Masking the Bioactivity of Hydroxamic Acids by Coordination to Cobalt: Towards Bioreductive Anticancer Agents.

The clinical use of many potent anticancer agents is limited by their non-selective toxicity to healthy tissue. One of these examples is vorinostat (SAHA), a pan histone deacetylase inhibitor, which shows high cytotoxicity with limited discrimination for cancerous over healthy cells. In an attempt to improve tumor selectivity, we exploited the properties of cobalt(III) as a redox-active metal center through stabilization with cyclen and cyclam tetraazamacrocycles, masking the anticancer activity of SAHA and other hydroxamic acid derivatives to allow for the complex to reach the hypoxic microenvironment of the tumor. Biological assays demonstrated the desired low in vitro anticancer activity of the complexes, suggesting effective masking of the activity of SAHA. Once in the tumor, the bioactive moiety may be released through the reduction of the CoIII center. Investigations revealed high long-term stability of the complexes, with cyclic voltammetry and chemical reduction experiments supporting the design hypothesis of SAHA release through the reduction of the CoIII prodrug. The results highlight the potential for further developing this complex class as novel anticancer agents by masking the high cytotoxicity of a given drug, however, the cellular uptake needs to be improved.

Kidney transplantation in people living with human immunodeficiency virus: An overview of the Australian experience.

Kidney transplantation in people living with HIV (PLWHIV) is occurring with increasing frequency. Limited international data suggest comparable patient and graft survival in kidney transplant recipients with and without HIV. All PLWHIV aged ≥18 years who received a kidney transplant between 2000 and 2020 were identified by retrospective data initially extracted from Australia and New Zealand Dialysis and Transplant Registry (ANZDATA), with additional HIV-specific clinical data extracted from linked local health-care records. Twenty-five PLWHIV and kidney failure received their first kidney transplant in Australia between January 2000 and December 2020. Majority were male (85%), with median age 54 years (interquartile range, IQR 43-57). Focal segmental glomerulosclerosis was the most common primary kidney disease (20%), followed by polycystic kidney disease (16%). 80% of patients underwent induction with basiliximab and none with anti-thymocyte globulin (ATG). Participants were followed for median time of 3.5 years (IQR 2.0-6.5). Acute rejection occurred in 24% of patients. Two patients lost their allografts and three died. Virological escape occurred in 28% of patients, with a maximum viral load of 190 copies/mL. In conclusion, kidney transplantation in PLWHIV in Australia is occurring with increasing frequency. Acute rejection is more common than in Australia's general transplant population, but this does not appear to be associated with higher rates of graft failure or mortality out to four years.

Balanced crystalloid solution versus saline in deceased donor kidney transplantation (BEST-Fluids): a pragmatic, double-blind, randomised, controlled trial.

