Simultaneous Pancreas-Kidney Transplant From Donors After Brain Death vs Donors After Circulatory Death: A Single-Center Follow-up Study Over 3 Decades.

BACKGROUND: Despite an increase in the number of pancreas transplants in the Scandiatransplant region in the last decade, there continues to be a gap between demand and supply of transplantable organs. This imbalance has encouraged the transplant community to consider new sources of grafts, such as the reintroduction of donors after circulatory death (DCD) who were the standard donors in our center before 1988. MATERIAL AND METHODS: In this long-term follow-up study, we compare 44 consecutive, simultaneous pancreas kidney transplants performed at Karolinska University Hospital between 1986 and 1991: 21 patients received DCD grafts and 23 received grafts from donors after brain death. RESULTS: Both groups had similar donor and recipient characteristics, but cold ischemia times were significantly shorter in the DCD group. Warm ischemia times were very short compared with other studies on DCDs. Patient and graft survival rates were similar in both groups. CONCLUSION: This study suggests that controlled DCD pancreas and kidney grafts transplanted simultaneously can be a feasible option for reducing organ shortage without any negative impact on the long-term results.

Decreasing incidence of cancer after liver transplantation-A Nordic population-based study over 3 decades.

Cancer remains one of the most serious long-term complications after liver transplantation (LT). Data for all adult LT patients between 1982 and 2013 were extracted from the Nordic Liver Transplant Registry. Through linkage with respective national cancer-registry data, we calculated standardized incidence ratios (SIRs) based on country, sex, calendar time, and age-specific incidence rates. Altogether 461 cancers were observed in 424 individuals of the 4246 LT patients during a mean 6.6-year follow-up. The overall SIR was 2.22 (95% confidence interval [CI], 2.02-2.43). SIRs were especially increased for colorectal cancer in recipients with primary sclerosing cholangitis (4.04) and for lung cancer in recipients with alcoholic liver disease (4.96). A decrease in the SIR for cancers occurring within 10 years post-LT was observed from the 1980s: 4.53 (95%CI, 2.47-7.60), the 1990s: 3.17 (95%CI, 2.70-3.71), to the 2000s: 1.76 (95%CI, 1.51-2.05). This was observed across age- and indication-groups. The sequential decrease for the SIR of non-Hodgkin lymphoma was 25.0-12.9-7.53, and for nonmelanoma skin cancer 80.0-29.7-10.4. Cancer risk after LT was found to be decreasing over time, especially for those cancers that are strongly associated with immunosuppression. Whether immunosuppression minimization contributed to this decrease merits further study.

Pediatric organ transplantation and risk of premalignant and malignant tumors in Sweden.

Increased cancer risks are well documented in adult organ transplant recipients. However, the spectrum of malignancies and risk in the pediatric organ transplant population are less well described. We identified all solid organ transplanted patients aged <18 in Sweden between 1970-2007 (n = 536) in the National Patient Register and linked to the Cancer Register. Nationwide rates were used to calculate standardized incidence rate ratios and 95% CI estimating the association between transplant and cancer during maximum 36 years of follow-up. Nearly 7% of pediatric solid organ transplant recipients developed a premalignant or malignant tumor during follow-up. Transplantation was associated with an increased risk of any cancer (n = 24, SIR = 12.5, 95% CI: 8.0-18.6): non-Hodgkin lymphoma (NHL) (n = 13, SIR = 127, 95% CI: 68-217), renal cell (n = 3, SIR = 105, 95% CI: 22-307), vulva/vagina (n = 3, SIR = 665, 95% CI: 137-1934) and nonmelanoma skin cancers (n = 2, SIR = 64.7, 95% CI: 7.8-233.8). NHL typically appeared during childhood, while other tumors were diagnosed during adulthood. Apart from short-term attention toward the potential occurrence of NHL, our results suggest cancer surveillance into adulthood with special attention to skin, kidneys and the female genitalia.

Liver transplantation with grafts from controlled donors after cardiac death: a 20-year follow-up at a single center.

