BSHI/BTS guidance on crossmatching before deceased donor kidney transplantation.

All UK H&I laboratories and transplant units operate under a single national kidney offering policy, but there have been variations in approach regarding when to undertake the pre-transplant crossmatch test. In order to minimize cold ischaemia times for deceased donor kidney transplantation we sought to find ways to be able to report a crossmatch result as early as possible in the donation process. A panel of experts in transplant surgery, nephrology, specialist nursing in organ donation and H&I (all relevant UK laboratories represented) assessed evidence and opinion concerning five factors that relate to the effectiveness of the crossmatch process, as follows: when the result should be ready for reporting; what level of donor HLA typing is needed; crossmatch sample type and availability; fairness and equity; risks and patient safety. Guidelines aimed at improving practice based on these issues are presented, and we expect that following these will allow H&I laboratories to contribute to reducing CIT in deceased donor kidney transplantation.

Is big bad or bearable? Long-term renal transplant outcomes in obese recipients.

BACKGROUND: The global obesity epidemic has implications for kidney transplantation. There are conflicting reports regarding the impact of obesity on long-term post-transplant outcomes. AIM: To explore the impact of body mass index (BMI) on long-term outcomes after kidney transplantation. DESIGN: The association between BMI and cardiovascular disease, cancer, post-transplant diabetes mellitus, graft and recipient survival was investigated in recipients who had been transplanted at least ten years previously. METHODS: All consecutive adult renal transplant recipients who received first, deceased donor, transplants between 1986 and 2005 in Northern Ireland were followed-up until 2016. RESULTS: A total of 328 patients were eligible. Of them, 96 were overweight with a BMI 25.0-29.9 kg/m2, and 56 were obese with a BMI exceeding 29.9 kg/m2. Median follow-up time was 16.7 years. In multivariate analysis recipient BMI was associated with the development of post-transplant diabetes mellitus (P=0.003), but not with new cardiovascular disease (P=0.78). Cancer was less common in recipients with a higher BMI (hazard ratio (HR) 0.58, P < 0.001). BMI at the time of transplantation did not significantly influence graft (P=0.28) or recipient survival (P=0.13). CONCLUSIONS: Increased BMI at time of transplantation is associated with an increased risk of post-transplant diabetes mellitus but not new cardiovascular disease or malignancy. Long-term graft and recipient survival is not impacted. Potential recipients should not be excluded from transplantation solely on the basis of obesity, rather it should be considered as one part of an individualized risk stratification, based on comorbidity and considering the risk of death on maintenance dialysis.

Muddy puddles - the microbiology of puddles located outside tertiary university teaching hospitals.

In the British Isles, the frequency of rain results in the formation of puddles on footpaths and roads in/around hospitals. No data are available demonstrating the microbiological composition of such puddles and therefore a study was undertaken to examine the microbiology of puddles in the grounds of two tertiary university-teaching hospitals (18 sites) and compared with control puddles from non-hospital rural environments (eight sites), estimating (i) total viable count; (ii) identification of organisms in puddles; (iii) enumeration of Escherichia coli: (iv) detection of Extended Spectrum ß-Lactamase producing organisms and (v) direct antimicrobial susceptibility testing. A mean count of 2·3 × 103  CFU per ml and 1·0 × 109  CFU per ml was obtained for hospital and non-hospital puddles respectively. Isolates (n = 77; 54 hospital and 23 non-hospital) were isolated comprising of 23 species among 17 genera (hospital sites), where the majority (10/16; 62·5%) of genera identified were Gram-negative approximately, a fifth (20·6%) were shared by hospital and non-hospital rural samples. Escherichia coli was detected in half of the hospital puddles and under-half (37·5%) of the rural puddles extended spectrum ß-lactamase organisms were not detected in any samples examined. Rainwater puddles from the hospital and non-hospital environments contain a diverse range of bacteria, which are capable of causing infections. SIGNIFICANCE AND IMPACT OF THE STUDY: This study demonstrated the presence of a wide diversity of bacterial taxa associated with rainwater puddles around hospitals, many of which are capable of causing human disease. Of clinical significance is the presence of Pseudomonas aeruginosa isolated from a hospital puddle, particularly for patients with cystic fibrosis. The presence of potentially disease-causing bacteria in puddles in and around hospitals identifies a new potential environmental reservoir of bacteria. Furthermore work is now needed to define their potential of entering or exiting hospital wards by contaminated footwear.

