Myocardial bioenergetic abnormalities in experimental uremia.

PURPOSE: Cardiac bioenergetics are known to be abnormal in experimental uremia as exemplified by a reduced phosphocreatine (PCr)/adenosine triphosphate (ATP) ratio. However, the progression of these bioenergetic changes during the development of uremia still requires further study and was therefore investigated at baseline, 4 weeks and 8 weeks after partial nephrectomy (PNx). METHODS: A two-stage PNx uremia model in male Wistar rats was used to explore in vivo cardiac and skeletal muscles' bioenergetic changes over time. High-energy phosphate nucleotides were determined by phosphorus-31 nuclear magnetic resonance ((31)P-NMR) and capillary zone electrophoresis. RESULTS: (31)P-NMR spectroscopy revealed lower PCr/ATP ratios in PNx hearts compared to sham (SH)-operated animals 4 weeks after PNx (median values given ± SD, 0.64±0.16 PNx, 1.13±0.31 SH, P<0.02). However, 8 weeks after PNx, the same ratio was more comparable between the two groups (0.84±0.15 PNx, 1.04±0.44 SH, P= not significant), suggestive of an adaptive mechanism. When 8-week hearts were prestressed with dobutamine, the PCr/ATP ratio was again lower in the PNx group (1.08±0.36 PNx, 1.55±0.38 SH, P<0.02), indicating a reduced energy reserve during the progression of uremic heart disease. (31)P-NMR data were confirmed by capillary zone electrophoresis, and the changes in myocardial bioenergetics were replicated in the skeletal muscle. CONCLUSION: This study provides evidence of the changes that occur in myocardial energetics in experimental uremia and highlights how skeletal muscle bioenergetics mirror those found in the cardiac tissue and so might potentially serve as a practical surrogate tissue during clinical cardiac NMR investigations.

Measuring the quality of end of life management in patients with advanced kidney disease: results from the pan-Thames renal audit group.

BACKGROUND: Despite a recent increased awareness of the need for quality End of Life (EOL) care for patients with advanced kidney disease, there is no established method for measuring or auditing outcomes relating to EOL care in this population. METHODS: We designed a one-page proforma, which was used to collect data on various aspects of EOL care relating to all deaths of patients on dialysis and patients dying on specialist renal wards, over a predefined 8-week period in 10 hospitals in London and South-East England. RESULTS: One hundred and thirty-eight deaths were recorded over the 8-week study period. The majority of patients (83%) were receiving maintenance haemodialysis prior to their terminal presentation. About 69% of deaths occurred during an in-patient hospital admission-of these, 36% were considered 'unexpected' and most quality markers of good EOL management were significantly less likely to be achieved in these patients, including use of palliative care strategies, good symptom control and overall quality of death. Thirty-six per cent of patients were from various ethnic minorities, and in this group, there was a trend towards lower use of palliative care pathways and lower rates of withdrawal from dialysis. CONCLUSIONS: This study confirms that it is possible to measure many important outcomes relating to quality of EOL care using a proforma completed at the time of death. Our findings suggest that many aspects of good EOL care are under-achieved in our region. This, in part, is due to a failure to recognize the worsening trajectory of the deteriorating patient, resulting in missed opportunities for EOL care planning and appropriate symptom control. Our observations suggest that there is a need for improved education and training in this area, particularly in detection of the dying patient, the value of advance care planning and the utility of tools such as the Liverpool Care Pathway.

The relationship of ethnicity to the prevalence and management of hypertension and associated chronic kidney disease.

BACKGROUND: The effect of ethnicity on the prevalence and management of hypertension and associated chronic kidney (CKD) disease in the UK is unknown. METHODS: We performed a cross sectional study of 49,203 adults with hypertension to establish the prevalence and management of hypertension and associated CKD by ethnicity. Routinely collected data from general practice hypertension registers in 148 practices in London between 1/1/07 and 31/3/08 were analysed. RESULTS: The crude prevalence of hypertension was 9.5%, and by ethnicity was 8.2% for White, 11.3% for South Asian and 11.1% for Black groups. The prevalence of CKD stages 3-5 among those with hypertension was 22%. Stage 3 CKD was less prevalent in South Asian groups (OR 0.77, 95% CI 0.67 - 0.88) compared to Whites (reference population) with Black groups having similar rates to Whites. The prevalence of severe CKD (stages 4-5) was higher in the South Asian group (OR 1.53, 95% CI 1.17 - 2.0) compared to Whites, but did not differ between Black and White groups. In the whole hypertension cohort, achievement of target blood pressure (< 140/90 mmHg) was better in South Asian (OR 1.43, 95% CI 1.28 - 1.60) and worse in Black groups (OR 0.79, 95% CI 0.74 - 0.84) compared to White patients. Hypertensive medication was prescribed unequally among ethnic groups for any degree of blood pressure control. CONCLUSIONS: Significant variations exist in the prevalence of hypertension and associated CKD and its management between the major ethnic groups. Among those with CKD less than 50% were treated to a target BP of ≤ 130/80 mmHg. Rates of ACE-I/ARB prescribing for those with CKD were less than optimal, with the lowest rates (58.5%) among Black groups.

