M. Alessiani

Liver, kidney, and thoracic organ transplantation under FK 506

The new immunosuppressive drug FK 506 was used from the outset with low doses of prednisone to treat 120 recipients of primary liver grafts and 20 more patients undergoing liver retransplantation. The patient survival rate after 2 to 8 months in the primary liver transplantation series is 93.3%, with original graft survival of 87.5%. Of the 20 patients in the hepatic retransplant series, 17 (85%) are living. Almost all of the surviving patients have good liver function. In addition 11 hearts, 2 double lungs, and a heart-lung have been transplanted under FK 506, with survival of all 14 patients. With all of the organ systems so far tested, including the kidney (which has been reported elsewhere), rejection usually has been controlled without additional drugs and with lower average steroid doses than in the past. Nephrotoxicity has been observed, but not to an alarming degree, and there has been a notable absence of hypertension. There is a suggestion that serum cholesterol may be lowered by FK 506, but this is unproved. Although the adverse reactions of FK 506 and the immunosuppressive mechanisms resemble those of cyclosporine, our preliminary observations suggest that FK 506 may have a more advantageous therapeutic index.

Conversion of liver allograft recipients from cyclosporine to FK506 immunosuppressive therapy : a clinicopathologic study of 96 patients

The effect of conversion from cyclosporine-steroid immunosuppression to the new agent FK506 was studied in 96 liver allograft recipients who were experiencing graft dysfunction or cyclosporine toxicity. Patients were stratified according to the cause of graft dysfunction that ultimately led to conversion to FK506. Response to FK506 introduction was monitored pathologically and biochemically. The outcome of a switch from CsA to FK506 was highly favorable in patients experiencing acute and the early stages of chronic rejection, despite optimal conventional therapy. Patients with later stages of chronic rejection did not respond to conversion to FK506 and most eventually lost their liver grafts in this process. Patients in whom we had difficulty separating chronic rejection from chronic persistent or low-grade chronic active hepatitis were mostly unaffected by conversion to FK506. Active hepatitis was a poor indication for conversion, because most of the patients experienced graft failure or died from liver failure. As a group, there was no statistically significant change in renal function 180 days after conversion to FK506. These findings expand the experience with FK506 in human liver allograft recipients.

The effect of graft function on FK506 plasma levels, dosages, and renal function, with particular reference to the liver

Plasma FK506 was studied in 49 liver, 13 heart, 3 double-lung or heart-lung, and 21 kidney recipients. The levels were correlated with the drug doses used, kidney function, and liver function. In all verieties of recipients, there was an early rise in the FK506 plasma levels that occurred at the time of intravenous administration of the drug. At the same time or shortly after, there were increases in serum creatinine that were transitory except in liver recipients with continuing suboptimal graft function. The quality of hepatic function dominated all aspects of FK506 management in the liver recipients. Those who received well-functioning grafts could be given about the same drug doses as recipients of kidneys and the thoracic organs. Liver recipients with defective grafts had astronomical rises in plasma FK506, a high incidence of renal failure, and probably increased neurotoxicity. In kidney transplant recipients, the FK506 plasma levels and doses were essentially the same in patients with prompt versus delayed renal function. These studies have highlighted the necessity, first of close pharmacologic monitoring of patients who are given FK506 in the presence of abnormal liver function, and second, of using smaller intravenous induction doses than in past practice.