Pseudomonas aeruginosa in cystic fibrosis patients with c.1652G>A (G551D)-CFTR treated with ivacaftor-Changes in microbiological parameters.

WHAT IS KNOWN AND OBJECTIVE: The CFTR potentiator, ivacaftor (IVA), has been widely used in the treatment of cystic fibrosis (CF) patients with the G551D mutation. To date, there has been limited information on the microbiological status of patients on this therapy and no data on the effect (if any) on the in vivo antibiotic susceptibility of Pseudomonas aeruginosa isolated from patients on therapy. Although IVA intervention is not designed per se as anti-infective, the effect (if any) of this molecule to CF patients' microbiological status merits careful monitoring. Therefore, it was the aim of this observational study to examine the effect in patients, both before and after commencement of IVA therapy, on several commonly reported microbiological markers in CF patients, including (i) bacterial density, (ii) frequency (rate) of isolation of bacterial pathogens, particularly P. aeruginosa, and (iii) antimicrobial susceptibility of these isolates to commonly prescribed oral and iv antibiotics. In addition, we wished to examine the requirements for these antibiotics in CF patients, before and after commencement of IVA therapy. METHODS: Archived data from 15 adult cystic fibrosis patients with the c.1652G>A (G551D) mutation were followed from two years pre-IVA therapy to two years after commencement of IVA therapy. The microbiological parameters examined included (i) oral antibiotic courses taken, (ii) intravenous (iv) antibiotic courses taken, (iii) rate of isolation of non-mucoid Pseudomonas aeruginosa (NM-PA) and mucoid P. aeruginosa (M-PA), (iv) density of NM-PA and M-PA and (v) antimicrobial susceptibility of NM-PA and M-PA to 11 antibiotics [aminoglycosides, beta-lactams, polymyxin and fluoroquinolone]. RESULTS AND DISCUSSION: Following commencement of IVA therapy, patients required less iv antibiotic courses but no change in number of oral antibiotics courses. There was significant reduction in both the rate of isolation and density of M-PA (P = .02; P = .006, respectively). In contrast, there was no significant reduction in both the rate of isolation and density of NM-PA (P = .90; P = .07, respectively). Antimicrobial susceptibility in NM-PA and M-PA was not significantly reduced within any of the antibiotics classes or individual antibiotics examined. Increased susceptibility was noted in the beta-lactam class for NM-PA and M-PA, in particular with ceftazidime. WHAT IS NEW AND CONCLUSION: Overall, (i) the requirement for less iv antibiotic therapy, (ii) a reduction in the rate and density of M-PA and (iii) no reduction in antibiotic susceptibility indicate that microbiological parameters with patients on IVA therapy were not detrimentally affected.

Relative resistance index (RRI) - a scoring system for antibiotic resistance in Pseudomonas aeruginosa.

BACKGROUND: There is a need to measure antibiotic resistance of Pseudomonas aeruginosa (PA) in cystic fibrosis (CF), either qualitatively or quantitatively, to inform patient management. The aim of this study was to develop a simple method by which resistance can be quantified by calculating a relative resistance index (RRI), and to assess correlation of RRIs with clinical variables. METHODS: In our model, RRIs were calculated based on resistance to aztreonam, ceftazidime, ciprofloxacin, colistin, meropenem, tazocin, temicillin and tobramycin. Eighty-five adults with CF and chronic PA colonisation were identified. For each, all PA cultures were allocated a score of 0 for susceptible, 0.5 for intermediate resistance or 1 for resistance for each antibiotic listed above, and the RRI calculated by dividing the sum of these by the number of antibiotics, giving a maximum score of 1. The mean RRIs for all cultures were correlated with key clinical variables monitored in CF patients (including age, FEV1, IV antibiotic days and BMI). RESULTS: RRIs for non-mucoid PA exhibited moderate positive correlation with total number of IV days (r = 0.405; p < 0.001) and moderate negative correlation with FEV1 % predicted (r = -0.437; p < 0.001). RRIs were not significantly correlated with duration of colonisation, typing (clonal vs other strain) or BMI. Median RRIs were significantly higher for females (0.26, IQR 0.13-0.54) than males (0.18, IQR 0.07-0.37) for non-mucoid PA only (p = 0.03). CONCLUSIONS: RRI is an easily calculated measure that correlates with other clinical variables in CF patients and enables quantitative monitoring of resistance.

