Sean W. Murphy

Higher risk for renal failure in first-degree relatives of white patients with end-stage renal disease: a population-based study.

To explore the possibility that hereditary factors increase the risk for end-stage renal disease (ESRD), 669 patients with ESRD in the province of Newfoundland, Canada from 1987 to 1993 were studied. Detailed family histories were obtained from 584 (87%) consecutive probands and 499 spousal control subjects. Diseases with a Mendelian pattern of inheritance accounted for 8.4% of the cases; 4.5% of the cases were caused by autosomal dominant polycystic kidney disease (ADPKD). Glomerulonephritis was the original cause of renal failure in 25% of the probands, diabetes mellitus (DM) in 20%, unknown in 14%, interstitial kidney disease in 11%, other disease in 12%, multifactorial in 4%, and hypertension in 5%. In the group without a Mendelian pattern of inheritance, 28% of the probands had a first-, second-, or third-degree relative with renal failure associated with death or dialysis versus 15% of the controls. Compared with 0.4% of the control group, 1.2% of the first-degree relatives of probands developed renal failure (odds ratio [OR]=3.0; 95% confidence interval [CI], 1.7 to 5.2). No difference was observed when risks were compared for second-degree relatives, but a highly significant increased risk was observed for third-degree relatives (OR=2.1; 95% CI, 1.2 to 3.4). The highest rates of affected first-degree relatives occurred in probands with hypertensive renal failure (2.3%), DM (1.6%), and interstitial kidney disease (1.6%). The annual provincial incidence of ESRD, registered with the Canadian Organ Replacement Registry (CORR) from 1981 to 1993 was 79 per million, excluding the 8% of patients with Mendelian inherited disease. The similar rate of ESRD in first-degree relatives of probands without Mendelian inherited disease was 297 per million. We conclude that not only is the contribution of Mendelian inherited diseases to ESRD high, but there is also an increased risk for renal failure in first-degree relatives of probands without a Mendelian inherited renal disease in a white population.

Prognostic significance of BAG-1 expression in nonsmall cell lung cancer.

The purpose of this study was to evaluate the expression of BAG‐1 in a cohort of patients with nonsmall cell lung cancer (NSCLC). The intensity and subcellular distribution of BAG‐1 expression were correlated with overall survival. Tumor samples were collected from 85 patients diagnosed with NSCLC between 1993–1995 in St. Johns, Newfoundland. Expression of BAG‐1 was determined by immunohistochemistry using polyclonal anti‐BAG‐1 antibody. There was significant variation in the immunohistochemical staining patterns of BAG‐1, including nonstaining and staining of either the cytoplasm, nucleus or both. Univariate Cox regression analysis showed that those patients whose tumor overexpressed BAG‐1 had a significant reduction in the risk of death (hazard ratio = 0.53, p = 0.03). The survival advantage of patients with BAG‐1 overexpression tumor was also demonstrated by Kaplan‐Meier analysis and log‐rank tests (median survival 30.10 months versus 17.04 months, p = 0.05). In addition, multivariate Cox regression analysis showed that patients whose tumor exhibited intense cytoplasmic staining had a further reduction of the risk of death (hazard ratio = 0.42, p = 0.03) and this effect was independent of age, stage and histology. All stages were included in the analysis. Our preliminary data strongly indicate that further investigation is warranted to better define the role of BAG‐1 as an independent prognostic factor in NSCLC.

BAG-1 Expression Correlates with Bcl-2, p53, Differentiation, Estrogen and Progesterone Receptors in Invasive Breast Carcinoma

BAG-1, a recently identified anti-apoptotic protein, is overexpressed in the majority of invasive breast carcinomas. Overexpression of BAG-1 is important for both multi-step oncogenesis and resistance of cancer cells to apoptosis induced by DNA-damaging alkylating agents. BAG-1 protein species are localized differentially; nuclear expression may be associated with a shorter disease-free and overall survival in early stage breast cancer, while cytoplasmic expression has been associated with longer survival in non-small cell lung cancer. Growing evidence suggests that Bcl-2 and p53 are also involved in the oncogenesis of breast cancer. Since BAG-1 interacts with Bcl-2 and is upregulated by mutant p53 in vitro, it would be interesting to determine if their expressions are correlated with each other and with other clinical prognostic factors in invasive breast cancer. To address this question we conducted a large scale retrospective study of BAG-1, Bcl-2 and p53 in 185 breast cancer patients. Our study again showed that BAG-1 is overexpressed in the majority of breast cancer patients. In addition, it demonstrated that the expression of BAG-1 correlates with that of Bcl-2, p53, differentiation, estrogen and progesterone receptors. Our clinical study supports the preclinical finding of the interaction between BAG-1 and Bcl-2, p53 and estrogen and progesterone receptors. Further experiments to explore the prognostic and therapeutic role of BAG-1 in breast cancer are warranted.

