Characterization of the long-term effects of lethal total body irradiation followed by bone marrow transplantation on the brain of C57BL/6 mice.

PURPOSE: Total body irradiation (TBI) followed by bone marrow transplantation (BMT) is used in pre-clinical research to generate mouse chimeras that allow to study the function of a protein specifically on immune cells. Adverse consequences of irradiation on the juvenile body and brain are well described and include general fatigue, neuroinflammation, neurodegeneration and cognitive impairment. Yet, the long-term consequences of TBI/BMT performed on healthy adult mice have been poorly investigated. MATERIAL AND METHODS: We developed a robust protocol to achieve near complete bone marrow replacement in mice using 2x550cGy TBI and evaluated the impact of the procedure on their general health, mood disturbances, memory, brain atrophy, neurogenesis, neuroinflammation and blood-brain barrier (BBB) permeability 2 and/or 16 months post-BMT. RESULTS: We found a persistent decrease in weight along with long-term impact on locomotion after TBI and BMT. Although the TBI/BMT procedure did not lead to anxiety- or depressive-like behavior 2- or 16-months post-BMT, long-term spatial memory of the irradiated mice was impaired. We also observed radiation-induced impaired neurogenesis and cortical microglia activation 2 months post-BMT. Moreover, higher levels of hippocampal IgG in aged BMT mice suggest an enhanced age-related increase in BBB permeability that could potentially contribute to the observed memory deficit. CONCLUSIONS: Overall health of the mice did not seem to be majorly impacted by TBI followed by BMT during adulthood. Yet, TBI-induced alterations in the brain and behavior could lead to erroneous conclusions on the function of a protein on immune cells when comparing mouse chimeras with different genetic backgrounds that might display altered susceptibility to radiation-induced damage. Ultimately, the BMT model we here present could also be used to study the related long-term consequences of TBI and BMT seen in patients.

Fourteen years of experience in uncontrolled organ donation after cardio-circulatory death.

BACKGROUND: Since 1999, a protocol for uncontrolled donation after cardio-circulatory death (DCD) has been carried out in our institution. We aimed at evaluating those 14 years of local experience. METHODS: We reviewed the charts of uncontrolled donors from 1999 till 2013. Potential donors with a no-flow period less than 30 minutes were considered. Kidneys were perfused by the use of a double balloon triple lumen catheter after at least a 2-minute period of no touch. We analyzed grafts outcome and warm and cold ischemia times. RESULTS: Thirty-nine procedures were initiated: 19 were aborted because of family refusal (n = 7), medical reasons (n = 7), or canulation failures (n = 5) and 20 harvesting procedures were completed. Transplantation was considered for 35 kidneys (cold storage [n = 5] and hypothermic preservation system [n = 30]). The causes of withdrawal from transplantation were mostly macroscopic lesions (poor perfusion, macroscopic parenchyma or vascular lesions, or infectious risk). We transplanted 22 kidneys locally and 3 were shipped to another Eurotransplant center. Mean donor age was 40 ± 13 years. Among the 20 donors, 13 came from the emergency unit and 7 from the intensive care unit. Mean no-flow time for out-hospital management was 8.7 ± 3.6 minutes. Mean time of cardiopulmonary resuscitation was 71 ± 46 minutes. Mean cold ischemia time was 19 ± 5 hours. Primary nonfunction and delayed graft function occurred in 1 and 12 cases (4.5% and 54%), respectively. Graft survival was 86% at 1 year. Causes of graft loss during the entire follow-up were graft rejection (n = 3), ischemically damaged kidney (n = 2), and recurrence of focal segmental glomerulosclerosis (n = 1). CONCLUSION: In our experience, uncontrolled donors represent a valuable source of kidney grafts, with a prognosis of graft function and survival similar to the literature. To increase the number of available DCD organs, new techniques, such as the use of Normothermic ExtraCorporeal Membrane Oxygenation (NECMO), as well as improvement of recruitment of out of hospital potential donors have to be considered.

[Pediatric nephrology from the fetal kidney to the kidney graft]. / La néphrologie pédiatrique du rein foetal au rein greffé.