BACKGROUND: Delayed graft function (DGF) is a major adverse complication of deceased donor kidney transplantation. Intravenous fluids are routinely given to patients receiving a transplant to maintain intravascular volume and optimise graft function. Saline (0·9% sodium chloride) is widely used but might increase the risk of DGF due to its high chloride content. We aimed to test our hypothesis that using a balanced low-chloride crystalloid solution (Plasma-Lyte 148) instead of saline would reduce the incidence of DGF. METHODS: BEST-Fluids was a pragmatic, registry-embedded, multicentre, double-blind, randomised, controlled trial at 16 hospitals in Australia and New Zealand. Adults and children of any age receiving a deceased donor kidney transplant were eligible; those receiving a multi-organ transplant or weighing less than 20 kg were excluded. Participants were randomly assigned (1:1) using an adaptive minimisation algorithm to intravenous balanced crystalloid solution (Plasma-Lyte 148) or saline during surgery and up until 48 h after transplantation. Trial fluids were supplied in identical bags and clinicians determined the fluid volume, rate, and time of discontinuation. The primary outcome was DGF, defined as receiving dialysis within 7 days after transplantation. All participants who consented and received a transplant were included in the intention-to-treat analysis of the primary outcome. Safety was analysed in all randomly assigned eligible participants who commenced surgery and received trial fluids, whether or not they received a transplant. This study is registered with Australian New Zealand Clinical Trials Registry, (ACTRN12617000358347), and ClinicalTrials.gov (NCT03829488). FINDINGS: Between Jan 26, 2018, and Aug 10, 2020, 808 participants were randomly assigned to balanced crystalloid (n=404) or saline (n=404) and received a transplant (512 [63%] were male and 296 [37%] were female). One participant in the saline group withdrew before 7 days and was excluded, leaving 404 participants in the balanced crystalloid group and 403 in the saline group that were included in the primary analysis. DGF occurred in 121 (30%) of 404 participants in the balanced crystalloid group versus 160 (40%) of 403 in the saline group (adjusted relative risk 0·74 [95% CI 0·66 to 0·84; p<0·0001]; adjusted risk difference 10·1% [95% CI 3·5 to 16·6]). In the safety analysis, numbers of investigator-reported serious adverse events were similar in both groups, being reported in three (<1%) of 406 participants in the balanced crystalloid group versus five (1%) of 409 participants in the saline group (adjusted risk difference -0·5%, 95% CI -1·8 to 0·9; p=0·48). INTERPRETATION: Among patients receiving a deceased donor kidney transplant, intravenous fluid therapy with balanced crystalloid solution reduced the incidence of DGF compared with saline. Balanced crystalloid solution should be the standard-of-care intravenous fluid used in deceased donor kidney transplantation. FUNDING: Medical Research Future Fund and National Health and Medical Research Council (Australia), Health Research Council (New Zealand), Royal Australasian College of Physicians, and Baxter.

Bowel Perforation Presenting as Head and Neck Subcutaneous Emphysema.

This patient with Crohn's disease underwent endoscopic balloon dilatation of an ileocolic stricture, and shortly thereafter developed subcutaneous emphysema in the soft tissues of her face, neck, and chest wall. Clinical evaluation and imaging revealed peritonitis from perforated bowel. She underwent laparotomy and bowel resection and recovered well. Subcutaneous emphysema in the head and neck from perforated bowel is a rare but recognized presentation of viscus perforation.

Levels of neonatal care among birth facilities in 20 states and other jurisdictions: CDC levels of care assessment toolSM (CDC LOCATeSM).

OBJECTIVE: Describe discrepancies between facilities' self-reported level of neonatal care and Centers for Disease Control and Prevention Levels of Care Assessment ToolSM (CDC LOCATeSM)-assessed level. STUDY DESIGN: CDC LOCATeSM data from 765 health facilities in the United States, including 17 states, one territory, one large multi-state hospital system, and one perinatal region within a state, was collected between 2016 and 2021 for this cross-sectional analysis. RESULT: Among 721 facilities that self-reported level of neonatal care, 33.1% had discrepancies between their self-reported level and their LOCATeSM-assessed level. Among facilities with discrepancies, 75.3% self-reported a higher level of neonatal care than their LOCATeSM-assessed level. The most common elements contributing to discrepancies were limited specialty and subspecialty staffing, such as neonatology or neonatal surgery. CONCLUSION: Results highlight opportunities for jurisdictions to engage with facilities, health systems, and partners about levels of neonatal care, and to collaborate to promote standardized systems of risk-appropriate care.

Regional Pain Blocks and Perioperative Pain Control in Patients Undergoing Breast Implant Removal With Capsulectomy.

