thickening. Because of the unclear nature of her cardiac disease, right ventricular endomyocardial biopsy was performed. Light microscopy showed diffuse myocyte vacuolization without myocarditis, and transmission electron microscopy demonstrated sarcoplasmic myelinoid and curvilinear bodies, diagnostic of hydroxychloroquine toxicity. Among patients with autoimmune connective disorders, cardiac dysfunction may be a result of the disease or occasionally of its treatment. Although the nature of the cardiac disease (myocardial, valvular, or pericardial) can generally be evaluated echocardiographically, endomyocardial biopsy may be indicated to rule out diseases with a specific microscopic appearance, such as myocarditis or hydroxychloroquine cardiotoxicity.

A case of fatal ephedra intake associated with lipofuscin accumulation, caspase activation and cleavage of myofibrillary proteins

Ephedra, a herb reported to suppress appetite and stimulate the sympathetic nervous system as well as cardiac performance, has recently been related to several adverse events, including seizure, stroke, hypertension, myocardial infarction, and sudden death. Here, we describe the case of a 45-year-old woman who died of cardiovascular collapse while taking ephedra. Tissue analysis revealed non-specific degenerative alterations in the myocardium (lipofuscin accumulation, basophilic degeneration and vacuolation of myocytes, as well as myofibrillary loss), associated with myocyte apoptosis, caspase activation, and extensive cleavage of miofibrillary proteins alpha-actin, alpha-actinin, and cardiac troponin T. Healthcare professionals are therefore urged to warn their patients about the risk of serious adverse effects, which may follow ephedra intake.

Clinical and pathological features of dilated cardiomyopathy in Holstein-Friesian cattle

Dilated cardiomyopathy is a primary disease of the heart muscle that has been reported in Holstein-Friesian cattle worldwide in the past 20 years. Nine cases of the condition were compared...

Autopsy Pathology (AP) in primate recipients of heterotopic xenografts (XG) functioning for >60 days

characterized in its mildest form by myocyte vacuolization and interstitial edema and its severest form by coagulative necrosis. No cellular infiltrates were observed and intramyocardial hemorrhage was rare. Vessels and capillaries were variably congested and thrombosed, but were often normal. Concentric intimal thickening resembling classic allograft vasculopathy was also observed (n 3). IHC in nine hearts showed that C5b was consistently negative, whereas there was focal to diffuse, moderately strong IgG and IgM staining of small vessel and capillary endothelium. Hearts with the least rejection tended to have weaker and more focal staining. Conclusions: XG vascular rejection in this model showed changes different from those previously described (less hemorrhage and thrombosis; more edema and coagulative necrosis). The notable preservation of myocardium in a number of recipients emphasizes the potential for successful cardiac xenotransplantation.

Changes in cerebral vessels during experimental hyperlipidemia

Both specific (lipid deposition in endotheliocytes, myocytes, and pericytes) and non-specific (intense formation of apical processes and vacuoles in endotheliocytes and vacuolization of myocytes) changes in cerebral vessels of different diameter were revealed in rabbits and rats after 4 months of experimental hyperlipidemia. These changes suggest reduced endothelium athrombogeneity and intensified transendothelial transport. Biochemical and morphological manifestations of hyperlipidemia in rabbits were more pronounced than in rats.

A canine model of heart failure by intracoronary adriamycin injection: Hemodynamic and energetic results

Background: To eliminate the noncardiac toxicities associated with Adriamycin (Pharmacia Upjohn, Kalamazoo, MI) and to avoid the need for surgical implantation of a coronary artery catheter, we proposed serial intracoronary infusions of Adriamycin (Pharmacia Upjohn) with a Judkins catheter to develop a nonsurgical but selective model of dilated cardiomyopathy in dogs. Methods and Results: Twenty-two dogs were entered onto the study. Each dog received four weekly injections of Adriamycin (Pharmacia Upjohn; 15 mg/wk) through a Judkins catheter and verapamil orally (5 mg/kg twice daily) for 4 weeks. Dogs were evaluated with echocardiography, right-sided cardiac catheterization, and endomyocardial biopsy at times 0 and 10 weeks. The left ventricular ejection fraction decreased from 0.65 ± 0.04 to 0.48 ± 0.11 ( P = .0006). The left ventricular end-diastolic and end-systolic diameter indices increased from 42.00 ± 2.17 to 46.92 ± 5.81 mm ( P = .0029) and from 27.65 ± 2.59 to 35.00 ± 6.84 mm, respectively ( P = .0210). The mechanical cardiac efficiency decreased from 28.55% ± 13.30% at baseline and 15.64% ± 9.09% at 10 weeks ( P = .001). Cardiac myocyte vacuolation was present on histological examination at 10 weeks. The mortality rate was 41%. Minimal systemic Adriamycin (Pharmacia Upjohn) toxicity was noticed. Conclusion: Intracoronary injection of Adriamycin (Pharmacia Upjohn) in dogs induced a chronic dilated cardiomyopathy.