The department of pediatric uro-nephrology was created in 1977 in Brugmann hospital. Since then, various sectors have been developed including: hemodialysis and peritoneal dialysis, kidney transplantation, urological and genital surgery, antenatal screening and rapid management of uronephropathies, treatment of voiding dysfunction and neurogenic bladder, management of tubular and glomerular diseases. The progress in genetics, medical imaging, obstetrics, neonatology and surgery has allowed us to take care of our young patients within a multidisciplinary framework. The most original contributions of the department are related to the performance of combined liver-kidney transplantation in primary hyperoxaluria, to the determination of the natural history of several congenital anomalies of the kidney and urinary tract, to the assessment of the role of genetic mutations on tubular and glomerular diseases, to the usefulness of radioisotopic tracers in the measurement of renal function in infants, and to the study of experimental tolerance of allografts. The transition of young renal patients from pediatric to adult care is actually well organized due to our 30 years experience and the excellent collaboration with the adult nephrologists.

What is the limiting factor for organ procurement in Belgium: donation or detection ? What can be done to improve organ procurement rates?

In trying to overcome the growing gap between demand and offer of organs for transplantation, solutions are usually searched for by comparing successful and unsuccessful models in different countries. In particular, one element in the more successful countries such as for instance presumed consent, or one element in the less successful countries such as for instance refusal by relatives, are seen as possible reasons for these differences. This article tackles the problem of organ donor shortage through a new multi-level approach. Organ donation can indeed be analyzed on three different levels: the macro-level, the meso-level and the micro-level. The macro-level refers to the governmental structure where legislation, policies and funding are three essential elements necessary to make donation possible. The meso-level refers to the health care organization and the professionals who surround the process of organ donation and transplantation. Facilitating this process through standardized protocols and improving detection of organ donors are the two major elements. The micro-level refers to the individual believes and personal attitudes towards organ donation. This new multi-level approach gives a thorough and complete analysis of problems and allows to propose potential solutions to try to overcome the chronic organ shortage.

Abdominal Transplant Surgery and Transplant Coordination University Hospitals Leuven 1997-2007: an overview.

The transplant surgery and transplant coordination department was created in 1997 to meet up with the demand of the growing abdominal transplant surgery and organ procurement activity at the University Hospitals in Leuven. Since then, the procurement activity has increased and is currently distributed within the University Hospital Gasthuisberg and a network of approximately 25 collaborative hospitals. The profile of the donors has changed with older donors and more co-morbidity factors (obesity, hypertension, etc.). This donor activity represents approximately 30% of the national donor pool. Over the last 10 years, more than 1100 kidneys, more than 500 livers, approximately 50 pancreas, and 5 intestines have been transplanted in both adults and children. One year survival equal to- or exceeding 90% has been achieved for all abdominal organs and this compares favorably with international registries. More than 40 multi-visceral transplants {liver in combination with abdominal (kidney, pancreas, intestine) or thoracic (heart, double lung, heart-lung) organs} have been performed with results equivalent to isolated liver transplants and very little immunological graft loss (probably due to the immunoprotective effect of the liver). A live donation program was started for the kidney (40 cases) and for the liver (10 cases) in adults and children and no surgical graft loss has been seen so far. Introduction of new machine perfusion systems (and development of donor protocols) has made it possible to restart a non-heart-beating donor program for kidney transplantation. Experimental demonstration that livers tolerate short periods of warm ischemia has also allowed to start liver transplantation from non-heart-beating donors. In the future, machine perfusion of livers, viability testing, and biological modulation are likely to widen the use of marginal livers for transplantation and improve the results. An immunomodulatory protocol proven in the lab to induce the development of regulatory T cells has been applied clinically to 5 consecutive intestinal transplants. All 5--at the time of writing--have been rejection-free and have achieved nutritional independence. Continuous research and development is warranted to increase the organ donor pool (currently the solely limiting factor of transplantation) and to optimize long-term graft and patient outcome.