EXPESSIVE DYSPHASIA POSSIBLY RELATED TO FK506 IN TWO LIVER TRANSPLANT RECIPIENTS

The principal side effects of the new immunosuppressive drug FK506 have been low-grade nephrotoxicity, a mild diabetogenic effect, and annoying but relatively minor manifestations of neurotoxicity (1). The neurotoxic symptoms have included tremors, paresthesias, insomnia, headaches, increased visual sensitivity to light, nightmares, a sense of racing, and mood changes. Such complaints, which are similar to those caused by cyclosporine, have provided a much-needed means of dose adjustment (1). However, we report here 2 examples of reversible expressive dysphasia that may have been caused by FK506 since it was reversed by dose reduction. Both patients were treated from the time of liver transplantation with FK506, starting with an initial intravenous dose of 0.15 mg/kg FK506 intraoperatively. Subsequent intravenous doses of 0.075 mg/kg were given every 12 hr, until the patients were able to take oral medications. At this time, 0.15 mg/kg FK506 was given orally every 12 hours. Methylprednisolone was started at 200 mg on day 1 and reduced by 40 mg steps/day to 20 mg on day 6. A 43-year-old man with end-stage postnecrotic cirrhosis (liver weight 1400 g) secondary to hepatitis B did not have disabling encephalopathy preoperatively. He had an uncomplicated orthotopic liver transplantation, with a 3000 ml blood loss. He was discharged from the ICU after 3 days. On day 12, he was noted to have slurring of speech. He complained of numbness and tingling in his feet and also that his head was “racing.” There was no arterial hypertension, nor any elevation of BUN or creatinine. Serum electrolytes were never abnormal, intraoperatively or later. The neurologic examination revealed an expressive dysphasia with slight tremors of the extremities. Fundoscopic findings, magnetic resonance imaging of the brain, and the spinal fluid were normal. A cerebral CT scan showed mild cortical atrophy, a finding that had been noted in the preoperative CT scan. An EEG showed generalized slowing. The neurologic symptoms gradually resolved after an FK506 dose reduction. Despite a minor rejection episode, he improved steadily, and by the time of discharge, 25 days postoperatively, the speech defect was barely perceptible. He is neurologically normal 4 months postoperatively on FK506 doses of 0.09 mg/kg/day (less than one-third of early postoperative oral dose) and 10 mg/day prednisone. A 38-year-old woman with chronic HBV hepatitis and grade III encephalopathy had an uncomplicated urgent liver transplantation. Preoperatively, she was agitated and disoriented. Later, she became drowsy, disoriented, and bradykinetic. Immunosuppression was as in case 1. Postoperatively, she required prolonged ventilatory support and developed nonoliguric renal insufficiency—the serum creatinine rising from normal preoperatively to a peak of 5.3 mg/dl. The intravenous dose of FK506 was decreased to .035 mg/kg/b.i.d. When the endotracheal tube was removed on day 6, she was noted to have an expressive speech deficit. Talking required a severe effort and there were occasional paraphasias. Her comprehension appeared to be normal, and repetitive speech was easier than spontaneous expression. A small subcortical left hemispheric stroke was suspected. However, a CT brain scan on days 6 and 12, carotid doppler examination, and echocardiogram (to rule out valve vegetations as an embolic source) were normal. The cerebrospinal fluid was normal. Her subsequent course was stormy and included Pseudomonas pneumonia, abdominal reoperation to remove a subhepatic hematoma, acute renal failure requiring 7 hemodialyses, tracheostomy, and CMV gastritis. The FK506 doses were intermittently stopped during this time and eventually resumed with oral doses of .07 mg/kg/day (about a quarter of the usual dose). When her tracheostomy was capped on day 41, she was noted still to have slurring of speech. Magnetic resonance imaging on the 41st postoperative day showed areas of demyelinization in the pons (Fig. 1). The oral dose of .07 mg/kg FK506 per day was maintained. The expressive dysphasia slowly improved and she was discharged on the 56th postoperative day. Her speech abnormalities completely resolved by postoperative day 90. She has never had a rejection. Maintenance immunosuppression 5 months postoperatively is with 0.06 mg/kg/day FK506 without steroids, which were stopped on the 16th postoperative day. Figure 1 NMR in patient 2 on the 41st postoperative day. Note the bright pontine lesion (arrow), which was thought to be an area of demyelinization. Pathologic changes can frequently be found in the central nervous system of patients who die of chronic liver disease (2). The same abnormalities have been seen at autopsy after unsuccessful transplantation under azathioprine and cyclosporine regimens (3,4). In order of frequency, these include Alzheimer type II changes in the glial tissue, depletion of the myelin in the pons (central pontine myelinolysis) or elsewhere in the brain stem or higher brain (extrapontine myelinolysis), and cortical atrophy. The neurologic syndromes have included prolonged obtundation or disorientation, flaccid quadriplegia, pseudobulbar palsy, expressive dysphasia, akinetic mutism, neuroopthomologic abnormalities, convulsions, and coma (3, 4). Similar Alzheimer and myelinolytic changes can be produced reliably in rats by surgical portacaval anastomosis, even though the animals may appear well clinically (5). Thus, vulnerability from underlying neuropathologic abnormalities of the central nervous system during the stressful period of liver transplantation is the background against which the role of any single factor, including drugs, must be evaluated in the event of a neurologic complication. The possible aggravating role of overly aggressive electrolyte correction has been emphasized by many workers, as summarized by Wszolek et al. (6). Nevertheless, the possible neurologic complications of FK506—including the reversible pontine demyelinization seen in case 2 by NMR–resemble some of those ascribed to cyclosporine (7). In the cyclosporine reports, the neurotoxicity was associated casually with low cholesterol (8), hypomagnesemia (7), and aluminum overload (9). These latter findings are probably epiphenomena even if they are contributory to the pathogenesis. A more fundamental explanation may be advanced for the neurotoxicity of these drugs.3 Although they are distinct, the binding sites of both cyclosporine and FK506 contain cis-trans peptidyl prolyl isomerase (10, 11). Inhibition of this enzyme could explain many metabolic effects of both drugs, including cholesterol regulation3 and reduction of magnesium (12). It is also doubtful that hypocholesterolemia has a direct casual role in the neurotoxicity (13). Although hypocholesterolemia is uniformly produced by FK506, the 2 examples of major neurologic complications herein reported were the only ones with a probable FK506 etiology seen in recipients of 180 livers, 55 kidneys, and 18 hearts, lungs, and heart-lungs treated primarily with this drug in the last 13 months. Seizures have occurred in our liver transplant recipients with a lower frequency than in the past. Although we are making a systematic search to establish a specific etiology in each case, this has been difficult because of the multifactorial nature of this complication in liver recipients. Seizures have not been seen in the recipients of extrahepatic organs. An important possibility is that there is a direct inhibitory effect of drugs like cyclosporine and FK506 on cis-trans peptidyl prolyl isomerase receptors in the central nervous system as has been suggested elsewhere.3 Focal CNS targets made more susceptible by previous liver disease or any of the contributory factors mentioned earlier could be selectively affected by Over-dosage. The first intravenous dose of 0.15 mg/kg FK506 used in our early experience has been reduced since to 0.075 mg/kg in order to reduce this possibility.

