Autosomal dominant tubulointerstitial kidney disease (ADTKD) in Ireland.

Introduction: Autosomal dominant tubulointerstitial kidney disease (ADTKD) is a rare genetic cause of renal impairment resulting from mutations in the MUC1, UMOD, HNF1B, REN, and SEC61A1 genes. Neither the national or global prevalence of these diseases has been determined. We aimed to establish a database of patients with ADTKD in Ireland and report the clinical and genetic characteristics of these families. Methods: We identified patients via the Irish Kidney Gene Project and referral to the national renal genetics clinic in Beaumont Hospital who met the clinical criteria for ADTKD (chronic kidney disease, bland urinary sediment, and autosomal dominant inheritance). Eligible patients were then invited to undergo genetic testing by a variety of methods including panel-based testing, whole exome sequencing and, in five families who met the criteria for diagnosis of ADTKD but were negative for causal genetic mutations, we analyzed urinary cell smears for the presence of MUC1fs protein. Results: We studied 54 individuals from 16 families. We identified mutations in the MUC1 gene in three families, UMOD in five families, HNF1beta in two families, and the presence of abnormal MUC1 protein in urine smears in three families (one of which was previously known to carry the genetic mutation). We were unable to identify a mutation in 4 families (3 of whom also tested negative for urinary MUC1fs). Conclusions: There are 4443 people with ESRD in Ireland, 24 of whom are members of the cohort described herein. We observe that ADTKD represents at least 0.54% of Irish ESRD patients.

Metastatic Solitary Fibrous Tumour of the Kidney Presenting more than a Decade Later with Pulmonary Disease

Introduction Solitary fibrous tumours are rare mesenchymal tumours that most commonly originate from the visceral pleura. Extra-thoracic primary sites including; head and neck, soft tissue, retroperitoneum and the urological tract, are associated with late recurrence. Case We present a case of metastatic pulmonary Solitary Fibrous Tumour presenting 11 years post resection of renal primary Solitary Fibrous Tumour. The patient underwent apical segmentectomy of the right lower lobe extending to wedge excision of right upper lobe due to fissure involvement with lymphadenectomy. The patient was discharged day 12 post surgery. Discussion Robust guidance regarding long-term management of solitary fibrous tumours is lacking. Salvage resection offers favourable long-term prognosis. This case demonstrates the importance of long-term surveillance.

Pre-transplant histology does not improve prediction of 5-year kidney allograft outcomes above and beyond clinical parameters.

Pre-implant kidney biopsy is used to determine suitability of marginal donor kidneys for transplantation. However, there is limited data examining the utility of pre-implant histology in predicting medium term graft outcome. This retrospective study examined kidney transplants over a 10-year period at a single center to determine if pre-implant histology can identify cases of eGFR ≤35 ml/min/1.73m2 at 5 year follow up beyond a clinical predictive logistic regression model. We also compared outcomes of dual kidney transplants with standard single kidney transplants. Of 1195 transplants, 171 received a pre-implant kidney biopsy and 15 were dual transplants. There was no significant difference in graft and patient survival rates. Median eGFR was lower in recipients of biopsied kidneys compared with standard kidney transplants (44 vs. 54 ml/min/1.73m2, p < .001). Median eGFR of dual transplant and standard kidney transplants were similar (58 vs. 54 ml/min/1.73m2, p = .64). Glomerular sclerosis (p = .05) and Karpinski Score (p = .03) were significant predictors of eGFR at 5-years in multivariate analysis but did not improve discrimination of eGFR ≤35 ml/min/1.73m2 at 5-years beyond a clinical prediction model comprising donor age, donor hypertension and terminal donor creatinine (C-statistic 0.67 vs. 0.66; p = .647). Pre-implant histology did not improve prediction of medium-term graft outcomes beyond clinical predictors alone. Allograft function of dual transplant kidneys was similar to standard transplants, suggesting that there is scope to increase utilization of kidneys considered marginal based on histology.

Relapsing tubulointerstitial nephritis in an adolescent with inflammatory bowel disease without aminosalicylate exposure.

A 14-year-old boy presented with ongoing constipation as a manifestation of newly diagnosed Crohn's disease (CD) and a concomitant decline in renal function with biopsy-proven interstitial nephritis. Initiation of steroid therapy and mesalazine was associated with an improvement in symptoms and renal function. We describe a rare case of a 5-aminosalicylic acid (5-ASA)-naïve patient who developed interstitial nephritis in association with CD with no evidence of other primary glomerulopathy. A unique feature of the case being a profound systemic inflammatory response at the time of diagnosis and a relapse in nephritis 2 months after cessation of mesalazine in the absence of any macroscopic colitis.