Background: Demand for breast implant removal is on the rise, with more than 36,000 explants performed in 2020, an increase of 7.5% from previous years. Postoperative (PO) analgesia is an important consideration in this patient group due to scar tissue surrounding the implant and the potential for extensive dissection during capsulectomy. Objectives: The authors sought to compare perioperative pain control between three different types of ultrasound (US)-guided regional anesthetic techniques in patients undergoing implant removal with capsulectomy. Methods: The authors reviewed all patients who received an US-guided block and underwent breast implant removal with capsulectomy at their outpatient surgical center over a 2-year period. They compared intraoperative (IO), PO opioid requirement, and patient-reported pain on the first postoperative day (POD1) between 3 different block techniques using chi-square analysis. A P-value of <.05 was considered statistically significant. Results: A total of 352 patients were included. Twenty-six patients (7.4%) underwent a serratus plane (SP) block, 13 (3.7%) underwent an erector spinae combined with pectointercostal fascial plane (ES + PIFP) block, and 313 (88.9%) underwent an erector spinae combined with pectoral nerve (ES + PECS1) block. ES + PECS1 was associated with less IO and PO opioid use compared with SP and ES + PIFP (1.9% vs 19.2% vs 61.5%, P < .001 for IO, 26.8% vs 34.6% vs 38.5% PO, P < .001). The ES + PECS1 block was associated with mild pain on POD1 compared with the other 2 regional block techniques (P = .001). Conclusions: Regional pain blocks, and specifically the ES block, offer effective pain control for patients undergoing breast implant removal with capsulectomy, demonstrating high patient satisfaction in the PO period with low opioid requirements.

Transplant Options for Patients With Diabetes and Advanced Kidney Disease: A Review.

Optimal glycemic control in kidney transplant recipients with diabetes is associated with improved morbidity and better patient and allograft survival. Transplant options for patients with diabetes requiring insulin therapy and chronic kidney disease who are suitable candidates for kidney transplantation should include consideration of ß-cell replacement therapy: pancreas or islet transplantation. International variation related to national regulatory policies exists in offering one or both options to suitable candidates and is further affected by pancreas/islet allocation policies and transplant waiting list dynamics. The selection of appropriate candidates depends on patient age, coexistent morbidities, the timing of referral to the transplant center (predialysis versus on dialysis) and availability of living kidney donors. Therefore, early referral (estimated glomerular filtration rate < 30 mL/min/1.73 m2) is of the utmost importance to ensure adequate time for informed decision making and thorough pretransplant evaluation. Obesity, cardiovascular disease, peripheral vascular disease, smoking, and frailty are some of the conditions that need to be addressed before acceptance on the transplant list, and ideally before dialysis becoming imminent. This review offers insights into selection of pancreas/islet transplant candidates by transplant centers and an update on posttransplant outcomes, which may have practice implications for referring nephrologists.

Epidemiology of Surgical Procedures, Anesthesia, and Imaging Studies by Gestational Age during the First Year of Life in Medicaid-Insured Infants.

OBJECTIVES: To evaluate the rate of surgical procedures, anesthetic use, and imaging studies by prematurity status for the first year of life we analyzed data for Texas Medicaid-insured newborns. STUDY DESIGN: We developed a retrospective population-based live birth cohort of newborn infants insured by Texas Medicaid in 2010-2014 with 4 subcohorts: extremely premature, very premature, moderate/late premature, and term. RESULTS: In 1 102 958 infants, surgical procedures per 100 infants were 135.9 for extremely premature, 35.4 for very premature, 15.5 for moderate/late premature, and 6.5 for term. Anesthetic use was 62.0 for extremely premature, 20.8 for very premature, 11.1 for moderate/late premature, and 5.6 for the term subcohort. The most common procedures in the extremely premature were neurosurgery, intubations, and procedures that facilitated caloric intake (gastrostomy tubes and fundoplications). The annual rates for the first year of life for chest radiograph ranged from 15.0 per year for the extremely premature cohort to 0.6 for term infants and for magnetic resonance imaging (MRI) from 0.3 to 0.01. MRI was the most common imaging study with anesthesia support in all maturity levels. MRIs were done in extremely premature without anesthesia in over 90% and in term infants in 57.2%. CONCLUSIONS: Surgical procedures, anesthetic use, and imaging studies in infants are common and more frequent with higher a degree of prematurity while the use of anesthesia is lower in more premature newborns. These findings can provide direction for outcome studies of surgery and anesthesia exposure.

Colonic mucosa-associated lymphoid tissue in a renal transplant recipient: a case report.