Donor categories: heart-beating, non-heart-beating and living donors; evolution within the last 10 years in UZ Leuven and Collaborative Donor Hospitals.

Over the past 10 years, the University Hospitals Leuven and their group of Collaborative Donor Hospitals (approximately 20) have tried to maximize their contribution to the national and Eurotransplant donor pool. In this time period, 1042 potential donors and 703 effective donors were coordinated and their organs allocated through Eurotransplant. This activity represented approximately 30% of the national donor pool and approximately 32% of the national organ pool. For Belgium, the non-heart-beating donor activity represented 11.38% of all donors in 2006. Since 1997, 167 potential live donors have been screened in our center. Of these, 48 transplants (28.74%) (39 kidneys--9 livers) have been performed. A boost of screened candidates was seen over the last 3 years, with a 500% increase of records being evaluated. Although the Belgian live donation activity remains one of the lowest in the world, there has been a clear increase over the last 3 years with about 10% of all kidney transplant activity originating now from live donors.

[The medico-surgical department of uro-nephrology, dialysis and renal transplantation in the Children's Hospital of Brussels]. / Le département médico-chirurgical d'uro-néphrologie, dialyse et transplantation rénale à l'HUDERF.

The department of pediatric uro-nephrology was created in 1977 in Brugmann hospital. Since then, various sectors have been developed including: hemodialysis and peritoneal dialysis, kidney transplantation, urological and genital surgery, antenatal screening and rapid management of uronephropathies, treatment of voiding dysfunction and neurogenic bladder, management of tubular and glomerular diseases. The progress in genetics, medical imaging, obstetrics, neonatology and surgery has allowed us to take care of our young patients within a multidisciplinary framework. The most original contributions of the department are related to the performance of combined liver-kidney transplantation in primary hyperoxaluria, to the determination of the natural history of several congenital anomalies of the kidney and urinary tract, to the assessment of the role of genetical mutations on tubular and glomerular diseases, to the usefulness of radioisotopic tracers in the measurement of renal function in infants, and to the study of experimental tolerization of

Sclerosing peritonitis: report of three cases.

Sclerosing peritonitis is a dramatic complication of continuous ambulatory peritoneal dialysis and chronic peritoneal inflammation. Both visceral and parietal surfaces of the peritoneal cavity are involved. A thickened peritoneum encloses the small intestine in a "cocoon" formation which often leads to intestinal occlusion. CT scan may help obtaining an early diagnosis but diagnosis is often established with some delay or even at the time of laparotomy. Our report describes three cases of this uncommon peritoneal fibrosis syndrome which caused intestinal obstruction requiring surgical intervention.

[The medico-surgical department of nephrology dialysis and renal transplantation]. / Le département médico-chirurgical de Néphrologie Dialyse et Transplantation Rénale.

The Department of Nephrology of the Hospital Erasme, opened 25 years ago, is now performing, each year, 22,000 hemodialysis sessions, 800 patient-weeks of peritoneal dialysis treatment and 70 renal grafts. Scientific contributions of the department deal with vascular access for hemodialysis, susceptibility to infections of dialyzed patients, parathyroid surgery, biocompatibility of dialysis membranes, predictive factors of renal graft survival, immunosuppression with monoclonal antibodies, experimental studies of graft tolerance and rejection, toxic nephropathies. The most original contributions are related to anaphylactoïd reactions in hemodialysis by association of acrylonitrile membranes with inhibition of the converting enzyme, to advantages and side effects of OKT3 monoclonal antibody and to discovery and study of the Chinese herbs nephropathy.

Persistent hyperparathyroidism requiring surgical treatment after kidney transplantation.