Higher tacrolimus trough levels on days 2-5 post-renal transplant are associated with reduced rates of acute rejection.

We analyzed the association between whole-blood trough tacrolimus (TAC) levels in the first days post-kidney transplant and acute cellular rejection (ACR) rates. Four hundred and sixty-four consecutive, deceased-donor kidney transplant recipients were included. All were treated with a combination of TAC, mycophenolate mofetil and prednisolone. Patients were analyzed in four groups based on quartiles of the mean TAC on days 2 and 5 post-transplant: Group 1: median TAC 11 ng/mL (n = 122, range 2-13.5 ng/mL), Group 2: median 17 ng/mL (n = 123, range 14-20 ng/mL), Group 3: median 24 ng/mL (n = 108, range 20.5-27 ng/mL) and Group 4: median 33.5 ng/mL (n = 116, range 27.5-77.5 ng/mL). A graded reduction in the rates of ACR was observed for each incremental days 2-5 TAC. The one-yr ACR rate was 24.03% (95% CI 17.26-32.88), 22.20% (95% CI 15.78-30.70), 13.41% (95% CI 8.15-21.63) and 8.69% (95% CI 4.77-15.55) for Groups 1-4, respectively (p = 0.003). This study suggests that higher early TACs are associated with reduced rates of ACR at one yr.

Trimethoprim-sulfamethoxazole induced acute interstitial nephritis in renal allografts; clinical course and outcome.

BACKGROUND: Acute interstitial nephritis (AIN) secondary to trimethoprim-sulfamethoxazole (TMP-SMX) is well documented as a cause of acute renal failure in native kidneys. TMP-SMX is the standard prophylactic agent against pneumocystis carinii (PCP) used in the early post-transplant period, however, it has to date only been indirectly associated with AIN in renal allografts. DESIGN, SETTING, PARTICIPANTS AND MEASUREMENTS: We describe eleven renal transplant patients with acute allograft dysfunction in whom a transplant biopsy demonstrated primary histopathologic features of allergic AIN, all of whom were receiving TMP-SMX in addition to other medications known to cause AIN. RESULTS: All cases occurred within 1 month of transplantation and accounted for 2.12% (11/518) of the total number of transplant biopsies performed during the study period. However, this figure increased to 10.1% (11/109) when those biopsies performed for early allograft dysfunction (< 1 month) were taken into account. After discontinuation of TMP- SMX alone, all patients had an immediate improvement in serum creatinine with excellent long term allograft function - mean improvement of serum creatinine from 465 micromol/l to 136 micromol/l at last follow-up (range 15 - 55 months). CONCLUSIONS: AIN secondary to TMP-SMX, although an uncommon cause of allograft dysfunction over the study period, accounted for over 10% of cases of allograft dysfunction within the first month of transplantation. Therefore, a high degree of clinical suspicion for TMP-SMX-induced AIN is warranted when confronted with early acute allograft dysfunction.

AA amyloidosis in psoriatic arthritis.

BACKGROUND: Amyloidosis is an extremely rare complication of psoriatic arthritis (PsA) and is associated with a poor prognosis. We report a case of amyloidosis secondary to severe PsA in a young patient and the course of his disease over a 13-year period of aggressive immunosuppression. METHODS: Diagnosis of renal amyloidosis was made on biopsy: multi-agent immunosuppressive therapy was continued with stabilisation of renal function. RESULTS: Marked deterioration in renal function subsequently occurred following a reduction in cyclosporin A (CyA) dose and repeat biopsy confirmed worsening amyloidosis. CONCLUSION: This case report emphasises the need for aggressive control of the inflammatory response in secondary amyloidosis.

Renal transplantation in the elderly--the Irish experience.