BACKGROUND: Extra-gastric (particularly colonic) lymphoma of mucosa-associated lymphoid tissue in the immunosuppressed solid organ transplant recipient is rare. We report a case of low-volume mucosa-associated lymphoid tissue lymphoma with colonic and bone marrow involvement in a renal transplant recipient that has been managed conservatively. CASE PRESENTATION: A 62-year-old Caucasian man, 14 years after kidney transplantation, was diagnosed as having extra-nodal marginal zone lymphoma of mucosa-associated lymphoid tissue with bone marrow and colonic involvement, after a colonoscopy identified mucosa-associated lymphoid tissue lymphoma in a sessile sigmoid polyp following surveillance fecal occult blood testing that returned a positive result. A gastric biopsy showed no evidence of Helicobacter pylori, but Helicobacter pylori immunoglobulin G was positive. He received Helicobacter pylori eradication treatment and is being managed expectantly. Immunosuppression was unchanged with prednisolone, mycophenolate mofetil, and cyclosporine A. Renal allograft function has remained stable. CONCLUSIONS: This case highlights the unexpected occurrence of colonic mucosa-associated lymphoid tissue lymphoma in a kidney transplant recipient. The case emphasizes the importance of histopathological diagnosis of colonic lesions in this patient cohort because the unusual diagnosis of low-volume mucosa-associated lymphoid tissue lymphoma can be managed expectantly as it does not appear to be clinically aggressive in the immunosuppressed solid organ transplant.

Geographical variation in palliative cancer care in a tax-based healthcare system: drug reimbursement in Denmark.

BACKGROUND: In Denmark, a tax-based universal healthcare setting, drug reimbursement for terminal illness (DRTI) should be equally accessible for all terminally ill patients. Examining DRTI status by regions provides new knowledge on inequality in palliative care provision and associated factors. This study aims to investigate geographical variation in DRTI among terminally ill cancer patients. METHODS: We linked socioeconomic and medical data from 135 819 Danish cancer decedents in the period 2007-15 to regional healthcare characteristics. We analyzed associations between region of residence and DRTI. Prevalence ratios (PR) for DRTI were estimated using generalized linear models adjusted for patient factors (age, gender, comorbidity and socioeconomic profile) and multilevel models adjusted for both patient factors and regional healthcare capacity (patients per general practitioner, numbers of hospital and hospice beds). RESULTS: DRTI allocation differed substantially across Danish regions. Healthcare capacity was associated with DRTI with a higher probability of DRTI among patients living in regions with high compared with low hospice bed supply (PR 1.13, 95% CI 1.10-1.17). Also, the fully adjusted PR of DRTI was 0.94 (95% CI 0.91-0.96) when comparing high with low number of hospital beds. When controlled for both patient and regional healthcare characteristics, the PR for DRTI was 1.17 (95% CI 1.14-1.21) for patients living in the Central Denmark Region compared with the Capital Region. CONCLUSION: DRTI status varied across regions in Denmark. The variation was associated with the distribution of healthcare resources. These findings highlight difficulties in ensuring equal access to palliative care even in a universal healthcare system.

Insulin-producing organoids engineered from islet and amniotic epithelial cells to treat diabetes.

Maintaining long-term euglycemia after intraportal islet transplantation is hampered by the considerable islet loss in the peri-transplant period attributed to inflammation, ischemia and poor angiogenesis. Here, we show that viable and functional islet organoids can be successfully generated from dissociated islet cells (ICs) and human amniotic epithelial cells (hAECs). Incorporation of hAECs into islet organoids markedly enhances engraftment, viability and graft function in a mouse type 1 diabetes model. Our results demonstrate that the integration of hAECs into islet cell organoids has great potential in the development of cell-based therapies for type 1 diabetes. Engineering of functional mini-organs using this strategy will allow the exploration of more favorable implantation sites, and can be expanded to unlimited (stem-cell-derived or xenogeneic) sources of insulin-producing cells.

Anticancer organorhodium and -iridium complexes with low toxicity in vivo but high potency in vitro: DNA damage, reactive oxygen species formation, and haemolytic activity.