There are not many publications describing long-term follow-up of persistent hyperparathyroidism requiring surgical treatment after kidney transplantation (PHSKT). In some patients adenomas, rather than multiglandular disease, have been incriminated as the cause of PHSKT. We reviewed the charts of 45 patients followed for 12 to 146 months (median 45 months) after parathyroidectomy for PHSKT. We compared them with (1) those of 951 patients receiving a kidney graft during the same period but not submitted to parathyroidectomy or (2) 90 matched controls selected from this cohort to determine the characteristics of PHSKT patients. The duration of pretransplant dialysis was significantly longer in PHSKT patients than in controls (5.78 +/- 0.41 vs. 3.41 +/- 0.24 years; p < 0.0001). A total of 166 glands were removed or biopsied. Except for one questionable case, no true adenoma was observed even when only one gland was enlarged. The outcome of surgery was not influenced by the technique (subtotal parathyroidectomy versus total parathyroidectomy and autografting) but depended on the amount of resected parathyroid tissue: no failures and 4 cases of hypoparathyroidism in 34 cases with no missing gland at cervical exploration; 3 failures and no permanent hypoparathyroidism in 11 cases with one or two missing glands. Excision of the enlarged glands only was sufficient to cure the patient. No recurrence was observed. Our results suggest that single gland enlargement in PHSKT results in most cases from different rates of involution of the parathyroids after successful kidney transplantation. When fewer than four glands are discovered, resection of all visible glands with or without grafting corrects hypercalcemia in more than 70% of the cases.

Urothelial carcinoma associated with the use of a Chinese herb (Aristolochia fangchi)

BACKGROUND: Chinese-herb nephropathy is a progressive form of renal fibrosis that develops in some patients who take weight-reducing pills containing Chinese herbs. Because of a manufacturing error, one of the herbs in these pills (Stephania tetrandra) was inadvertently replaced by Aristolochia fangchi, which is nephrotoxic and carcinogenic. METHODS: The diagnosis of a neoplastic lesion in the native urinary tract of a renal-transplant recipient who had Chinese-herb nephropathy prompted us to propose regular cystoscopic examinations and the prophylactic removal of the native kidneys and ureters in all our patients with end-stage Chinese-herb nephropathy who were being treated with either transplantation or dialysis. Surgical specimens were examined histologically and analyzed for the presence of DNA adducts formed by aristolochic acid. All prescriptions written for Chinese-herb weight-reducing compounds during the period of exposure (1990 to 1992) in these patients were obtained, and the cumulative doses were calculated. RESULTS: Among 39 patients who agreed to undergo prophylactic surgery, there were 18 cases of urothelial carcinoma (prevalence, 46 percent; 95 percent confidence interval, 29 to 62 percent): 17 cases of carcinoma of the ureter, renal pelvis, or both and 1 papillary bladder tumor. Nineteen of the remaining patients had mild-to-moderate urothelial dysplasia, and two had normal urothelium. All tissue samples analyzed contained aristolochic acid-related DNA adducts. The cumulative dose of aristolochia was a significant risk factor for urothelial carcinoma, with total doses of more than 200 g associated with a higher risk of urothelial carcinoma. CONCLUSIONS: The prevalence of urothelial carcinoma among patients with end-stage Chinese-herb nephropathy (caused by aristolochia species) is a high.

Long-term results of subcutaneous parathyroid grafts in uremic patients.