The clinical course of kidney transplant recipients after 20 years of graft function.

There is a growing population of kidney transplant recipients who have survived 20 years with a functioning graft. This study identified the factors associated with prolonged survival and described the clinical course of recipients after two decades of transplant function. All recipients transplanted in Northern Ireland between 1968 and 1993 were included (n = 706) and data were collected prospectively. At 20 years, 25% had a functioning transplant; in multivariate analysis younger recipient age and living donation were associated with 20-year survival. The median recipient survival beyond two decades was 13.3 years; cancer was the commonest cause of death. De novo malignancy developed in 37% of recipients and cardiovascular disease in 27% after 20 years of graft function. The median graft survival after 20 years was 9.3 years; 69% of graft loss was due to death with a functioning transplant. Advances in kidney transplantation have improved the long-term survival of both graft and recipient. After two decades the majority of patients die with a functioning graft. The focus of management in long-term survivors may need to be on the prevention of cancer and cardiovascular disease to allow further improvements in graft and recipient survival.

Recurrent dense deposit disease after renal transplantation: an emerging role for complementary therapies.

Dense deposit disease is a rare glomerulonephritis caused by uncontrolled stimulation of the alternative complement pathway. Allograft survival after kidney transplantation is significantly reduced by the high rate of disease recurrence. No therapeutic interventions have consistently improved outcomes for patients with primary or recurrent disease. This is the first reported case of recurrent dense deposit disease being managed with eculizumab. Within 4 weeks of renal transplantation, deteriorating graft function and increasing proteinuria were evident. A transplant biopsy confirmed the diagnosis of recurrent dense deposit disease. Eculizumab was considered after the failure of corticosteroid, rituximab and plasmapheresis to attenuate the rate of decline in allograft function. There was a marked clinical and biochemical response following the administration of eculizumab. This case provides the first evidence that eculizumab may have a place in the management of crescentic dense deposit disease. More information is necessary to clarify the effectiveness and role of eculizumab in dense deposit disease but the response in this patient was encouraging. The results of clinical trials of eculizumab in this condition are eagerly awaited.

Predictors of mortality in adults with cystic fibrosis.

Assessment of prognostic indicators in patients with cystic fibrosis (CF) is important. The study's aim was to assess the relative contribution of gender, genetics and microbiology on survival in adults with CF. Adult patients were studied from 1995 to 2005 and data collected included FEV(1) (%predicted), body mass index (BMI), genetics, and microbiology. Data was available on 183 patients in 1995. Forty-five patients died in the subsequent 10 years. Patients who died during the study had lower mean (SD) FEV(1) %predicted in 1995 when compared to those remaining alive, 41.5 (15.2)% versus 69.8 (23.2)% predicted, respectively, P<0.001 and they had lower mean (SD) BMI in 1995, 19.2 (3.3) kg/m(2) in comparison to those remaining alive, 20.7 (3.4) kg/m(2), P=0.008. The proportion of patients infected with Pseudomonas aeruginosa and Burkholderia cepacia complex was higher in the group who died during the study compared to those remaining alive, odds ratio 20.9 P<0.0001 and 7.1 P<0.0001, respectively. The presence of the Delta F508 homozygous mutation did not alter survival, P=0.3. Patients infected with either P.aeruginosa or B.cepacia complex had reduced survival compared to those without infection, P=0.01 and P<0.0001, respectively. FEV(1)% (P<0.0001), infection with P.aeruginosa (P=0.005) or B.cepacia complex (P=0.03) were the only significant predictors of mortality. This study demonstrates adults who died were more likely to have worse lung function and be infected with either P.aeruginosa or B.cepacia complex. FEV(1)% and infection with P.aeruginosa or B.cepacia complex were the most significant predictors of survival in adults with CF.