Screening for cardiovascular disease in dialysis patients

The burden of cardiac disease in dialysis patients is high, resulting from cardiomyopathy and from coronary artery disease. Asymptomatic dialysis patients, patients with heart failure, patients with symptomatic ischaemic heart disease, and patients being evaluated for renal transplantation all require investigation to determine the presence or the extent of heart disease. Echocardiography is very useful for screening for cardiomyopathy, but should be undertaken when patients are euvolaemic. Non-invasive tests for coronary artery disease, particularly exercise-based tests, are less sensitive and less specific in dialysis patients than in the general population. Dobutamine stress echocardiography may be more sensitive in patients with renal failure than other investigations. Patients with abnormal screening tests or symptomatic ischaemic heart disease should undergo coronary angiography and subsequent revascularization procedures if indicated.

THE CLINICAL EPIDEMIOLOGY OF CARDIOVASCULAR DISEASES IN CHRONIC KIDNEY DISEASE: Management of Heart Failure and Coronary Artery Disease in Patients with Chronic Kidney Disease

Cardiovascular disease (CVD) is a major contributor to the mortality and morbidity of patients who suffer from chronic kidney disease (CKD). Heart failure and ischemic heart disease (IHD) are both highly prevalent in this population. The diagnosis of myocardial dysfunction is usually based on echocardiography. As in the general population, systolic dysfunction is treated with a combination of diuretics, renin‐angiotensin system blockade, and β‐receptor antagonists. Diastolic dysfunction is best managed by eliminating the cause. Non‐invasive tests for coronary artery disease (CAD) may be less reliable in patients with renal disease compared with nonuremic patients. Medical therapy of IHD in this population is generally similar to that for other patient groups, but surgical revascularization appears to carry a higher risk of complications with poorer clinical outcomes. The choice of revascularization procedure (coronary artery bypass grafting versus percutaneous transluminal angioplasty) should be based on the specific coronary anatomy of a given patient as well as a consideration of other comorbid factors.

Reliability of the Interprofessional Collaborator Assessment Rubric (ICAR) in Multi Source Feedback (MSF) with post-graduate medical residents

BackgroundIncreased attention on collaboration and teamwork competency development in medical education has raised the need for valid and reliable approaches to the assessment of collaboration competencies in post-graduate medical education. The purpose of this study was to evaluate the reliability of a modified Interprofessional Collaborator Assessment Rubric (ICAR) in a multi-source feedback (MSF) process for assessing post-graduate medical residents’ collaborator competencies.MethodsPost-graduate medical residents (n = 16) received ICAR assessments from three different rater groups (physicians, nurses and allied health professionals) over a four-week rotation. Internal consistency, inter-rater reliability, inter-group differences and relationship between rater characteristics and ICAR scores were analyzed using Cronbach’s alpha, one-way and two-way repeated measures ANOVA, and logistic regression.ResultsMissing data decreased from 13.1% using daily assessments to 8.8% utilizing an MSF process, p = .032. High internal consistency measures were demonstrated for overall ICAR scores (α = .981) and individual assessment domains within the ICAR (α = .881 to .963). There were no significant differences between scores of physician, nurse, and allied health raters on collaborator competencies (F2,5 = 1.225, p = .297, η2 = .016). Rater gender was the only significant factor influencing scores with female raters scoring residents significantly lower than male raters (6.12 v. 6.82; F1,5 = 7.184, p = .008, η 2 = .045).ConclusionThe study findings suggest that the use of the modified ICAR in a MSF assessment process could be a feasible and reliable assessment approach to providing formative feedback to post-graduate medical residents on collaborator competencies.

Clinical research of kidney diseases IV: standard regression models

Statistical modelling is similar to the engineering concept of the study outcome being a mixture of signal and noise. For example, the signal of a model of left ventricular mass (LVM) as a function of systolic blood pressure (SBP) [1] is the average change in LVM as SBP changes (systematic component). The noise is what remains to be explained of LVM variability once the effect of SBP has been taken into account (random component). Statisticians assess the characteristics of these two elements in different ways, to establish whether a model is appropriate [2]. The present review introduces two popular families of standard regression models: generalized linear models and models for time-to-event data. The conditions that make each model appropriate are summarized along with the epidemiological meaning of its coefficients (parameters). The interested reader is referred to specific textbooks for details on model specification and assumption verification methods [3–8].

