Transplantation of Kidneys From Donors With Acute Kidney Injury: Friend or Foe?

The gap between supply and demand in kidney transplantation has led to increased use of marginal kidneys; however, kidneys with acute kidney injury are often declined/discarded. To determine whether this policy is justified, we analyzed outcomes of donor kidneys with acute kidney injury (AKI) in a large UK cohort. A retrospective analysis of the UK Transplant Registry evaluated deceased donors between 2003 and 2013. Donors were classified as no AKI, or AKI stage 1-3 according to Acute Kidney Injury Network (AKIN) criteria. Relationship of AKI with delayed graft function/primary nonfunction (DGF/PNF), estimated glomerular filtration rate (eGFR), and graft-survival at 90 days and 1 year was analyzed. There were 11 219 kidneys (1869 [17%] with AKI) included. Graft failure at 1 year is greater for donors with AKI than for those without (graft survival 89% vs. 91%, p = 0.02; odds ratio (OR) 1.20 [95% confidence interval (CI): 1.03-1.41]). DGF rates increase with donor AKI stage (p < 0.005), and PNF rates are significantly higher for AKIN stage 3 kidneys (9% vs. 4%, p = 0.04) Analysis of association between AKI and recipient eGFR suggests a risk of inferior eGFR with AKI versus no AKI (p < 0.005; OR 1.25 [95% CI: 1.08-1.31]). We report a small reduction in 1-year graft-survival of kidneys from donors with AKI. We conclude that AKI stage 1 or 2 kidneys should be used; however, caution is advised for AKI stage 3 donors.

Past, Present, and Future of Dynamic Kidney and Liver Preservation and Resuscitation.

The increased demand for organs has led to the increased usage of "higher risk" kidney and liver grafts. These grafts from donation after circulatory death or expanded criteria donors are more susceptible to preservation injury and have a higher risk of unfavorable outcomes. Dynamic, instead of static, preservation could allow for organ optimization, offering a platform for viability assessment, active organ repair and resuscitation. Ex situ machine perfusion and in situ regional perfusion in the donor are emerging as potential tools to preserve and resuscitate vulnerable grafts. Preclinical findings have ignited clinical organ preservation research that investigates dynamic preservation, its various modes (continuous, preimplantation) and temperatures (hypo-, sub, or normothermic). This review outlines the current status of dynamic preservation of kidney and liver grafts and describes ongoing research and emerging clinical trials.

Sonosensitive theranostic liposomes for preclinical in vivo MRI-guided visualization of doxorubicin release stimulated by pulsed low intensity non-focused ultrasound.

The main goal of this study was to assess the theranostic performance of a nanomedicine able to generate MRI contrast as a response to the release from liposomes of the antitumor drug Doxorubicin triggered by the local exposure to pulsed low intensity non focused ultrasounds (pLINFU). In vitro experiments showed that Gadoteridol was an excellent imaging agent for probing the release of Doxorubicin following pLINFU stimulation. On this basis, the theranostic system was investigated in vivo on a syngeneic murine model of TS/A breast cancer. MRI offered an excellent guidance for monitoring the pLINFU-stimulated release of the drug. Moreover, it provided: i) an in vivo proof of the effective release of the liposomal content, and ii) a confirmation of the therapeutic benefits of the overall protocol. Ex vivo fluorescence microscopy indicated that the good therapeutic outcome was originated from a better diffusion of the drug in the tumor following the pLINFU stimulus. Very interestingly, the broad diffusion of the drug in the tumor stroma appeared to be mediated by the presence of the liposomes themselves. The results of this study highlighted either the great potential of US-based stimuli to safely trigger the release of a drug from its nanocarrier or the associated significant therapeutic improvement. Finally, MRI demonstrated to be a valuable technique to support chemotherapy and monitoring the outcome. Furthermore, in this specific case, the theranostic agent developed has a high clinical translatability because the MRI agent utilized is already approved for human use.

Quantitative assessment of cancer vascular architecture by skeletonization of high-resolution 3-D contrast-enhanced ultrasound images: role of liposomes and microbubbles.

The accurate characterization and description of the vascular network of a cancer lesion is of paramount importance in clinical practice and cancer research in order to improve diagnostic accuracy or to assess the effectiveness of a treatment. The aim of this study was to show the effectiveness of liposomes as an ultrasound contrast agent to describe the 3-D vascular architecture of a tumor. Eight C57BL/6 mice grafted with syngeneic B16-F10 murine melanoma cells were injected with a bolus of 1,2-Distearoyl-sn-glycero-3-phosphocoline (DSPC)-based non-targeted liposomes and with a bolus of microbubbles. 3-D contrast-enhanced images of the tumor lesions were acquired in three conditions: pre-contrast, after the injection of microbubbles, and after the injection of liposomes. By using a previously developed reconstruction and characterization image processing technique, we obtained the 3-D representation of the vascular architecture in these three conditions. Six descriptive parameters of these networks were also computed: the number of vascular trees (NT), the vascular density (VD), the number of branches, the 2-D curvature measure, the number of vascular flexes of the vessels, and the 3-D curvature. Results showed that all the vascular descriptors obtained by liposome-based images were statistically equal to those obtained by using microbubbles, except the VD which was found to be lower for liposome images. All the six descriptors computed in pre-contrast conditions had values that were statistically lower than those computed in presence of contrast, both for liposomes and microbubbles. Liposomes have already been used in cancer therapy for the selective ultrasound-mediated delivery of drugs. This work demonstrated their effectiveness also as vascular diagnostic contrast agents, therefore proving that liposomes can be used as efficient "theranostic" (i.e. therapeutic 1 diagnostic) ultrasound probes.