Further evidence of the increased risk for malignant peripheral nerve sheath tumour from a Scottish cohort of patients with neurofibromatosis type 1.

A recent study, looking at the lifetime risk of developing malignant peripheral nerve sheath tumour (MPNST) in patients with neurofibromatosis type 1 (NF1), estimated the risk to be 8-13%. Prior to this, longitudinal studies had shown that patients with NF1 had a risk of 4-5% of developing MPNST, and cross-sectional studies had found that only 1-2% of patients with NF1 had MPNST. The aim of this study was to estimate the lifetime risk of MPNST in patients with NF1 in southern Scotland, using patient records obtained from the Edinburgh and Glasgow Genetic Units and Scottish Cancer Register. In the period 1993-2002, 14 patients with NF1 were diagnosed with MPNST in a population of 3.5 million. The lifetime risk of MPNST in the Scottish patients with NF1 was calculated to be 5.9-10.3%. This provides further evidence that patients with NF1 are at greater risk of developing MPNST than was previously estimated, and emphasises the importance of educating patients about suspicious symptoms, which may need an urgent medical opinion. The mean age at diagnosis of MPNST (p<0.05) and 5-year survival (p<0.01) were significantly lower in patients with NF1 than in unaffected individuals. This may be due to patients with NF1 presenting later, because the tumour is mistaken for a neurofibroma, or due to MPNST having a more aggressive course in NF1.

Successful decolonization of methicillin-resistant Staphylococcus aureus in paediatric patients with cystic fibrosis (CF) using a three-step protocol.

Methicillin-resistant Staphylococcus aureus (MRSA) is recognized as a bacterial pathogen in patients with cystic fibrosis (CF) although its clinical effects can be variable. The aim of this study was to evaluate the efficacy of a three-step decolonization protocol for MRSA (Belfast CF MRSA decolonization protocol). Of the 17 paediatric patients treated during the five years of the study, eight (47%) were successfully decolonized following one five-day course of oral rifampicin and fusidic acid. The success rate increased to 12 (71%) patients after a second five-day oral treatment course in the 11 patients who remained culture positive at the end of the first treatment cycle. In a further four patients, clearance was achieved with a course of intravenous teicoplanin, increasing the decolonization rate to 16 of 17 patients (94%). These results compare favourably with other published studies and show that MRSA decolonization can be successful in a high proportion of paediatric CF patients.

Clinical outcome after acquisition of Burkholderia cepacia in patients with cystic fibrosis.

BACKGROUND: Respiratory disease is the major cause of morbidity and mortality in cystic fibrosis (CF). The significance of Burkholderia cepacia (B. cepacia) in the pathogenesis of lung disease in CF is debated, but its exact role remains unclear. AIM: To assess the impact of respiratory tract colonisation with B. cepacia in patients with CF by measuring changes in pulmonary function and body mass index (BMI). METHODS: Three groups of patients were defined based on sputum culture isolates: Group 1 were B. cepacia and Pseudomonas aeruginosa (P. aeruginosa) positive patients; Group 2 were P. aeruginosa positive; and Group 3 were colonised with neither organism. Forced expiratory volume (FEV) and BMI were measured annually from 1987 to 1995 and the year of acquisition of P. aeruginosa or B. cepacia was recorded. RESULTS: The mean annual decrease in FEV1 was significantly different in all three groups: Group 1, -5.4 (5.1)%; Group 2, -3.9 (6.5)%; and Group 3, -1.6 (1.0)%, (p<0.05). The mean percentage decrease in FEV1 of a sub-group of Group 1 patients where the B. cepacia acquisition date was known was 6.1% per year versus 1.55% in Group 2 patients (p<0.05). CONCLUSIONS: Acquisition of B. cepacia may be a cause of, rather than a marker for, a decrease in pulmonary function.

Photodynamic therapy: a review.