BACKGROUND: The aim of this paper was to evaluate patient and kidney graft survival rates in renal transplant recipients and compare the outcomes between the different patient age groups. METHODS: A retrospective review of all adult renal transplants performed at Beaumont Hospital between the years 1986-2001 was carried out. Patients were defined as 'elderly' if they were 65 years of age or older and 'younger' if less than 65 years at the time of transplantation. Patient and transplant graft survival rates were analysed for each age group. RESULTS: Data were analysed on 1462 'younger' patients and 105 'elderly' renal transplant recipients. Estimated patient survival at 1, 5 and 10 years were 96%, 87% and 74% in the younger patient group compared to 85%, 59% and 33% in the elderly group. The adjusted graft survival rates (adjusted for death due to other causes and with a functioning graft in situ) for the younger group were 89%, 77% and 64% at one, five and ten years respectively, while for the elderly group, adjusted one, five and ten year survival rates were 89%, 83% and 70% respectively. CONCLUSIONS: Although the elderly have a shorter life expectancy than the younger population they do benefit from renal transplantation similar to the younger recipients.

A novel approach to improve undergraduate surgical teaching.

BACKGROUND: Undergraduate surgery is at an important crossroads. Many departments report significant difficulties delivering effective teaching. Our student feedback indicated a dated surgical curriculum lacking structure, quality and uniformity. We report on a new "blended" approach employing a combination of professional DVDs, case based discussions, online material and traditional bedside teaching designed to provide structure, standardization, and equality of learning . METHODS: Year 4 students who had undertaken the new course and year 5 students who had participated in the traditional teaching programme were compared. Students completed a 20 item questionnaire about their experiences of the surgical teaching programme. RESULTS: One hundred and seventy-one year 4 (70%) and 148 year 5 students (66%) responded. Domains relating to "Overall Satisfaction with the course", "Approval of innovative teaching methods and interactivity" and "Satisfaction with the clarity of course information" showed improvements when comparing the new and old programmes. However bedside teaching was not rated as highly in the new programme (p<0.05). CONCLUSION: This blended approach has resulted in improved student understanding and engagement. The apparent compromise of bedside teaching may be a reflection of higher expectations. We believe that a similar blended approach has the potential to re-invigorate surgical teaching elsewhere.

DNA array analysis in a Microsoft Windows environment.

Microsoft Windows-based computers have evolved to the point that they provide sufficient computational and visualization power for robust analysis of DNA array data. In fact, smaller laboratories might prefer to carry out some or all of their analyses and visualization in a Windows environment, rather than alternative platforms such as UNIX. We have developed a series of manually executed macros written in Visual Basic for Microsoft Excel spreadsheets, that allows for rapid and comprehensive gene expression data analysis. The first macro assigns gene names to spots on the DNA array and normalizes individual hybridizations by expressing the signal intensity for each gene as a percentage of the sum of all gene intensities. The second macro streamlines statistical consideration of the confidence in individual gene measurements for sets of experimental replicates by calculating probability values with the Student's t test. The third macro introduces a threshold value, calculates expression ratios between experimental conditions, and calculates the standard deviation of the mean of the log ratio values. Selected columns of data are copied by a fourth macro to create a processed data set suitable for entry into a Microsoft Access database. An Access database structure is described that allows simple queries across multiple experiments and export of data into third-party data visualization software packages. These analysis tools can be used in their present form by others working with commercial E. coli membrane arrays, or they may be adapted for use with other systems. The Excel spreadsheets with embedded Visual Basic macros and detailed instructions for their use are available at http://www.ou.edu/microarray.

Adenosquamous carcinoma of the prostate: a case report.

Mixed types of carcinoma of the prostate are rare. The majority of those described (22 cases) are examples of mixed adenocarcinoma and transitional cell carcinoma. Much more unusual is the mixed adenosquamous carcinoma, of which only three cases have been described. This report presents an additional case of the rare adenosquamous carcinoma of the prostate. It discusses the clinicopathologic features and the possible histogenesis of this tumor and suggests a role for stilbestrol in its development.

Specificity of colon specific antigen and colon ovarian tumour antigen.

Sections (5 microns thick) from 101 primary adenocarcinomas (including ovarian, colorectal, gastric, breast, oesophageal, prostatic, pancreatic, endometrial and gall bladder) were incubated wtih anticolon specific antigen (CSA) and anticolon ovarian tumour antigen (COTA) antibodies using the peroxidase antiperoxidase technique with positive and negative controls. Anti-CSA positivity was seen in 19 of 20 colonic adenocarcinomas, but it was also seen in a large number of the other tumours. While anti-COTA staining was positive in 16 of 20 colonic adenocarcinomas and 20 of 30 ovarian adenocarcinomas, it was also positive in a large number of the tumours. Anti-CSA and anti-COTA are not adequately specific in the identification of a colonic or ovarian origin of an adenocarcinoma and cannot reliably be applied to the identification of a metastatic adenocarcinoma of unknown primary site.