The first liver transplantation (LTx) in Sweden was performed in 1984, but brain death as a legal death criterion was not accepted until 1988. Between November 1984 and May 1988, we performed 40 consecutive LTxs in 32 patients. Twenty-four grafts were from donors after cardiac death (DCD) and 16 grafts from heart-beating donors (HBD). Significantly, more hepatic artery thrombosis and biliary complications occurred in the DCD group (p < 0.01 and p < 0.05, respectively). Graft and patient survival did not differ between the groups. In the total group, there was a significant difference in graft survival between first-time LTx grafts and grafts used for retransplantation. There was better graft survival in nonmalignant than malignant patients, although this did not reach statistical significance. Multivariate analysis revealed cold ischemia time and post-LTx peak ALT to be independent predictive factors for graft survival in the DCD group. In the 11 livers surviving 20 years or more, follow-up biopsies were performed 18-20 years post-LTx (n = 10) and 6 years post-LTx (n = 1). Signs of chronic rejection were seen in three cases, with no difference between DCD and HBD. Our analysis with a 20-year follow-up suggests that controlled DCD liver grafts might be a feasible option to increase the donor pool.

Similar lipid profile but improved long-term outcomes with sirolimus after cyclosporine withdrawal compared to sirolimus with continuous cyclosporine.

Renal transplant recipients show an increased risk of cardiovascular disease compared with a nontransplant population. Herein we have shown an analysis of a randomized controlled trial wherein 525 patients receiving a first or second (9.7%) renal allograft from a deceased (89.1%), a living-related (7.8%), or a living-unrelated donor (3.1%) received sirolimus (SRL), cyclosporine (CsA), and steroids (ST) at the time of transplantation with randomization at 3 months after transplantation of 430 eligible patients to continue on SRL-CsA-ST or to have CsA withdrawn with increased SRL trough targets (SRL-ST group). Graft survival, patient survival, and renal function at 5 years were analyzed by average fasting total cholesterol (200 mg/dL) and triglyceride (240 mg/dL) subgroups. At 5 years, total, high-density lipoprotein (HDL), and low-density lipoprotein [LDL] cholesterol and triglyceride values were similar between the groups. Statins ( approximately 80% of patients of both groups) were most effective to lower cholesterol ( approximately 50 mg/dL; P < .001; both groups), and fibrates ( approximately 25% of patients of both groups) were most effective to decrease triglycerides ( approximately 100 mg/dL; P < .001; both groups). Renal function and blood pressure were significantly better with SRL-ST. Hypercholesterolemia and hypertriglyceridemia were associated with reduced graft survival, patient survival, and calculated GFR, but the only significant difference was lower graft survival among SRL-CsA-ST patients with hypertriglyceridemia. Cardiovascular-related deaths were reported in 3.7% and 2.8% of patients in the SRL-CsA-ST and SRL-ST groups, respectively. In conclusion, when compared with continuous SRL-CsA-ST, CsA withdrawal at 3 months followed by SRL-ST significantly improved glomerular filtration rate (GFR) and blood pressure without a further increase in lipid parameters or an incidence of untoward effects from hyperlipidemia, despite a 2-fold higher SRL exposure.

Domino liver transplantation: risks and benefits.

Domino liver transplantation, wherein a patient who himself undergoes liver transplantation in turn donates his liver to another recipient, has been performed since the mid-1990 s. Although livers from a handful of metabolic disorders cured by liver transplantation have been used for domino transplantation, familial amyloidotic polyneuropathy (FAP) livers are by far the most common source. FAP is an inherited disorder never presenting its clinical manifestation before the age of 15. In many carriers, the genetic disorder never manifests during lifetime. Thus, only a proportion of patients with FAP develop disease symptoms, which has been the rationale for using such livers for other patients on the waiting list for liver transplantation. According to the Familial Amyloidotic Polyneuropathy World Transplant Registry (FAPWTR), only 2 out of more than 500 patients so far have developed symptoms after domino liver transplantation using an FAP liver. Domino recipients with nonmalignant indications for liver transplantation show excellent long-term survivals. With careful selection of recipients, the procedure helps to reduce the organ shortage and the time on the waiting list for patients with malignant disorders.