Sources of variation in performance on a shared OSCE station across four UK medical schools.

CONTEXT: High-stakes undergraduate clinical assessments should be based on transparent standards comparable between different medical schools. However, simply sharing questions and pass marks may not ensure comparable standards and judgements. We hypothesised that in multicentre examinations, teaching institutions contribute to systematic variations in students' marks between different medical schools through the behaviour of their markers, standard-setters and simulated patients. METHODS: We embedded a common objective structured clinical examination (OSCE) station in four UK medical schools. All students were examined by a locally trained examiner as well as by a centrally provided examiner. Central and local examiners did not confer. Pass scores were calculated using the borderline groups method. Mean scores awarded by each examiner group were also compared. Systematic variations in scoring between schools and between local and central examiners were analysed. RESULTS: Pass scores varied slightly but significantly between each school, and between local and central examiners. The patterns of variation were usually systematic between local and central examiners (either consistently lower or higher). In some cases scores given by one examiner pair were significantly different from those awarded by other pairs in the same school, implying that other factors (possibly simulated patient behaviour) make a significant difference to student scoring. CONCLUSIONS: Shared undergraduate clinical assessments should not rely on scoring systems and standard setting which fail to take into account other differences between schools. Examiner behaviour and training and other local factors are important contributors to variations in scores between schools. The OSCE scores of students from different medical schools should not be directly compared without taking such systematic variations into consideration.

Failing finals is often a surprise for the student but not the teacher: identifying difficulties and supporting students with academic difficulties.

Weak students often continue with little guidance and feedback, and often have ongoing difficulties. Early support may stop students experiencing a cycle of failure. Key to supporting struggling students is to identify reasons for poor performance. We explored the reasons for poor performance in a cohort of fifth year students who failed their final clinical examinations. Qualitative methods (interviews and a focus group) identified several themes. Many of the students had experienced personal problems or issues. They regarded themselves as competent students although they had significantly greater problems with earlier exams than the year mean, and significantly lower scores in formative assessments during the year leading up to these exams than their peers. Factors relating to the exam itself were seen as relevant to failure. More specific support and feedback throughout the MBcHB was seen as desirable. They tended to take little personal responsibility for their performance and were reluctant to seek help. We conclude that while the onus is on Faculty to identify and support failing students, the results indicate that students would benefit from support in developing self-reflection skills in such a way to support life-long learning.

Factor analysis can be a useful standard setting tool in a high stakes OSCE assessment.

BACKGROUND: No method of standard setting for objective structured clinical examinations (OSCEs) is perfect. Using scores aggregated across stations risks allowing students who are incompetent in some core skills to pass an examination, which may not be acceptable for high stakes assessments. AIM: To assess the feasibility of using a factor analysis of station scores in a high stakes OSCE to derive measures of underlying competencies. METHODS: A 12-station OSCE was administered to all 192 students in the penultimate undergraduate year at the University of Aberdeen Medical School. Analysis of the correlation table of station scores was used to exclude stations performing unreliably. Factor analysis of the remaining station scores was carried out to characterise the underlying competencies being assessed. Factor scores were used to derive pass/fail cut-off scores for the examination. RESULTS: Four stations were identified as having unpredicted variations in station scores. Analysis of the content of these stations allowed the underlying problems with the station designs to be isolated. Factor analysis of the remaining 8 stations revealed 3 main underlying factors, accounting for 53% of the total variance in scores. These were labelled "examination skills", "communication skills" and "history taking skills". CONCLUSION: Factor analysis is a useful tool for characterising and quantifying the skills that are assessed in an OSCE. Standard setting procedures can be used to calculate cut-off scores for each underlying factor.

Structural remodeling of resistance arteries in uremic hypertension.

BACKGROUND: Structural remodeling of the resistance vasculature is present in many forms of human and experimental hypertension. In particular, an increase in the ratio of wall thickness to lumen diameter develops, and might in itself maintain hypertension by increasing vascular resistance. Because uremia is associated with raised peripheral resistance, hypertension, and histologic changes suggestive of vascular remodeling, we sought to formally examine the structural and mechanical (elastic) properties of isolated pressurized resistance arteries in uremic hypertension. METHODS: Cremaster, cerebral and mesenteric arteries from subtotally nephrectomised Wistar-Kyoto rats, normotensive control Wistar-Kyoto rats, and spontaneously hypertensive rats were mounted on a pressure myograph and relaxed in calcium-free buffer. Wall thickness and lumen diameter were measured at increasing lumen pressures from 10 to 200 mm Hg, and from this wall:lumen ratio, wall cross-sectional area, and an index of elasticity were derived. RESULTS: In uremic hypertensive animals increased wall:lumen ratio and decreased lumen diameter was seen in cremaster and mesenteric arteries, although no significant changes were observed in cerebral arteries, compared to normotensive controls. In spontaneously hypertensive animals increased wall thickness and wall:lumen ratio was seen in cerebral and mesenteric arteries, decreased lumen diameter in cremaster and mesenteric arteries, and increased wall cross-sectional area in cerebral arteries, compared to normotensive controls. Elasticity of the arterial wall in uremic and spontaneously hypertensive animals did not differ from normotensive controls. CONCLUSION: Cremaster and mesenteric resistance arteries undergo predominantly eutrophic inward remodeling in uremic hypertension, broadly similar to that seen in spontaneous hypertension.