Long-term noninvasive mechanical ventilation for children at home: a national survey.

Experience with domiciliary noninvasive mechanical ventilation (NIMV) in children is limited. The aim of this study was to determine the number of patients and categorize the use of domiciliary NIMV in children in France. An anonymous cross-sectional national study was performed, using a postal questionnaire sent to all specialist centers utilizing domiciliary NIMV for chronic respiratory failure. Patients aged <18 years and receiving home NIMV were included in the study. Detailed information was obtained from 102 patients from 15 centers: 4/15 centers cared for 84% of patients; 7% of patients were under 3 years old; 35% were between 4-11 years old; and 58% were older than 12 years. Underlying diagnoses included neuromuscular disease (34%), obstructive sleep apnea (OSA) and/or cranio-facial abnormalities (30%), cystic fibrosis (17%), congenital hypoventilation (9%), scoliosis (8%), and other disorders (2%). NIMV was started because of nocturnal hypoventilation (67%), acute exacerbation (28%), and/or failure to thrive (21%). Volume-targeted ventilation was preferred in restrictive disorders (56%) and central hypoventilation (56%), while pressure support ventilation (PSV) was preferred in cystic fibrosis (71%). Patients with OSA and/or cranio-facial abnormalities were ventilated with continuous positive airway pressure (45%) or bilevel PSV (52%). In conclusion, NIMV is currently used in France for the domiciliary management of children with a variety of conditions causing chronic respiratory failure. However, NIMV in children is still performed on a small scale, and combined with the heterogeneity of the patient population, its application would best be served by centers specializing in the initiation and long-term follow-up of these patients.

[Chronic respiratory insufficiency in France]. / L'insuffisance respiratoire chronique en France.

The data concerning the prevalence of chronic respiratory insufficiency (CRI) in France are scarce: in 1994 official numbers were 14,000 deaths due to chronic bronchitis, 2,000 due to asthma for a total number of 40,000 deaths with respiratory cause; the same year 27,000 new patients were compensated for chronic respiratory insufficiency by social security services. On January 1st 2000 the non-profit organizations was in charge of 21,500 patients with long term oxygen therapy and 10,500 with home ventilation, and the commercial companies respectively 30,000 and 6,000. Accordingly the total of patients treated at home for CRI is about 68,000. The repartition by cause of CRI, the characteristics of patients and the prognosis can be evaluated thanks to the ANTADIR observatory which collects medical data since 1981. Chronic obstructive pulmonary diseases (chronic bronchitis, emphysema, asthma, bronchiectasis) count for more than half of the total of cases. Other causes comprise pleuro-parietal diseases (tuberculosis sequelae, kyphoscoliosis), neuro-muscular diseases and interstitial lung diseases. CRI is a severe disease with a survival median of three years for chronic obstructive pulmonary diseases, and a prognosis slightly better for kyphoscoliosis and neuro-muscular diseases, and worse for pulmonary fibrosis.

Treatment with biosynthetic growth hormone of short thalassaemic patients with impaired growth hormone secretion.

OBJECTIVE: Impairment of linear growth is a common clinical feature in patients with beta-thalassaemia major. Although growth hormone secretion appears to be normal in many short thalassaemic patients, it proves to be deficient in some of them. In these cases, administration of biosynthetic growth hormone seems justified. The aim of this study was to evaluate the effect of such treatment in a group of patients with beta-thalassaemia major presenting with growth failure and impairment of growth hormone secretion. DESIGN: Recombinant human growth hormone, 0.6 U/kg body weight per week, given subcutaneously in three divided doses, was administered for 12 months. PATIENTS: Eight prepubertal patients with beta-thalassaemia major, presenting with severe growth retardation and impaired growth hormone secretion in response to provocative stimuli (insulin-induced hypoglycaemia, L-dopa and growth hormone-releasing hormone), were investigated. MEASUREMENTS: Height and pubertal stage of the patients, as well as plasma levels of insulin-like growth factor I, were determined before, during and after biosynthetic growth hormone treatment. RESULTS: During the first 6 months of therapy, a significant increase of growth velocity was observed, from a mean pretreatment value of 2.1 +/- 0.45 cm/year to a value of 4.8 +/- 0.66 cm/year (P less than 0.002). Mean growth rate at 12 months (4.1 +/- 0.50 cm/year), though slightly decreased in comparison to that recorded at 6 months, was still significantly higher than basal (P less than 0.001). A significant increase in plasma levels of insulin-like growth factor I was recorded during treatment (2.82 +/- 0.47 vs 0.96 +/- 0.22 U/ml, P less than 0.005). No side-effects, adverse reactions or alterations in routine laboratory examinations ensued during or after therapy. CONCLUSIONS: It appears from these data that biosynthetic growth hormone administration is worth serious consideration in patients with beta-thalassaemia major presenting growth retardation and impaired growth hormone secretion.