Liver transplantation for familial amyloidotic polyneuropathy (FAP): a single-center experience over 16 years.

Orthotopic liver transplantation (LTx) is currently the only available treatment that has been proven to halt the progress of familial amyloidotic polyneuropathy (FAP). The aim of this study was to assess mortality and symptomatic response to LTx for FAP. All 86 FAP patients transplanted at our hospital between April 1990 and November 2005 were included in the study. Five patients underwent retransplantation. The 1-, 3- and 5-year patient survival rates in patients transplanted during 1996-2005 were 94.6%, 92.3% and 92.3%, respectively, a significant difference from the rates of 76.7%, 66.7% and 66.7%, respectively, during 1990-1995 (p = 0.0003). Multivariate analysis revealed that the age at the time of LTx (>or=40 years), duration of the disease (>or=7 years) and modified body mass index (mBMI) (<600) were independent prognostic factors for patient survival. A halt in the progress of symptoms was noted in most patients, but only a minority experienced an improvement after LTx. To optimize the posttransplant prognosis, LTx should be performed in the early stages of the disease, and close post-LTx monitoring of heart function by echocardiography and of heart arrhythmia by Holter ECG is mandatory.

Changing donation pattern in central Sweden.

Since 1990, the Organisation for Organ donation in Central Sweden has registered the numbers of donations at the various hospitals in the area. During this period, a significant decrease in donation rate was observed in the large hospitals, while there was an increase in donation rate in the smaller hospitals. Taken together, the small hospitals are now at least as important as the large hospitals. Possible reasons for the observed change in donation pattern are discussed.

Adipocyte-derived hormones in heroin addicts: the influence of methadone maintenance treatment.

Heroin addiction markedly affects the nutritional and metabolic status and frequently leads to malnutrition. The aim of our study was to compare circulating concentration of adipose tissue-derived hormones leptin, adiponectin and resistin in 12 patients with heroin addiction before and after one-year methadone maintenance treatment with the group of 20 age- and body mass index-matched healthy subjects. Basal serum leptin and adiponectin levels in heroin addicts were significantly decreased (3.4+/-0.4 vs. 4.5+/-0.6 ng/ml and 18.9+/-3.3 vs. 33.9+/-3.1 ng/microl, respectively; p 0.05) while serum resistin concentrations were increased compared to healthy subjects (10.1+/-1.2 vs. 4.6+/-0.3 ng/ml; p 0.05). Moreover, positive correlation of serum leptin levels with body mass index was lost in the addicts in contrast to control group. One year of methadone maintenance treatment normalized serum leptin, but not serum adiponectin and resistin concentrations. In conclusion, circulating concentrations of leptin, adiponectin and resistin are markedly altered in patients with chronic heroin addiction. These alterations appear to be relatively independent of nutritional status and insulin sensitivity.

[Serum lipids in drug addicts]. / Sérové lipidy u drogove závislých osob.

UNLABELLED: The background and aim is to study profile of serum lipids in drug addicts using heroin. METHODS AND RESULTS: The study involved 107 drug addicts using heroin (83 men and 24 women). Mean age was 29.3 years (variation 20-47 years). Mean time of using heroin was 6.5 years. Serum lipids (total cholesterol, HDL-cholesterol, triacylglycerol) were measured using enzyme methods. LDL-cholesterol and Body Mass Index (BMI) were calculated. All parameters were significantly decreased (mean levels of total cholesterol 4.31, triacylglycerol 1.29, HDL-cholesterol 1.08 and LDL-cholesterol 2.70 mmol/l). Levels of HDL-cholesterol under 1.0 mmol/l were found in 32%. Statistical measurments were performed by t-test and results compared with control group. CONCLUSIONS: Levels of HDL-cholesterol lower than 1.0 mmol/l (32%) are of importance and patients must be further controlled.