Combined immunosuppressive therapy with tacrolimus and mycophenolate mofetil for small bowel transplantation in pigs

In a swine model of orthotopic small bowel transplantation, we assessed the efficacy of combined therapy with a low dose of tacrolimus plus mycophenolate mofetil, compared with high-dose tacrolimus monotherapy. The bowel was replaced in 25 piglets: group 1 (n = 5), no immunosuppression; group 2 (n = 10), tacrolimus, 0.3 mg/kg daily i.m. for 7 days, followed by b.i.d. oral doses to maintain blood levels of 15-25 ng/ml; and group 3 (n = 10), tacrolimus, 0.1 mg/kg i.m., in a single dose on day 0 and thereafter oral doses to maintain blood levels of 5-15 ng/ml, plus oral mycophenolate mofetil (10 mg/kg twice daily). Follow-up time was limited to 60 days. Median survival time as 11, 27, and > 60 days in groups 1, 2, and 3, respectively (P = 0.001). Survival rates were 0%, 40%, and 80% at 30 days and 0%, 0%, and 70% at 60 days in groups 1, 2, and 3, respectively (P = 0.03), group 1 vs. group 2; P = 0.003, group 1 vs. group 3; P = 0.02, group 2 vs. group 3). One animal in group 1 (20%) and two animals each in groups 2 and 3 (20%) died of technical complications. Rejection was the cause of death of 80% of animals of group 1 and of no animals in either group 2 or 3. None of the immunosuppressed animals developed clinical or histopathological evidence of graft-versus-host disease. Sixty percent of animals in group 2 (n = 6) and 10% in group 3 (n = 1) died from infections; two other animals in group 2 died of emaciation. The seven animals of group 3 that were alive at 60 days had immunosuppression stopped at that time. All died of rejection within 1 month. In conclusion, double-drug therapy with tacrolimus and mycophenolate mofetil consistently allowed extended survival after small bowel transplantation in swine, preventing or controlling acute cellular rejection without a high incidence of lethal complications related to overimmunosuppression.

Abdominal spilled stones: ultrasound findings

Laparoscopic cholecystectomy (LC) is the treatment of choice for uncomplicated symptomatic gallstones. Spillage of stones due to gallbladder rupture has been reported in up to 33% of all LCs, but clinical sequelae caused by dropped gallstones are uncommon. We recently observed two patients with retained stones after LC. Correct diagnosis was made by abdominal ultrasonography (US) in both cases. In the first patient, who presented with fever, malaise, and weight loss 18 months after LC, abdominal US revealed hypoechoic focal lesions containing hyperechoic images with posterior shadowing of the liver and spleen. US-guided aspiration biopsies of these lesions yielded purulent material, and the injection and aspiration of saline solution provoked rolling movements of the hyperechoic images. Laparotomy confirmed the diagnosis of abscess-containing spilled gallstones. In the second patient, multiple hyperechoic images with posterior shadowing were observed in the Morison pouch during a routine US examination. The diagnosis of retained stones was consistent with the history of gallstone spillage during LC performed 2 months previously and was confirmed by computed tomographic findings of hyperdense images in the Morison pouch. The patient was asymptomatic, and treatment was thus deferred. Our experience suggests that US can be very useful in the detection of gallstones spilled during LC.