[Audiologic evaluation of patients with thalassemic syndromes treated with desferrioxamine B]. / Valutazione audiologica in pazienti affetti da sindromi talassemiche trattati con desferossamina B.

Following various articles in literature which have appeared in the last 3 years regarding the neurotoxicity of desferrioxamine B we studied, from the auditory functionality point of view, 95 patients affected with transfusion-dependent thalassemic syndromes, under regular chelation treatment with desferrioxamine B. Our results lead us to conclude that at standard doses, between 40 and 60 mg/Kg/day, desferrioxamine B does not demonstrate a neurotoxicity enough to cause an organic deficit in the auditory sphere, while maintaining therapeutic efficacy.

Insulin dependent diabetes in thalassaemia.

Diabetes mellitus was observed in 29 of 448 patients with thalassaemia major attending seven Italian centres. Twelve patients, at onset of clinical diabetes, presented with an asymptomatic glycosuria, 13 with ketosis, and four with ketoacidosis. All were diagnosed after 1979, at a mean age of 17 years. Mean age at diagnosis of diabetes was lower in patients born in the last two decades. In these patients transfusions were started at a younger age and pre-transfusion haemoglobin concentration, serum ferritin concentration, incidence of liver disease, and the presence of a family history of diabetes were higher than in patients born previously. Although 27 (93%) cases had iron chelating treatment the mean serum ferritin concentration was 5600 micrograms/l; 25 (92%) of these patients had signs of liver impairment. The determination of C peptide in 10 patients showed a wide variation in pancreatic beta cell function, and insulin requirements ranged between 0.15 and 1.72 U/kg body weight. Metabolic control was generally poor. The onset of diabetes mellitus was followed in most patients by the appearance of other endocrine or cardiac complications, or both. Fourteen patients died within three years of presenting with overt diabetes. Haemosiderosis, liver infections, and genetic factors seemed to be crucial in diabetes development. Thalassaemic patients developing clinical diabetes mellitus are at high risk for other complications and should be strictly monitored, especially for thyroid impairment.

[Preliminary data on the endocrinologic evaluation of thalassemic adolescents]. / Dati preliminari sulla valutazione endocrinologica di adolescenti talassemici.

Endocrine disfunction are well known in young patients with thalassaemia major and are mainly due to iron overload. Gonadotrophin releasing hormone (GnRH) was administered to 13 boys aging more than 14 years and to 13 girls aging more than 13 years to assess pituitary function. Human Chorionic gonadotrophin (HCG) was also administered to 13 boys to evaluate their gonadal function. Most of the patients had evidence of pituitary hypofunction and in 4 boys there was evidence of gonadic failure. This study is mandatory for a correct therapeutic approach.

[Critical evaluation of the causes of death in thalassemic subjects]. / Valutazione critica delle cause di morte nei soggetti talassemici.

We discuss 25 cases of death observed from 1971 to 1983 in a casistic of 155 patients with Thalassaemic Syndrome. Anemia as a cause of death is disappearing, new triggers are involved such as Yersinia Enterocolitica who can cause severe sepsis even in non-splenectomized patients. Iron overload appears to be the most severe complication in the second decade.

[Clinico-therapeutic findings on diabetic complications in thalassemia]. / Considerazioni clinico-terapeutiche sulla complicanza diabetica nella talassemia.

We describe 6 patients with thalassaemia major who developed diabetes. Etiopathogenesis, poor metabolic control, previous transfusion and chelation regimens are discussed. Antiaggregant therapy with A.S.A. and Dipiridamole may play a role in these patients for preventing thrombotic risk.

[Intrapulmonary deposition of submicron-size particles]. / Deposizione intrapolmonare delle particelle submicroniche.

Inhalation studies of ultrafine aerosol particles are described. Chambers with controlled atmospheres have been built, in which known volumes of clear air and aerosol particles are introduced. By means of an electrical mobility analyzer the size distribution of the aerosol in the chamber determined down to a mean diameter of 0,01 micron. Such aerosol is inhaled by the subject and exhaled into an identical chamber, previously filled with clean air. The size distribution of the resulting aerosol is determined with the same measuring system. The particle number distributions of inhaled and exhaled particles are then suitably correlated and compared. In this paper data are reported based on the retention of cigarette smoke referred to male subjects in the age group from 24 to 44 years old. These results are compared with the experimental data which appeared most recently in the medical literature. A standardization is proposed of the experimental conditions for measurements of intrapulmonary deposition of inhaled particles. This is because of the importance that the results of such studies might have in the field of prevention and industrial hygiene, in particular in the nuclear field.