[Serum leptin levels in patients with heroin addiction, the effect of one year of methadone substitution]. / Sérové koncentrace leptinu u osob závislých na heroinu, vliv rocní substituce metadonem.

BACKGROUND AND AIM: The aim of the study was to explore the influence of heroin addiction and one year methadone maintenance treatment respectively on serum leptin levels. METHODS AND RESULTS: 14 heroin addicted subjects (9 men and 5 women) with average age 27.1 years (variation 22-38 years) and 17 control healthy subjects were included into the study. Mean duration of heroin addiction was 9 years. The subjects were treated for one year with mean daily dose of 90 mg of methadone. Serum leptin levels were measured by enzymoimmunoassay, the rest of the biochemical parameters was measured by standard laboratory methods. Body Mass Index (BMI) was calculated by conventional method (kg/m2). Statistical analysis was performed using t test and paired t test. Serum leptin levels in heroin addicts (7.08 +/- 2.80 ng/ml) did not significantly differ from those of control group (6.10 +/- 1.23 ng/ml). One year of methadone maintenance treatment significantly increased serum leptin levels to 12.10 +/- 3.17 ng/ml vs control group (< 0.05). The same was true for BMI which increased significantly from basal 21.47 +/- 2.54 to 24.61 +/- 2.82 (< 0.05). CONCLUSIONS: Long term addiction to heroin did not change serum leptin levels as compared with control group. One year of methadone maintenance treatment significantly increased serum leptin levels as well as BMI values. We suggest that the increase in serum leptin levels could be explained by the restoration of hypopituitary-hypothalamo-adrenal and/or hypopituitary-hypothalamo-gonadal axis by methadone maintenance treatment. Alternatively, the improvement of nutritional status with subsequent decrease in the infectious complications may be involved.

The alterations of immunological reactivity in heroin addicts and their normalization in patients maintained on methadone.

Drug addiction influences many physiological functions including reactions of the immune system. The higher occurence of infectious and other diseases in drug addicts has been explained by the depression of immunity due to the harmful effects of the drug. To test this assumption, we tested the proliferative responsiveness and cytokine production of PBL from a group of heroin addicts (N = 19), patients maintained on methadone (N = 15) and healthy controls (N=15). The results show that Con A-induced proliferation of PBL from heroin addicts was even enhanced in comparison with PBL from the control group. Similarly, production of IL-2, IL-10 and IFNgamma was higher in the group of heroin addicts than in healthy controls. The enhanced proliferation of PBL or the increased production of cytokines observed in heroin addicts was partially or completely normalized in the group of patients maintained on methadone. A significantly higher production of IL-6 was found in both unstimulated and stimulated PBL from heroin addicts and patients maintained on methadone, when compared with PBL from healthy controls. The results thus showed enhanced proliferative activity and increased production of various cytokines in heroin addicts and partial or complete adjustment of these alterations in patients maintained on methadone.

[Comprehensive care of drug addiction during a 5-year period at the methadone center in Prague]. / Nekteré poznatky z komplexní péce o drogove závislé za 5 roku cinnosti metadonového centra ve VFN Praha.

Methadone maintenance program in General Faculty Hospital in Prague has been in operation for five years since August 1997. During this period a broad spectrum of complex care was supported to opioid drug addicts. Not only substitution of methadone or buprenorphine but also psychiatric, social and health care was guaranteed. The goal of this article is the information about our experience achieved during the five-year existence of the methadone maintenance program.

[Bone metabolism in individuals dependent on heroin and after methadone administration]. / Kostní metabolizmus u osob závislých na heroinu a po substituci metadonem.