Prognostic significance of BAG-1 expression in non-small cell lung cancer

The purpose of this study was to evaluate the expression of BAG-1 in a cohort of patients with nonsmall cell lung cancer (NSCLC). The intensity and subcellular distribution of BAG-1 expression were correlated with overall survival. Tumor samples were collected from 85 patients diagnosed with NSCLC between 1993-1995 in St. Johns, Newfoundland. Expression of BAG-1 was determined by immunohistochemistry using polyclonal anti-BAG-1 antibody. There was significant variation in the immunohistochemical staining patterns of BAG-1, including nonstaining and staining of either the cytoplasm, nucleus or both. Univariate Cox regression analysis showed that those patients whose tumor overexpressed BAG-1 had a significant reduction in the risk of death (hazard ratio = 0.53, p = 0.03). The survival advantage of patients with BAG-1 overexpression tumor was also demonstrated by Kaplan-Meier analysis and log-rank tests (median survival 30.10 months versus 17.04 months, p = 0.05). In addition, multivariate Cox regression analysis showed that patients whose tumor exhibited intense cytoplasmic staining had a further reduction of the risk of death (hazard ratio = 0.42, p = 0.03) and this effect was independent of age, stage and histology. All stages were included in the analysis. Our preliminary data strongly indicate that further investigation is warranted to better define the role of BAG-1 as an independent prognostic factor in NSCLC.

Divalent Ion Abnormalities and Hyperparathyroidism in the Etiology of Cardiovascular Disease of Patients with Chronic Renal Failure

Cardiovascular disease is the most common cause of death in patients with end-stage renal disease (ESRD) and accounts for much of the morbidity in this population. Dialysis patients are subject to atherosclerosis and consequent ischemic heart disease, but myocardial dysfunction and overt heart failure also are highly prevalent. Some 84% of patients have left ventricular hypertrophy (LVH), left ventricular (LV) dilatation, or low fractional shortening at the initiation of ESRD therapy, and LVH has been found in 38% of patients with chronic renal failure (CRF) prior to the requirement for dialysis (1–3). The presence of LVH or LV dilatation (or both) is clearly a poor prognostic factor (1, 2). The etiology of myocardial dysfunction in renal failure, often calleduremic cardiomyopathy , is considered to be multifactorial (4). The presence of hypertension, anemia, fluid overload, arteriovenous fistulas, acidosis, electrolyte disturbances, and myocardial ischemia may all play a role. It has long been postulated, however, that uremic patients have substances in their serum capable of adversely affecting myocardial cells. There is no single uremic toxin, but numerous substances exhibiting toxic effects have been identified in the serum of uremic patients. Parathyroid hormone (PTH) is one such factor that has been implicated in the pathogenesis of a number of cardiovascular abnormalities seen in association with renal failure (Table 1). Secondary hyperparathyroidism, resulting in a chronic excess of PTH, remains a very common feature of advanced CRF, despite the widespread availability of effective measures to control it. Hyperparathyroidism and the associated derangements in calcium, magnesium, and phosphate are most recognized for their role in renal bone disease, but an adverse effect of excess PTH on cardiac function was first hypothesized in the 1960s by Selye (5) and by Lehr (6). A substantial amount of evidence now exists that suggests a role for excess PTH and the changes in ion regulation induced by PTH in the pathogenesis of uremic cardiomyopathy. In addition, PTH may be important in the dysfunction of virtually every other organ system that is affected as part of the uremic syndrome (7). PTH now is regarded by many nephrologists as a key uremic toxin. In this article, the evidence regarding the role of divalent ion abnormalities and excess PTH in the development of cardiovascular disease in patients with CRF is considered. Both atherosclerotic disease and uremic cardiomyopathy are discussed. The implications for patient management and the potential benefits of controlling these risk factors also is examined.

Sleep apnea in patients with chronic kidney disease: a single center experience

Abstract Purpose: The primary objective of this cross-sectional study was to test factors associated with sleep apnea in patients with chronic kidney disease (CKD). The prevalence of sleep apnea was also assessed. Methods: We recruited patients with CKD Stage 3–5 who lived in the St. John’s area from September 2012 to December 2012. The Berlin Questionnaire and Short Form 36 Quality of Life Health Survey Questions (SF-36) were administered to all participants. Results: We recruited 303 patients (41% female). A total of 157 (51.8%) patients had a high risk for sleep apnea. Higher body mass index and young age were correlated with sleep apnea. Physical component score of SF-36 (PCS) tested as a continuous variable indicated a significant association with the risk for sleep apnea (OR: 0.97, 95% CI: 0.94–0.99, p = 0.03). The association implies 3% change per one point increase in PCS. We categorized mental component score of SF-36 (MCS) into four quartiles, as the linearity assumption was violated. There was a 61% risk increase for poor sleep in those with an MCS score less than the 75th percentile, when compared to those above the 75th percentile (OR: 0.39, 95% CI: 0.21–0.71, p = 0.002). Conclusions: Sleep apnea is common in kidney patients. People who have low PCS and MCS scores are more prone to sleep apnea or vice versa. Our results also indicate that high BMI and young age are associated with sleep apnea.