Redox-modulating anticancer drugs allow the exploitation of altered redox biology observed in many cancer cells. We discovered dinuclear RhIII(Cp*) and IrIII(Cp*) complexes that have in vitro anticancer activity superior to cisplatin and the investigational drug IT-139, while being less toxic in haemolysis and in vivo zebrafish models. The mode of action appears to be related to DNA damage and ROS-mediated stress pathways.

Eculizumab therapy in gemcitabine-induced thrombotic microangiopathy in a renal transplant recipient.

A renal transplant recipient 7 years post-transplantation, diagnosed with locally advanced pancreatic adenocarcinoma developed thrombotic microangiopathy (TMA) after treatment with gemcitabine and nab-paclitaxel. Gemcitabine was the most likely cause for TMA and was ceased. He received methylprednisolone and plasma exchange with fresh frozen plasma and albumin. Despite plasma exchange, his renal allograft function worsened, and he had persistent haematological evidence of haemolysis. Eculizumab was commenced with resolution-significant improvement in his renal and haematological markers. This case highlights an unusual occurrence of progressive gemcitabine-induced TMA in a renal allograft that had an excellent response to eculizumab. The clinical response also demonstrates involvement of complement dysregulation in gemcitabine-induced TNA.

Health system factors and caesarean sections in Kosovo: a cross-sectional study.

OBJECTIVE: To investigate the association of caesarean section rates with the health system characteristics in the public hospitals of Kosovo. DESIGN: Cross-sectional survey. SETTING: Five largest public hospitals in Kosovo. PARTICIPANTS: 859 women with low-risk deliveries who delivered from April to May 2015 in five public hospitals in Kosovo. OUTCOME MEASURES: The prespecified outcomes were the crude and adjusted OR of births delivered with caesarean section by health system characteristics such as delivery by the physician who provided antenatal care, health insurance status and other. Additional prespecified outcomes were caesarean section rates and crude ORs for delivery with caesarean in each public hospital. RESULTS: Women with personal monthly income had increased odds for caesarean (OR 1.55, 95% CI 1.06 to 2.27), as did women with private health insurance coverage (OR 3.44, 95% CI 1.20 to 9.85). Women instructed by a midwife on preparation for delivery had decreasing odds (OR 0.32, 95% CI 0.19 to 0.51) while women having preference for a caesarean had increasing odds for delivery with caesarean (OR 3.84, 95% CI 1.96 to 7.51). The odds for caesarean increased also in the case of delivery by a physician who provided antenatal care (OR 2.06, 95% CI 1.16 to 3.67) and delivery during office hours (OR 2.36, 95% CI 1.37 to 4.05), while delivery at the University Clinical Centre of Kosovo decreased the odds for caesarean (OR 0.46, 95% CI 0.24 to 0.90). CONCLUSIONS: We found that several health system characteristics are associated with the increase of caesarean sections in a low-risk population of delivering women in public hospitals of Kosovo. These findings should be explored further and addressed via policy measures that would tackle provision of unnecessary caesareans. The study findings could assist Kosovo to develop corrective policies in addressing overuse of caesareans and may provide useful information for other middle-income countries.

National practice trends for the surgical management of lung cancer in the CMS population: an atlas of care.