BACKGROUND: The aim of the work was to determine how the prolonged opioid addiction influence bone metabolism. In heroin addicts and after one year of methadone maintenance we investigated bone mineral density, biochemical markers of bone metabolism and serum levels of testosterone. METHODS AND RESULTS: The study involved 37 persons, 31 men and 6 women in average age of 26 years (variation 18 to 39 years). Values of type I collagen cross-linked telopeptide, osteocalcin, propeptide of type I collagen and testosterone in serum were measured by radioimmunoassy and immunoanalysis. Bone mineral density was measured by dual energy absorptiometry. Body Mass Index was calculated. In heroin addicts at the femoral neck and in distal forearm osteopenia was found. After one year of methadone maintenance treatment the bone density remained unchanged. Concentrations of osteoresorption marker (type I collagen cross-linked telopeptide) and osteoformation markers (osteocalcin and propeptide of type I collagen) were in heroin addicts in comparison with control group significantly increased (averages 814 ng/l, 43.1 mu/l, 76.4 mu/l). Testosterone level in serum in addicted men was significantly decreased (3.3 nmol/l). After one year of methadone maintenance treatment biochemical markers of bone metabolism restored when compared with the control group, testosterone levels remained unchanged. Statistical measurements were performed by t-test and paired t-test. CONCLUSIONS: Prolonged heroin addiction is associated with accelerated bone turnover and osteopenia in cortical bone without evidence of metabolic bone disease. Methadone maintenance treatment restores altered bone turnover only. One possible explanation of high bone turnover in heroin addicts may be the influence of hypopituitary-hypothalamo-gonadal axis. However, it may not be the only mechanism involved.

[Prevalence of serological markers of viral hepatitis B and hepatitis C in drug-dependent individuals treated at the Drop Methadone Center in Prague]. / Prevalence sérologických markeru infekcí virem hepatitidy B a hepatitidy C u drogove závislých osob lécených v prazském metadonovém centru drop in o.p.s.

BACKGROUND: The survey of viral infections in the liver investigated by means of serological markers of hepatitis A, B and C in drug addicts on methadone maintenance treatment is important for the next procedures. The goal of this study was to assign profile of the viral liver infections in patients on the methadone maintenance treatment. In selected persons hepatological examination or treatment are urgent. METHODS AND RESULTS: In 154 patients, 127 men and 27 women (mean age 28.5 years, variation from 21 to 49 years) serological markers detecting hepatitis A, B and C were evaluated. CONCLUSIONS: In 72% of patients a contact with hepatitis B and/or hepatitis C was identified. 67.6% of patients represented a high-risk group and hepatological care or treatment was necessary. Only 7% were serologicaly completely negative in all tested parameters.

[Opioids and their immunomodulatory properties]. / Opiáty a jejich imunomodulacní vlastnosti.

Opiates have been recently used for suppression of the neuropathic pain or to relieve pain in patients with cancer diseases. However, opiates are also used by drug abusers to achieve feeling of euphoria. These drugs influence not only the nervous system but they can also modulate many other physiological functions including those of the immune system. Since opioid receptors have been found on the surface of cells of the immune system, two possible mechanisms of opiate actions have to be considered. The first one represents a direct action of the opiates through the opioid receptors on immune cells; the second mechanism is mediated by the nervous system. The immunomodulatory properties of the opiates have been demonstrated in numerous models. Especially the enhanced sensitivity to viral and bacterial infections, observed in drug abusers, is accounted to the side effects of opiates. Experimental animal models have shown even more complex actions of opiates, which can lead to suppression as well as to stimulation of individual immunological parameters. Although proliferation of lymphocytes tested in vitro after application of opiates in vivo is generally reduced, production of the pro-inflammatory cytokines and some functions of macrophages can be enhanced. Effects of opiate action depend on the experimental model used, the drug dose, way of drug application, time of testing and on the tested immunological parameter. This article summarizes recent knowledge of effects of opiates on the functions of cells of the immune system. It also refers global problems of exploitation of illegal drugs and the importance of methadone in the substitution treatment.

Sirolimus experience at a Swedish transplantation center.