Ploidy of smooth muscle tumours: retrospective image analysis study of formalin fixed, paraffin wax embedded tissue.

The feasibility of using an image analyser, the CAS 100, to assess the ploidy of smooth muscle tumours on formalin fixed paraffin wax embedded tissue was assessed. Various different methods of assessment were compared. A paraffin wax block of 15 leiomyomata and 13 leiomyosarcomata yielded serial sections of 3 microns, 5 microns, and 7 microns and a cytospin preparation (from a 50 micron section). Sections and cytospin preparations were stained with Feulgen and quantified using the CAS 100. The suitability of lymphocytes, previously suggested to be unsuitable as control cells in tissue sections due to the compact nature of their DNA, was assessed in sections and cytospin preparations and compared with endothelial cells, the standard alternative, on the same slide. Despite having a mean nuclear area of only 18.5 microns 2 in sections lymphocytes had a similar diploid peak--that is, 4.1 pg--to endothelial cells (mean nuclear area 39 microns 2). A comparison of 3 microns, 5 microns, and 7 microns sections showed 5 microns to be the optimal thickness. Cytospin preparations yielded histograms of superior quality than those from tissue sections. All 15 leiomyomata had a 5C exceeding rate of less than 0.3%. Ten of 11 histologically malignant tumours had a 5C exceeding rate of more than 5% (mean 14%) in sections and cytospins. Two leiomyosarcomata that had arisen in the lower gastrointestinal tract had a mitotic rate of less than or equal to 1/10 per high power fields and yielded histograms similar to those of the leiomyomata. It is concluded that formalin fixed, paraffin wax embedded tissue can be used for DNA quantification by image analysis; that tissue sections yield poorer results than cytospin preparations; that lymphocytes are reliable control cells in cytospin preparations; and that a population of cell greater than 5C is seen in 90% of leiomyosarcomata.

DNA quantitation of Wilms' tumour (nephroblastoma) using flow cytometry and image analysis.

AIMS: To compare flow cytometry (FCM) with image analysis (IA) in the DNA quantitation of Wilms' tumour (WT) and to correlate data so obtained with recognised clinical and pathological prognostic parameters. METHODS: Thirty six patients with histologically proved WT diagnosed between 1980-89 were investigated. Fifteen patients had stage I disease, 10 stage II, six stage III, two stage IV and three stage V. Suspension of nuclei obtained by pepsin digestion of paraffin wax embedded tumour tissue was analysed using a FAC-Scan flow cytometer, and a CAS-100 image analyser. RESULTS: Tumours were concordant in most instances, however, IA identified aneuploidy in two tumour samples which were diploid by FCM. Aneuploidy was detected in 5/33 tumours with favourable histology and 3/3 with unfavourable histology. Three of 28 patients with Stage I, II and V disease and 5/8 patients with stage III and IV had aneuploid tumours. All patients with unfavourable histology died of disease. In the group with favourable histology, 4/5 patients with aneuploid tumours developed recurrent disease compared with 1/27 diploid tumours (p less than 0.0001). CONCLUSIONS: Ploidy may be a useful additional prognostic indicator in Wilms' tumour with favourable histology. Larger scale studies are needed to confirm the relation of ploidy to survival in early stage WT.

Deoxyribonucleic acid ploidy studies in choroidal melanomas.

In several tumors of different organ sites, the amount of DNA in a cell (ploidy) is associated with malignancy. We performed DNA quantitation in 21 choroidal melanomas and compared flow cytometry with image analysis in 11 of these melanomas. We modified our preparation technique to overcome problems with pigment and control cell populations in the image analysis group. Fifteen tumors were diploid and two tumors were tetraploid. Four tumors were unprocessable by flow cytometry, but two of these tumors were diploid by image analysis. Image analysis also detected tetraploidy in two tumors that were diploid by flow cytometry. During image analysis, cells were classified according to the Callendar classification and histograms were plotted for each cell type. All spindle A cells were diploid and most tetraploid peaks were formed by epithelioid cells. The use of image analysis on small samples of choroidal melanomas may be of value both in confirmation of diagnosis and prognosis of these lesions, and perhaps therapeutically, for example, in the monitoring of radiation treatment.

Six year follow up of forty five pregnant opiate addicts.