Hamartoma of mature cardiac myocytes

The clinical and pathological findings of three patients with hamartomas of mature cardiac myocytes resembling localized hypertrophic cardiomyopathy are presented. Hypertrophic cardiomyopathy is manifest by a poorly demarcated area of cardiac hypertrophy, microscopically demonstrating myofiber disarray and intramural coronary thickening. Localized, nonencapsulated masses of hypertrophied cardiac myocytes in locations other than the left ventricle or ventricular septum have not been reported. The clinical and pathological data of three patients with localized hamartomas were retrospectively retrieved. The patients were 9, 22, and 28 years old, respectively; none had a known family history of heart disease or cardiomyopathy. Two patients had cardiac arrhythmias: one patient died suddenly, and one patient had the Wolff-Parkinson-White syndrome. The third patient was asymptomatic. Two patients treated surgically had single masses in the right atrium and right ventricle, respectively. The patient who died suddenly had multiple discrete masses throughout the atrial and ventricular myocardium, including the left ventricular free wall. None of the three patients had septal asymmetry suggestive of hypertrophic cardiomyopathy Histologically, there were discrete but unencapsulated nodules of marked myocyte hypertrophy with disorganization, focal scarring, and thickened intramural arteries. There was no myocyte vacuolization suggestive of cardiac rhabdomyoma. Ultrastructurally, the myocytes showed abundant and disorganized myofilaments and normal intercellular junctions. Hamartoma of mature cardiac myocytes is a previously undescribed cardiac tumor that shares some features of hypertrophic cardiomyopathy and rhabdomyoma, but is currently best considered a separate entity.

Patients with epilepsy who die suddenly have cardiac disease.

Approximately 1 in 1000 patients with epilepsy dies suddenly and unexpectedly with no obvious medical cause. The purpose of this study was to determine if the hearts of such individuals harbor occult cardiac pathology. Following a comprehensive protocol, we performed careful pathologic evaluations of the hearts of 7 patients with epilepsy who died suddenly and 13 previously healthy people who died by hanging or a drug overdose. Hearts were studied only when there was no history or gross anatomical evidence of heart disease or the use of adrenergic drugs. Multiple sections of each heart were evaluated independently by 2 cardiac pathologists who were blinded to patient group. Pathologic conditions were found in 5 hearts in the group with epilepsy and in none of the hearts in the comparison group. Four of the 7 hearts in the group with epilepsy had evidence of irreversible pathology in the form of perivascular and interstitial fibrosis. These 4 hearts plus a fifth had evidence of reversible pathology in the form of myocyte vacuolization. Lesions occurred predominantly in the subendocardium. Our results support the hypothesis that patients with epilepsy who die suddenly and unexpectedly have cardiac pathologic conditions that may be responsible for their deaths.

Myocardial vacuolization, a marker of ischemic injury, in surveillance cardiac biopsies posttransplant: Correlations with morphologic vascular disease and endothelial dysfunction

Allograft vasculopathy (AV) causes intimal thickening with progressive luminal obstruction, endothelial dysfunction, and abnormal vasomotion. Subendocardial vacuolization indicating ongoing ischemia was observed at autopsy in transplanted hearts with severe AV. Whether myocyte vacuolization can be observed with lesser degrees of AV in cardia transplant patients has not been reported. Thirty-nine cardiac transplant patients without flow-limiting disease in large epicardial arteries underwent invasive assessment of AV. Eight to 10 segments of the left anterior descending artery were analyzed by intracoronary ultrasound, and an average intimal index was calculated. Endothelial response to acetylcholine was assessed with serial quantitative angiography. Endomyocardial biopsies taken 5 to 7 days prior to the invasive studies were histopathologically reviewed for the presence of small intramyocardial arteries and myocyte vacuolization. Myocyte vacuolization was evident in biopsies from 20 patients (51%). Intramyocardial arteries were observed in 30 cases (76%); 14 had abnormal arteries. All patients had some degree of intimal thickening by intracoronary ultrasound, and 7 (17 %) had severely abnormal average intimal index (>0.2). Endothelial dysfunction was present in 23 patients (58%). Vacuolization failed to show an association with abnormal small artery histology or large epicardial artery ultrasound disease. However, a significant association between vacuolization and endothelial dysfunction was observed ( p = 0.05). Myocyte vacuolization, possibly indicating ischemic injury, is common in biopsies from cardiac transplant patients and is associated with abnormal acetylcholine response in large epicardial arteries. We speculate that myocyte vacuolization may be caused at least in part by impaired coronary flow associated with endothelial dysfunction.

Cardiotoxicity as a dose-limiting factor in a schedule of high dose bolus therapy with interleukin-2 and alpha-interferon. An unexpectedly frequent complication.