HYPOTHESIS: Parathyroid glands are normally surrounded (entirely or partially) by fatty tissue. Subcutaneous parathyroid grafts are thus located in a normal environment. Therefore, we postulated that the late results of subcutaneous implantation of parathyroid tissue in uremic patients should be at least as good as those reported for intramuscular grafting. We also challenged the idea that the recurrence rate of renal hyperparathyroidism after surgery depended solely on the type of hyperplasia (diffuse vs nodular) observed in the implanted tissue. DESIGN: A retrospective study of a series of patients without loss to follow-up. SETTING: A university hospital and 9 affiliated dialysis units. PATIENTS AND INTERVENTIONS: Fifty-nine patients (33 women and 26 men) operated on for renal hyperparathyroidism underwent the resection of at least 4 parathyroid glands followed by presternal subcutaneous implantation of parathyroid tissue. They were followed up for 12 to 130 months (median, 38 months). MAIN OUTCOME MEASURES: Failure of treatment, recurrence of disease, and hypoparathyroidism. RESULTS: During the study period, 9 patients had to undergo another operation: 2 (3%) for persistent hyperparathyroidism due to a fifth ectopic gland and 7 (12%) for recurrence of hyperparathyroidism resulting from hypertrophy of the subcutaneous grafts. Four patients received a kidney transplant. The prevalence of hypoparathyroidism (intact parathyroid hormone serum level <1.6 pmol/L with a normal or low serum calcium concentration) was 14% (8 of 59 patients), and the curve representing the distribution of intact parathyroid hormone serum concentrations among operated on patients was shifted to the left when compared with the curve of patients who underwent hemodialysis and who had no indication for parathyroid surgery. In this latter group, the peak of the curve was situated between 1 and 2 times the upper normal limit, while it was in the normal range 12 to 130 months after total parathyroidectomy and subcutaneous parathyroid autotransplantation. No relation was observed between the recurrence rate of the disease and the histological characteristics of the parathyroid grafts. Also, their function was not influenced by the presence or absence of aluminum deposits in bone biopsy specimens that were obtained at the time of cervical exploration. CONCLUSIONS: The late results of total parathyroidectomy and presternal subcutaneous grafting compare favorably with the published data on other surgical techniques proposed for the treatment of renal hyperparathyroidism. The ease with which the hypertrophied grafts are removed when the disease recurs warrants further use of this procedure.

[What degree of freedom is there for living donors?]. / Quel degré de liberté y a-t-il pour un donneur vivant?

The shortage of cadaveric donors has induced a renewed interest in living kidney donation. This paper describes the legal, religious and ethical factors which ensure or restrict the autonomy of the potential donor. We conclude that it is possible with appropriate measures to protect his freedom of choice.

Male recipients of kidneys from female donors are at increased risk of graft loss from both rejection and technical failure.

The aim of the present retrospective study was to uncover the factor(s) responsible for the poor outcome of cadaver kidney grafts from female donors in male recipients. The 741 transplantations performed at our center from August 1983 to September 1997 were distributed into four groups according to recipient and donor gender: female donor to female recipient (F to F: n = 117), male donor to female recipient (M to F: n = 172), female donor to male recipient (F to M: n = 170), and male donor to male recipient (M to M: n = 282). All the patients received immunosuppressive therapy based on corticosteroids and cyclosporine, associated or not with either azathioprine or prophylactic anti-lymphocyte globulin. Overall graft survival was lower in the F to M group than in the three other groups (p = 0.009). Failures due to rejection were more frequent during the 1st post-transplant trimester in female than in male donor grafts, irrespective of recipient gender (p = 0.025). All failures due to technical problems occurred during the first 3 months post-transplantation: they were more frequent in the F to M group than in the three other groups (p = 0.040): this could be related to the older age of the donors in the former group. After the first post-transplant year, failures due to causes other than rejection remained low in the F to F group but increased steadily in the three other groups (p = 0.007). Specific survival rates were not correlated with the time-evolution of mean serum creatinine values, daily doses and trough levels of cyclosporine in the four groups of grafts. In conclusion, the poor outcome of F to M grafts results from combined immunologic and technical factors exerting their effects early in the course of transplantation.

Experience with the Wujciak-Opelz allocation system in a single center: an increase in HLA-DR mismatching and in early occurring acute rejection episodes.

The present single-center, retrospective study was undertaken to assess the impact of the Wujciak-Opelz allocation system (XCOMB), currently used within Eurotransplant for renal allografts, on the incidence of early occurring rejection episodes (RE). Implementation of the system resulted in an increase of HLA-DR mismatches (MM), while the incidence of HLA-A + B + DR MM remained unchanged. During the 1st post-transplant month, the total number of RE, expressed per patient-months, increased by 64% (0.326 vs 0.199, P = 0.007); when considering only severe and irreversible RE, the increase was 76% (0.158 vs 0.090, P = 0.011). In contrast, from the 2nd to the 12th post-transplant month, the incidence of RE, regardless of severity, was similar before and after implementation of XCOMB. As early occurring RE have detrimental effects on long-term graft outcome, these observations, if confirmed on a larger scale, would justify changes in the allocation algorithm.