Forty five pregnant addicts had attended the National Drug Treatment Centre between 1984-1986. At that time they received intensive counselling, low dose Methadone maintenance and both ante natal and post natal care. Our aim was to follow these women six years later focusing on their drug use and outcome of their children. The women were followed up by chart review, individual interviews and liaison with the social and probation services. Results indicate that a high proportion of the women abused chaotically (50%). There is a worrying high incidence of HIV positive patients (53.4%) and a mortality figure of 15.5% (7). However only 13 women (28.6%) have had further children and 22 women (49%) are currently using some form of contraception. Only 23 women (51.1%) have had further contact with probation services. Five children (11.3%) are under formal care order and 4 children have become HIV positive in their own right. In conclusion, while these women have benefitted in certain areas e.g. family planning, contact with probation services, in other areas they have remained chaotic e.g. continued drug abuse or HIV risk taking behaviour. Thus the authors believe that future programmes should concentrate more directly on detoxification and rehabilitation after pregnancy. We also believe that because of the chaotic nature of these women some review of an "at risk" register for the children should be carried out.

Hepatitis C infection among injecting drug users attending the National Drug Treatment Centre.

During a one year period from August 1992 to August 1993, 272 injecting drug users attending the National Drug Treatment Centre were tested for antibody to Hepatitis C Virus with a second generation EIA test. The overall sero-prevalence was 84% (N = 229). A significantly greater proportion of females tested positive than males (Female: Male, 94% v 80%, p < 0.012). Looking at sero-prevalence of Hepatitis C in relation to duration of intravenous drug misuse, we found that in those patients with a duration of misuse of greater than two years (N = 156) the sero-prevalence was 95% and in those with a duration of intravenous drug misuse of less than two years (N = 116) the sero-prevalence was 70%. We conclude that needle sharing continues to occur among injecting drug users during their first two years of injecting, despite the existence of harm minimization programmes. Our results would suggest that female injecting drug users are involved in greater at risk behaviour in relation to Hepatitis C than their male counterparts.

HIV risk behaviour in Irish intravenous drug users.

The aim of the study was to measure HIV prevalence and risk behaviour in 185 Irish Intravenous Drug Misusers. Information was obtained by application of a standardised WHO questionnaire covering HIV risk behaviour in the preceding 6 months. HIV serostatus was obtained by saliva/blood sample testing. One hundred and 3 (55.7 per cent) shared and 114 (61.6 per cent) lent used injecting equipment in the previous 6 months. 97 (94.2 per cent) of those who shared always cleaned the needles before use but only 48 (49.5 per cent) of these always cleaned in an efficient manner. One hundred and 14 (79.2 per cent) males and 28 (68.3 per cent) females reported heterosexual activity in the preceding 6 months. On examination sexual risk behaviour was found to be high. 50.5 per cent of males and 63 per cent of females never used condoms with regular partners. 32.6 per cent of males never used condoms with casual partners. The large majority of partners of male I.D.U'.s (both regular and casual) were non injectors. Therefore there is potential for sexual spread of HIV into the non-injecting heterosexual population. Conversely the vast majority of partners of female IDU's were injectors. This suggests that female IDU's are at higher risk of HIV infection than their male counterparts. HIV prevalence in the study group was 8.4 per cent. Implications of results for future intervention are discussed.

The prevalence of chemical substance and alcohol abuse in an obstetric population in Dublin.

OBJECTIVE: To determine the prevalence of illicit drug abuse and alcohol use in an obstetric population based in an urban maternity hospital. SETTING: A collaborative study between the Rotunda Hospital, Dublin and the Irish National Drug Advisory & Treatment Centre. DESIGN: A prospective study consisting of anonymous, unlinked urine testing of 504 'first visit' antenatal patients and a separate group of 515 patients six weeks after delivery. METHODS & OUTCOME MEASURES: Toxicological screening using enzyme-linked immunoassay techniques, with all positive samples being reanalysed. Drug histories were taken and samples were tested for alcohol and six of the most commonly abused drugs. The pre- and postnatal prevalence of abuse was matched with demographic data. RESULTS: The prevalence of chemical substance misuse in the antenatal population was 2.8% and 5.6% in the postnatal population. Substances identified included benzodiazepines, cannabis, amphetamines, opiates and cocaine. Less than 2% of samples tested positive for alcohol. None of the women yielding positive samples had been pre-identified on the basis of history. A significant proportion of the women were in the high risk categories with regard to age and socio-economic status. CONCLUSION: The prevalence of drug misuse antenatally was nearly 3% and postnatally almost 6%. Substance abusers in pregnancy are more likely to be single, unemployed, and to have had a previous pregnancy.