Calpain is activated in experimental uremia: is calpain a mediator of uremia-induced myocardial injury?

BACKGROUND: The cysteine proteases calpain and caspase-3 are known mediators of cell death. The aim of this study was to assess their contribution to the tissue damage found in experimental uremia. METHODS: Calpain and caspase-3 activities were measured in the hearts of rats that were sham-operated (control), sham-operated and spontaneously hypertensive (SHR), and those rendered uremic by 5/6 nephrectomy (uremic). In an in vitro study, heart myoblasts (Girardi) were incubated with human serum from healthy subjects (control serum conditioned media, CSCM) or uremic patients (uremic serum conditioned media, USCM), in the presence and absence of calpain and caspase-3 inhibitors. After 48 hours the activity of calpain and caspase-3 was measured, and cell injury determined by DNA fragmentation (ELISA) and lactate dehydrogenase (LDH) release. An in situ assay was designed to study how USCM affects calpain activity over time. RESULTS: In the in vivo study, mean calpain activities were almost identical in the control and SHR groups, but calpain and caspase-3 activities were much elevated in the uremic group (P < 0.01 and 0.001 respectively vs. control). The SHR group had significantly higher mean arterial blood pressure (P < 0.001 vs. control, 0.01 vs. uremic). In the in vitro study calpain activity and DNA fragmentation were markedly higher in USCM treated cells compared to CSCM (both P<0.05). Both were reduced in USCM cells containing calpain inhibitors (E64d, calpastatin, or PD 150606). LDH release was raised also in USCM treated cultures (P < 0.05), which only the E64d treatment could significantly reduce (P < 0.02). Caspase-3 activities were similar in USCM and CSCM groups. The in situ assay showed significant increases in calpain activity in USCM treated cells compared to CSCM after just 3.5 hours (P<0.01). CONCLUSIONS: In vivo results suggest that the increases in calpain and caspase-3 activity in uremic rat hearts were primarily due to uremia and not to hypertension. In vitro data demonstrate that uremia-induced cell injury can be attenuated by calpain inhibition. Therefore, it is likely that calpain is a mediator of uremia-induced myocardial injury.

The myogenic response in uremic hypertension.

BACKGROUND: The constriction of resistance arteries in response to an increase in transmural pressure, the myogenic response, is thought to be an important determinant of peripheral vascular resistance and therefore of arterial blood pressure. Since raised peripheral resistance is known to occur in uremic hypertension, abnormal myogenic constriction might be responsible. We sought to assess the myogenic response of resistance arteries from the subtotal nephrectomy rat model of uremic hypertension. METHODS: Uremic Wistar-Kyoto (WKYU) rats, and sham-operated normotensive (WKYC) and spontaneously hypertensive (SHRC) controls were studied in parallel. Skeletal muscle arteries were mounted on a pressure myograph and allowed to develop myogenic constriction. The active internal diameter was measured at increasing lumen pressures from 20 to 200 mm Hg. Vascular smooth muscle then was relaxed in a calcium free solution containing nitroprusside, and the passive internal diameter measured at the same pressure steps. The ratio of active to passive diameter at any given pressure was used to assess the myogenic response. RESULTS: Myogenic constriction was not increased in either WKYU or SHRC compared to WKYC at pressures up to 180 mm Hg. CONCLUSIONS: Increased myogenic tone is not the cause of uremic hypertension.

Cardiac troponin T and creatine kinase MB content in skeletal muscle of the uremic rat.

BACKGROUND: The assertion that creatine kinase MB (CK-MB) and the developmental isoforms of cardiac troponin T (cTnT) are expressed by skeletal muscle in some clinical settings is an extrapolation from nonuremic rodent studies. We studied the content of CK-MB and cTnT in skeletal muscle of the renal-insufficient rat. METHODS: Skeletal muscles (gastrocnemius) were collected from both five-sixths nephrectomized rats (n = 11) and sham-operated controls (n = 11). cTnT content was analyzed by Elecsys (Roche), immunoblotting, and immunohistochemistry with antibodies M7 and M11-7 (Roche). CK isoenzymes were analyzed electrophoretically. RESULTS: Trace concentrations of cTnT were detected in some of the skeletal muscle samples [controls (3 of 11) and uremic rats (1 of 11)] at concentrations <0.01% of that detected in heart. By contrast, positive staining appeared in both groups with M11-7 by immunoblotting and immunohistochemistry. No immunoreactivity was detected in skeletal muscle using M7 in the immunoblot format, although immunoreactivity was detected by immunohistochemistry in all samples. The median percentages of CK-MB were 6.0% and 4.1% for the skeletal muscle from control and uremic rats, respectively. CONCLUSION: The detection of cTnT and CK-MB in skeletal muscle does not differ for uremic rats compared with sham-operated controls. cTnT isoforms detected by qualitative methods are not detected with the cTnT immunoassay. Observations with rodents should not necessarily be extrapolated to humans.