In a group of patients with metastatic melanoma treated with high dose immunotherapy, there was an unexpectedly high incidence of severe cardiac adverse effects. Sixteen patients with metastatic melanoma were treated with high dose interleukin-2 (IL-2) and alpha-interferon (alpha-IFN). Each treatment cycle consisted of IL-2 at a dose of 12 MIU/m2 and alpha-IFN at a dose of 3 MIU/m2, given as intravenous bolus injections every 8 hours on Days 1-5, every 3 weeks for a total of three cycles. Before treatment, careful cardiologic screening was performed, including electrocardiogram (ECG), stress test, cardiac multiple uptake-gated acquisition (MUGA) scan, and echocardiography. During therapy, patients were monitored with daily ECG and creatine phosphokinase measurements. Once cardiac damage was suspected, IL-2 and alpha-IFN were discontinued, and echocardiography, stress test and MUGA-scan were repeated. If indicated, cardiac catheterization with endomyocardial biopsies was performed. Despite pretreatment cardiac screening, seven patients (44%) exhibited myocardial injury. Acute myocardial infarction occurred in one patient, cardiomyopathy developed in four, asymptomatic ECG changes appeared in one, and 1 patient died of acute cardiac arrest. Echocardiography showed hypokinesis and decreased left ventricular ejection fraction. These abnormalities disappeared within 6 months. Cardiac catheterization in four affected patients revealed normal coronary arteries, but endomyocardial biopsies showed interstitial edema, vacuolation, and degeneration of myocytes. Electron-microscopic examination showed fragmentation of myofibrils, swelling of mitochondria and loss of mitochondrial cristae. This intensive treatment schedule of IL-2 and alpha-IFN is prohibited by severe and life-threatening cardiac toxicity.

Systemic Toxicity Associated With Doxorubicin Administration in Cats

The systemic toxicity of doxorubicin, 30 mg/m2 body surface area (BSA) every 21 days to a cumulative dose of 300 mg/m2, was evaluated in six cats. Appetite, body weight, and the presence of vomiting and/or diarrhea were monitored throughout the study. Renal function was monitored by measuring serum blood urea nitrogen (BUN) and creatinine concentrations, urine specific gravity, and creatinine clearance before each treatment. Electrocardiograms and echocardiograms were also done before each treatment. The cats were killed 3 weeks after the last treatment, and complete necropsies were performed. Partial or complete anorexia occurred in all cats with significant weight loss occurring after a cumulative doxorubicin dose of 150 mg/m2 BSA. Mild vomiting and diarrhea that required no treatment also occurred sporadically in all cats. Echocardiographic changes consistent with doxorubicin-induced cardiomyopathy occurred in four cats after cumulative doses of 170 to 240 mg/m2 BSA. Clinical heart disease and electrocardiographic changes were not observed. Subsequent histological examination revealed myocyte vacuolization and myocytolysis in all six hearts. Renal dysfunction, characterized by increasing azotemia with progressively more dilute urine, was detected in two cats. Mean creatinine clearance values also decreased significantly throughout the study. At necropsy, all cats had histological evidence of renal disease.

Cardiotoxicity of human recombinant interleukin-2 in rats. A morphological study.

One of the side effects of interleukin 2 (IL-2) cancer immunotherapy in humans is the vascular leak syndrome, which is frequently associated with depression of myocardial function, myocarditis, and myocardial necrosis. To investigate this cardiotoxicity, IL-2 (three doses of 5 x 10(5) Cetus units/day i.p.) was given to rats for 2, 3, or 5 days. Heart, lung, liver, spleen, and kidney tissues were studied by light and electron microscopy and with immunoperoxidase techniques. Cardiac changes consisted of focal lymphocytic and eosinophilic infiltration, myocyte vacuolization, myofibrillar loss, and necrosis. Ultrastructural alterations included swelling of endothelial cells, with dissociation of intercellular junctions, migration of lymphocytes into the interstitium, and interstitial hemorrhage and edema. Close contact between infiltrating lymphocytes, particularly large granular lymphocytes, and cardiac myocytes was often observed in areas of tissue damage. All lesions were more severe on day 5 than on days 2 and 3. Immunoperoxidase stains demonstrated asialo GM1 ganglioside antibody-positive, granular lymphocytes to be much more frequent in myocardium of IL-2-treated rats than in that of control rats. Although we cannot exclude the possibility of a direct toxic effect of IL-2 on myocytes, our observations suggest that the myocardial damage produced by this agent is triggered by IL-2-activated lymphocytes that exert cytolytic effects, first on endothelial cells and then on cardiac myocytes, thus producing lesions that involve both the cardiac microcirculation and the muscle cells.

The Histopathological Changes Associated with Allograft Rejection and Drug Toxicity in Renal Transplant Recipients Maintained on FK506

The histopathological changes in 51 renal allograft biopsies from patients immunosuppressed with FK506 were compared with those seen in 30 needle biopsies obtained from patients on cyclosporine. The frequency and severity of rejection episodes were similar in both groups. Tubular vacuolation and myocyte vacuolation were found to be useful morphological markers to monitor short-term drug toxicity associated with both drugs. Long-term administration of FK506 led to striped interstitial fibrosis and arteriolar hyalinosis, similar to that previously documented for cyclosporine. One case each of hemolytic uremic syndrome and necrotizing arteriopathy was noted in patients receiving FK506. FK506 and cyclosporine are structurally unrelated compounds; hence the parallelism observed in their nephrotoxicity profile suggests that the interactions of these drugs with renal tissue involves the operation of two different initial signal-transducing mechanisms, ultimately activating the same final metabolic pathways.