BACKGROUND: Video-assisted thoracoscopic surgery (VATS) has been established as a safe and effective alternative to an open approach for the treatment of early-stage lung cancer. Despite this, differences in utilization across the nation are present. The aims of this study were to: (I) characterize trends in the use of open surgery and VATS for the management of lung cancer across the United States, and (II) describe if particular regions of the country utilize minimally invasive surgery more frequently. METHODS: We studied all Medicare beneficiaries from the ages of 65 to 99 years with full Part A and B coverage and no HMO coverage for the years of 2006 and 2014 (the most recent year available at the time of this analysis). Beneficiaries with a diagnosis of lung cancer (ICD-9 codes: 162.0 162.2 162.3 162.4 162.5 162.8 162.9) were selected. Rates of thoracoscopic surgery (CPT codes: 32663, 32666, 32667, 32668, 32669, 32670, 32671) and open lung resections (32505, 32506, 32507, 32608, 32440, 32442, 32445, 32480, 32482, 32484, 32486, 32488) were calculated by year and region. Rates in 2006 and 2014 with descriptive statistics and a univariate analysis were performed using Student's t-test and chi-square, as appropriate. A two-sided P value <0.05 was considered statistically significant. RESULTS: A total of 24,368,333 and 23,921,059 beneficiaries for the years of 2006 and 2014 were analyzed. A diagnosis of lung cancer was detected in claims of 167,418 patients (0.7%) in 2006 and 167,506 patients in 2014 (0.7%), which was not significantly different (P=0.7). Among these lung cancer patients, a surgical intervention was performed in 17,249 patients (10.3%) during 2006 and 18,603 patients (11.1%) in 2014 (P=0.01). Among those undergoing surgery, a VATS approach was performed in 2,512 patients (15%) during 2006 and 9,578 patients (54%) during 2014 (P=0.001). In 2006, California, New York, and New Jersey performed the most VATS procedures, in comparison to 2014, when New York, Florida, and California performed the highest number of VATS procedures. CONCLUSIONS: While the prevalence of lung cancer in the United States was unchanged between 2006 and 2014, the use of VATS techniques increased five-fold. Further studies to better understand the adoption or availability of new surgical techniques in lung cancer populations across geographic regions and patient populations are necessary.

Death at no cost? Persons with no health insurance claims in the last year of life in Switzerland.

BACKGROUND: Lack of health insurance claims (HIC) in the last year of life might indicate suboptimal end-of-life care, but reasons for no HIC are not fully understood because information on causes of death is often missing. We investigated association of no HIC with characteristics of individuals and their place of residence. METHODS: We analysed HIC of persons who died between 2008 and 2010, which were obtained from six providers of mandatory Swiss health insurance. We probabilistically linked these persons to death certificates to get cause of death information and analysed data using sex-stratified, multivariable logistic regression. Supplementary analyses looked at selected subgroups of persons according to the primary cause of death. RESULTS: The study population included 113,277 persons (46% males). Among these persons, 1199 (proportion 0.022, 95% CI: 0.021-0.024) males and 803 (0.013, 95% CI: 0.012-0.014) females had no HIC during the last year of life. We found sociodemographic and health differentials in the lack of HIC at the last year of life among these 2002 persons. The likelihood of having no HIC decreased steeply with older age. Those who died of cancer were more likely to have HIC (adjusted odds ratio for males 0.17, 95% CI: 0.13-0.22; females 0.19, 95% CI: 0.12-0.28) whereas those dying of mental and behavioural disorders (AOR males 1.83, 95% CI:1.42-2.37; females 1.65, 95% CI: 1.27-2.14), and males dying of suicide (AOR 2.15, 95% CI: 1.72-2.69) and accidents (AOR 2.41, 95% CI: 1.96-2.97) were more likely to have none. Single, widowed, and divorced persons also were more likely to have no HIC (AORs in range of 1.29-1.80). There was little or no association between the lack of HIC and characteristics of region of residence. Patterns of no HIC differed across main causes of death. Associations with age and civil status differed in particular for persons who died of cancer, suicide, accidents and assaults, and mental and behavioural disorders. CONCLUSIONS: Particular groups might be more likely to not seek care or not report health insurance costs to insurers. Researchers should be aware of this aspect of health insurance data and account for persons who lack HIC.

Skin cancer history, sun-related attitudes, behaviour and sunburn among renal transplant recipients versus general population.