Photodynamic therapy (PDT) of malignant tumours is a new technique for treating cancers. After intravenous injection, a photosensitiser is selectively retained by the tumour cells so after time there is more sensitiser in the tumour than in the normal adjacent tissue. The photosensitiser must be able to absorb the wavelength of light being delivered to it, and the amount of light getting to the photosensitiser depends on the characteristics of the tissue it passes through. When exposed to light with the proper wavelength, the sensitiser produces an activated oxygen species, singlet oxygen, that oxidises critical elements of neoplastic cells. Because there is less sensitiser in the adjacent normal tissue, less reaction occurs to it. Since this is an entirely different process, the use of chemotherapy, ionising radiation or surgery does not preclude the use of PDT. Also, unlike ionising irradiation, repeated injections and treatments can be made indefinitely. Different molecules and atoms absorb different wavelengths of energy. Since the light energy must be absorbed to start the photochemical reaction, the absorption spectrum of the photosensitiser determines the wavelength used to initiate the reaction. However, this can be qualified by the tissue the light has to travel through to get to the photosensitiser. The photosensitiser porfimer sodium has a peak absorption in the area of 405 nm (blue-violet) and a much lower absorption peak at 630 nm (red). However, because the longer red wavelength penetrates tissue deeper than 405 nm, we use the red wavelength, usually delivered from a laser system. This permits coupling of the red light beam to quartz fibres which can then be used with modifications to treat external surface tumours, inserted interstitially directly into large tumours, passed though any endoscope to treat intraluminal tumours, or inserted behind the retina to treat tumours of the retina. Twenty years after the pioneering work of Dr. Thomas Doherty, the US Food and Drug Administration (FDA) has approved the use of porfimer sodium for photodynamic therapy of endobronchial and oesophageal tumours. Research continues towards approval for management of skin cancers and metastatic cutaneous and subcutaneous breast cancers. The realisation that one of the mechanisms of photodynamic therapy is thrombosis of vessels led to the development of verteporfin to treat macular degeneration. Multiple other areas are being investigated as well as new photosensitisers. Photodynamic therapy is an entirely new treatment modality and its development can be likened to that of the discovery of antibiotics. This is just the beginning, and its possible uses are only limited by the imagination.

Survival after photodynamic therapy to non-pulmonary metastatic endobronchial tumors.

BACKGROUND: For the past 15 years we have used photodynamic therapy (PDT) to treat endobronchial tumors. Unfortunately patients who have non-primary lung cancer metastatic to bronchi and who have failed other treatment regimens may not be offered endobronchial tumor management. Thirteen patients with endobronchial tumors metastatic from non-pulmonary primaries were treated with PDT. We: 1) evaluated the effects of PDT on the tumor, the quality of life, and the length of survival; and 2) compared their survival after PDT to that of 27 patients with stage IV primary endobronchial tumors treated with PDT after they failed all other treatment regimens. MATERIALS AND METHODS: Photodynamic therapy was performed using 630-nm light delivered through cylinder diffusing tip quartz fibers passed through the biopsy channel of a flexible bronchoscope after intravenous injection of the photosensitizer dihematoporphyrin ether. One to two days after PDT bronchoscopy was repeated and necrotic tissue was mechanically removed and, if necessary, that site or other new sites were treated. Two days after this another bronchoscopy was performed and the necrotic tissue was mechanically removed. Bronchoscopy was repeated one month after PDT and periodically thereafter as needed to re-treat symptomatic residual tumor. The percent obstruction of the bronchus due to tumor was estimated before and at the end of each bronchoscopy. Clinical effects were evaluated using Wilcoxon signed rank tests for scaled parameters of dyspnea, cough, hemoptysis, and Karnofsky Performance Status (KPS) before and one month after PDT. All patients were followed until their death. RESULTS: The mean percent obstruction due to metastatic non-pulmonary tumors at 38 different endobronchial treated sites decreased from 85% to 13% at discharge after PDT. The 72% mean decrease of obstruction was statistically significant using the Wilcoxon signed rank test (P < .0001). There was a statistically significant improvement in the level of dyspnea (P = .012), hemoptysis (P = .028), cough (P = .027), and KPS (P = .020). Kaplan-Meier survival curves and Mann-Whitney U rank tests showed the median survival of stage IV primary tumor patients (4 months) vs. metastatic tumor patients (14 months) was statistically significant (P = .008). CONCLUSION: PDT of endobronchial metastatic tumors effectively decreased the amount of endobronchial obstruction, and improved the quality of life.