Preoperative Oral Carbohydrate Load Versus Placebo in Major Elective Abdominal Surgery (PROCY): A Randomized, Placebo-controlled, Multicenter, Phase III Trial

Objective: To explore whether preoperative oral carbohydrate (CHO) loading could achieve a reduction in the occurrence of postoperative infections. Background: Hyperglycemia may increase the risk of infection. Preoperative CHO loading can achieve postoperative glycemic control. Methods: This was a randomized, controlled, multicenter, open-label trial. Nondiabetic adult patients who were candidates for elective major abdominal operation were randomized (1:1) to a CHO (preoperative oral intake of 800 mL of water containing 100 g of CHO) or placebo group (intake of 800 mL of water). The blood glucose level was measured every 4 hours for 4 days. Insulin was administered when the blood glucose level was >180 mg/dL. The primary endpoint was the occurrence of postoperative infection. The secondary endpoint was the number of patients needing insulin. Results: From January 2011 through December 2015, 880 patients were randomly allocated to the CHO (n = 438) or placebo (n = 442) group. From each group, 331 patients were available for the analysis. Postoperative infection occurred in 16.3% (54/331) of CHO group patients and 16.0% (53/331) of placebo group patients (relative risk 1.019, 95% confidence interval 0.720–1.442, P = 1.00). Insulin was needed in 8 (2.4%) CHO group patients and 53 (16.0%) placebo group patients (relative risk 0.15, 95% confidence interval 0.07–0.31, P < 0.001). Conclusions: Oral preoperative CHO load is effective for avoiding a blood glucose level >180 mg/dL, but without affecting the risk of postoperative infectious complication.

The challenge of extraabdominal desmoid tumour management in patients with Gardner's syndrome: radiofrequency ablation, a promising option

Desmoid tumours are benign, myofibroblastic stromal neoplasms common in Gardner’s syndrome, which is a subtype of familial adenomatous polyposis characterized by colonic polyps, osteomas, thyroid cancer, epidermoid cysts, fibromas and sebaceous cysts. The primary treatment is surgery, followed by adjuvant radiotherapy, but the local recurrence rate is high, and wide resection can result in debilitating loss of function. We report the case of a 39-year-old man with Gardner’s syndrome who had already undergone a total prophylactic colectomy. He developed desmoid tumours localized in the mesenteric root, abdominal wall and dorsal region, which were treated from 2003 through 2013 with several surgical procedures and percutaneous radiofrequency ablation. In 2008 and 2013, RFA was applied under ultrasonographic guidance to two desmoid tumours localized in the dorsal thoracic wall. The outcomes were low-grade pain and one case of superficial skin necrosis, but so far there has been no recurrence of desmoid tumours in these locations. Surgical resection remains the first-line therapy for patients with desmoid tumours, but wide resection may lead to a poor quality of life. Radiofrequency ablation is less invasive and expensive and is a possible therapeutic option for desmoid tumours in patients with Gardner’s syndrome.

Bacteremia After Liver Transplantation; Few Issues in Selection of Antibiotics for Treatment and Prophylaxis

Infections after liver transplantation are still associated with significant morbidity and mortality. Bacterial infections account for up to 50% of such events according to various series. The majority of these infections are nosocomial and many of them are associated with technical surgical problems. Bacteremia represents “invasive” infection and knowing the common agents involved helps in selection of antibiotics for treatment and prophylaxis. Successful use of antibiotics requires familiarity with their characteristics, potential side effects and interactions with other medications.

Early experience with FK 506 in liver transplantation

Since the introduction of cyclosporine-steroid therapy in 1980 for liver transplantation, 1 year clinical survival rates have approached 70% for most of the common indications for liver replacement and 5 year survival rates are better than 60%. Nevertheless, allograft rejection continues to be a significant cause of retransplantation or death. Clinical rejection occurs in 70% of liver allograft recipients on cyclosporine-steroid therapy. Many patients require treatment with polyclonal or monoclonal antibody preparations to control acute cellular rejection. An increased risk of opportunistic infection, especially from cytomegalovirus, is associated with such therapy.