Sirolimus is an interesting drug due to its original mechanism of action and because it seems to lack the nephrotoxicity associated with calcineurin inhibitors. During the past 10 years, sirolimus has undergone several clinical trials. Beginning with phase I studies, our first patient given sirolimus was enrolled in 1993, after which we participated in sirolimus phase II trials and finally conducted the large phase III study that led to registration of sirolimus in the European Union (EU) in 2001. Altogether, 111 patients have been treated with sirolimus in our department. Initially, we participated in clinical trials evaluating sirolimus in combination with cyclosporine, but later we focused on studies using sirolimus as base therapy. We found sirolimus to be an effective immunosuppressant lacking several of the disturbing side effects associated with calcineurin inhibitors. It has a high antirejection efficacy and yields excellent survival results, with better renal function than that achieved by calcineurin inhibitors. The main side effects, hyperlipidemia and leukothrombocytopenia, are usually easily manageable. Sirolimus presents an alternative to prophylactic immunosuppression with calcineurin inhibitors and, in the field of transplantation, it represents a welcome addition to the immunosuppressive armamentarium.

Augmented production of proinflammatory cytokines and accelerated allotransplantation reactions in heroin-treated mice.

Heroin treatment or abusive drug addiction influences many physiological functions, including the reactions of the immune system. Although suppression of various manifestations of the immune system after heroin (or morphine) administration has been reported, we show here that production of proinflammatory cytokines and nitric oxide (NO) was enhanced and allotransplantation reactions were accelerated significantly in heroin-treated recipients. Mice were treated by a subcutaneous administration of heroin (diacetylmorphine) given in one or repeated daily doses. The ability of spleen cells from treated mice to respond in vitro to alloantigens and to produce IL-2, IL-4, IL-10 and IFN-gamma, and the production of IL-1beta, IL-12 and NO by peritoneal macrophages, were tested. Within 2 h after heroin administration, proliferative responses to alloantigens and the production of IL-1beta, IFN-gamma, IL-12 and NO were enhanced significantly. In contrast, the production of anti-inflammatory cytokines IL-4 and IL-10 was at the same time rather decreased. As a consequence, skin allografts in heroin-treated mice were rejected more promptly than in untreated or vehicle-treated recipients. Similarly, the growth of allogeneic tumours induced by high doses of tumour cells was suppressed significantly in heroin-treated mice. The enhancing effects of heroin on the production of proinflammatory cytokines were antagonized by naltrexone, a specific inhibitor of classic opioid receptors. These results show that heroin treatment augments production of proinflammatory cytokines and accelerates allotransplantation reactions. The observations thus illustrate the complexity of the effects of heroin on the immune system and should be taken into account during medical treatment of opiate addicts and in the use of morphine to decrease pain in various clinical situations.

[Long-term follow-up of the health status of opiate abusers treated with methadone--pilot study]. / Pilotní studie k dlouhobému sledování zdravotního stavu abuzéru závislých na opiátech lécených metadonem.

BACKGROUND: Examination of the health status of patients abusing opiates can be substantiated by their high morbidity. The aim of the work was to describe the actual health status and the extent and seriousness of the affliction before the substitution therapy with opioid receptors agonist--methadone. METHODS AND RESULTS: The group of drug abusers consisted of 101 persons (average age was 28.5 years, within the range of 20 to 47 years, 77 men and 24 women). Among the pathological findings, values of the levels of hepatic enzymes ALT, AST (35 and 31%), GMT (9%), low haemoglobin levels (24%) and elevated values of IgM (38%) and CRP (25%) belonged to the most frequent ones. Because of the simultaneously positive tests for hepatitis (C and B, 70% and 61%), the alteration is fully obvious. Low testosterone levels in males (63%) indicate the dysfunction of the hypothalamus-hypophysis-gonadas axis. Increased values of thyroxin (14%), P (20%) and atherogenity index (19%) remain unexplained. Several other laboratory-biochemical parameters remained within the physiological range. Imaging methods revealed hepatomegaly in 28% and splenomegaly in 27%, echotexture indicating steatosis was found in 15% of studied persons. CONCLUSIONS: In chronic drug abusers before the onset of the substitution therapy, it is possible to expect frequent alterations, namely that of hepatic functions, positive test for hepatitis B and C, alteration of immunoglobulines level and testosterone deficits (in males).