Photodynamic therapy for obstructive esophageal malignancies.

Objectives Determine factors affecting survival rates, benefits and complications of patients with obstructive esophageal cancer treated with photodynamic therapy (PDT). Methods From 1982 to January 1998, we used PDT to treat 140 patients with obstructive adeno or squamous carcinoma and evaluated survival up to November 1998. All patients had failed, refused, or were ineligible for surgery, ionizing radiation or chemotherapy. The effect of different variables on survival was estimated using multivariate analysis. The Karnofsky Performance Status (KPS), weight, diet and complications were recorded and biopsies and brushings were taken at each endoscopy. At the beginning and end of each endoscopy the minimal diameter open of the esophagus, and the length, thickness and color of the tumor were recorded. Edema, exudate, bleeding, and mucositis were evaluated and recorded on an ordinal scale.Results The only significant variable affecting survival was the clinical stage. The median survival after PDT for all patients was 6.5 months (mean = 13.9). Kaplan-Meier survival after PDT curves were statistically significantly different when stratified by the clinical Stage at the time of PDT (p < 0.0001). Median survival (months) were for: Stage I = 56; Stage II = 12; Stage III = 6.5; Stage IV = 3.5. Analysis of each individual stage showed the KPS was the only confounding variable with a statistically significant effect on survival after PDT and this was only for Stages III and IV. The most significant effect occurred when the KPS was >/= 70. For Stage III the median survival when the KPS was >/= 70 was 7.7 months and for a KPS < 70 it was 5.0 months (p = 0.0001). For Stage IV the median survival when the KPS was >/= 70 was 5.5 months and for a KPS < 70 it was 2.5 months (p = 0.0002). The mean minimum diameter open before PDT was 6.2 mm (median 6.0mm) and at the end of the PDT treatment endoscopy 11.1 mm (median 12.0 mm) for a mean increase in the minimum diameter open of 4.9 mm (median 5.0 mm) This was statistically significant using paired t-tests (p < 0.0001).Conclusions Photodynamic therapy for esophageal carcinoma caused minimal complications and procedure related mortality. Complete obstruction can be relieved by the end of the PDT endoscopy. The length of palliation for "non-curative" patients was equal to or better than that reported historically for most other treatment regimens.

Photodynamic therapy for endobronchial malignant disease: a prospective fourteen-year study.

BACKGROUND: After intravenous injection, the photosensitizer dihematoporphyrin either is selectively retained in tumor cells. This photosensitizer absorbs 630 nm wavelength light energy and produces a singlet oxygen that destroys the tumor. Photodynamic therapy was performed on endobronchial tumors with the use of light generated by an argon dye laser system delivered through cylinder diffusing tip quartz fibers passed through the biopsy channel of a flexible endoscope. OBJECTIVES: Our objectives were to determine factors affecting survivals, benefits, and complications. METHODS: From 1982 to May 1996, photodynamic therapy was performed on 175 patients with endobronchial tumors. Sixteen had stage I disease, 9 stage II, 42 stage IIIA, 64 stage IIIB, and 44 stage IV. All were followed up until death or November 1996. RESULTS: Multivariate analysis of survival of the effects of age, sex, race, histologic features, Karnofsky Performance Status, and clinical stage showed the clinical stage (p < 0.0001) to be the most statistically significant factor. Sixteen patients with stage I disease had a 93% 5-year disease-related estimated survival. Median (months) survivals were as follows: stage I = not reached; stage II = 22.5; stage IIIA = 5.7; stage IIIB = 55; and stage IV = 5.0. Performance status does become significant when it reaches 50 but was not significant for stages I or II. CONCLUSIONS: Photodynamic therapy may be considered as an alternative treatment for patients under consideration for surgical treatment for stage I carcinoma in whom the risk of surgery is high. The length of palliation for patients with noncurative disease was equal to or better than that reported historically for most other treatment regimens.