BACKGROUND/OBJECTIVES: Renal transplant recipients (RTR) have both an excessive skin cancer incidence and a high mortality rate. In Australia RTR receive extensive public education on skin cancer and many undergo further education pre/post-transplant. This study examines whether RTR have sufficiently rigorous sun protection behaviour compared with the general population. METHODS: Altogether 179 RTR from two large Melbourne hospitals involving skin clinic teams in patient care were recruited to undergo cross-sectional telephone interviews. Comparisons were made with residents (25-69 years) surveyed using equivalent measures and methods in adjacent summers (2006-2007, n = 904; 2010-2011, n = 942) for regular population monitoring surveys. Multivariate analyses of weekend behaviour were adjusted for related ambient temperature records. RESULTS: RTR were more compliant with sun protection behaviour on the weekend prior to interview than the residents surveyed. For example, for 2006-2007 and 2010-2011, the odds ratio and confidence intervals (CI 95%) were respectively: used sunscreen: 2.0 (1.1-3.8) and 2.8 (1.4-5.3); wore a long-sleeved top: 4.5 (2.4-8.5) and 3.6 (1.9-7.0). RTR sunburn prevalence (5%) appeared similar to that of residents (odds ratios comparing 2006-2007 and 2010-2011 0.6 [95% CI, 0.2-1.6] and 0.7 [95% CI, 0.3-1.9]). Despite generally good sun protection behaviour, many RTR (47%) had skin cancers treated. CONCLUSION: The intensive education of RTR may have contributed to their better sun protection. Some RTR with excessive exposure to UV radiation introduction of may benefit from implementation of further photoprotection strategies. These findings may be particularly relevant to other RTR groups receiving education about sun protection.

Intractable ascites associated with mycophenolate in a simultaneous kidney-pancreas transplant patient: a case report.

BACKGROUND: Mycophenolic acid (MPA), either given as an ester pro-drug or as an enteric-coated sodium salt, is the most commonly prescribed anti-proliferative immunosuppressive agent used following organ transplantation and widely applied in immune-mediated diseases. Clinicians are well aware of common adverse reactions related to MPA treatment, in particular diarrhea, leukopenia and infections. Here we report a case of severe, persistent ascites associated with MPA treatment. The otherwise unexplained and intractable ascites, requiring repeated paracenteses for more than 8 months, rapidly ceased with stopping the MPA treatment. To our knowledge this is the first case of severe ascites associated with MPA treatment reported in the scientific literature. CASE PRESENTATION: A 45-year old female with type 1 diabetes mellitus received a simultaneous kidney-pancreas transplant. The surgery was uneventful. However, post-operatively she developed severe transudative ascites requiring in total more than 40 paracenteses treatments draining in the average 2.8 l of ascites fluid. The ascites formation persisted despite exclusion of a surgical complication, fully functioning kidney and pancreas allografts, lack of any significant proteinuria, normalization of circulating albumin levels, intensive use of diuretics and deliberate attempts to increase the intervals between the paracentesis treatments. Various differential diagnoses, including infectious, hepatic, vascular and cardiac causes were ruled out. Nine months after surgery enteric-coated mycophenolate sodium was switched to azathioprine after which ascites completely resolved. When mycophenolate was recommenced abdominal fullness and weight gain reoccurred. The patient had to be switched to long-term azathioprine treatment. More than 1 year post-conversion the patient remains free of ascites. CONCLUSION: MPA is the most widely used antimetabolite immunosuppressive agent. We suggest to consider MPA treatment in the differential diagnosis of severe and unexplained ascites in transplant and non-transplant patients.

Combination of Leflunomide and Everolimus for treatment of BK virus nephropathy.

BK nephropathy (BKN) is a common cause of graft dysfunction following kidney transplantation. Minimization of immunosuppressive therapy remains the first line of therapy, but this may lead to rejection and graft loss. In some cases, despite lowering immunosuppression, BK infection can persist, leading to chronic damage and kidney failure. Currently, there is no specific anti-BK viral therapy. Recent in vitro experiments have demonstrated a reduction in BK viral replication when infected cells are treated with the combination of Leflunomide and Everolimus. This study aims to explore the effect of this drugs combination on viral clearance and graft function in patients with persistent disease despite reduction in immunosuppression. We treated three patients with combination Leflunomide and Everolimus. Data on medical history, biochemical parameters and viral loads were collected. Significant improvement in viral loads was observed in two cases with resolution of viremia in another (Table 1). Two recipients had preserved allograft function. The remaining graft was lost because of combination of obstruction and BKN. No adverse reactions such as bone marrow toxicity were observed. Combination of Leflunomide and Everolimus is safe and should be considered as a rescue therapy in treatment of BKN, especially in those who fail to clear this infection despite reduction of immunosuppressive therapy.