Pre-test Cortisol Levels in Predicting Short Synacthen Test Outcome: A Retrospective Analysis.

Objective: Short Synacthen tests (SSTs) are expensive, dependent on Synacthen availability, and need supervision. To reduce SST testing, we examined the utility of pre-test cortisol (Cort0) and related parameters in predicting outcome. Design and Measurements: We retrospectively examined the following in all SSTs; (i) Cort0 (ii) indications (iii) and time and place of testing. Receiver operated characteristic (ROC) curves were devised for Cort0 to obtain the best cut-off for outcome prediction in those who had SSTs between 8 and 10 am (Group 1) and at other times (Group 2). Results: Of 506 SSTs, 13 were unsuitable for analysis. 111/493 SSTs (22.5%) were abnormal. (1) ROC curves predicted - (a) SST failure with 100% specificity when Cort0 was ⩽124 nmol/L (Group 1), or ⩽47 (Group 2); (b) a normal SST with 100% sensitivity when Cort0 ⩾314 nmol/L (Group 1) and ⩾323 nmol/L (Group 2). (2) There was significant correlation between Cort0 and 30-minute cortisol (rs = 0.65-0.78, P < .001). (3) Median Cort0 was lower in those who failed SSTs compared to those who passed (147 vs 298 nmol/L respectively, P < .001). (4) SST failure was commoner in Group 1 vs 2 (P = .001). (5) There was no difference in outcome between out-patient and inpatient SSTs. (6) SST failure was most common for 'steroid related' indications (39.6%, P < .001). Conclusions: This study indicates that (1) Cort0 ⩾ 323 (Group1) and ⩾314 nmol/L (Group 2) predicted a normal SST with 100% sensitivity; (2) Using these cut offs 141/493 (28.6%) tests may have been avoided; (3) supporting evidence should be considered in those with a lower pre-test predictability of failure.

Prepared and motivated to work in midwifery continuity of care? A descriptive analysis of midwifery students' perspectives.

BACKGROUND: Internationally, midwifery education and maternity services are evolving to promote midwifery continuity of care. It is unclear whether current Australian midwifery education programs are graduating a midwifery workforce prepared and motivated to work in this way. AIM: To discover how well midwifery students in Australia feel they have been prepared and motivated to work in midwifery continuity of care when they enter practice. METHODS: A pragmatist approach was used. Participants were final year midwifery students at one Australian university participating in the Midwifery Student Evaluation of Practice (MidSTEP) project over three consecutive years. Descriptive analysis of selected scaled and free text responses was undertaken to ascertain how students' clinical practice experiences had influenced their learning, development and career aspirations. RESULTS: Exposure to midwifery continuity of care had profound impact on students' learning, enabling them to provide woman-centred midwifery care whilst increasing confidence and preparedness for practice. The majority were motivated to work in midwifery continuity of care upon graduation. A small minority of participants felt unprepared to work in midwifery continuity of care, attributing this to their family commitments, a sense of needing more experience or unsupportive workplace cultures. SUMMARY: Midwifery continuity of care experiences are highly valued by midwifery students and positively influence confidence, preparation and motivation for beginning practice. It is necessary to review education standards to ensure quality, consistency, and adequacy of these experiences throughout pre-registration midwifery education. This will assist in generating a midwifery workforce prepared and motivated to deliver the goals of maternity service reform.

Thyroid Autoimmunity and Dysfunction in Sri Lankan Children and Adolescents After 22 Years of Sustained Universal Salt Iodization.

Background: Sri Lanka introduced universal salt iodization (USI) in 1995 after which we demonstrated a high thyroglobulin antibody (TgAb) prevalence in 1998. However, it is unclear whether thyroid autoimmunity persists in the long term in populations exposed to sustained USI and whether such populations have an excess of thyroid dysfunction. We evaluated the prevalence of thyroid autoantibodies and dysfunction in Sri Lankan children and adolescents after more than two decades of sustained USI. Methods: We selected 10- to 18-year-old subjects of both sexes (randomized cluster sampling) from all 9 provinces of Sri Lanka in this cross-sectional study. Blood, urine, and anthropometric data were collected and thyroid ultrasound scans were performed. Validated statistical methods were used to derive local population-specific reference ranges for all thyroid parameters. We also measured urine iodine concentration (UIC), salt, and water iodine concentrations. Results: Blood and urine samples from 2507 and 2473 subjects respectively, and ultrasound scans from 882 subjects were analyzed. Population-derived upper limits for thyroid peroxidase antibody (TPOAb) and TgAb, and reference ranges for triiodothyronine, thyroxine, and thyrotropin (total and age-year-related groups) were significantly different from manufacturer's reference ranges. Using these derived ranges, the prevalence of TPOAb was 10.3% and TgAb was 6.4%. Of the TPOAb-positive subjects, TPOAb were of low concentration in 66.2% (1-3 times the upper limit of the reference range [ULRR]) and showed the strongest association with subclinical hypothyroidism (SCH) at the highest concentrations (>4 ULRR). The prevalence of SCH was 3%. Median UIC (interquartile range) was 138.5 µg/L (79.4-219.0) with regional variability, and median thyroglobulin was 8.3 ng/mL (4.1-13.5). Goiter prevalence was 0.6% and 1.93% (thyroid volume compared to age and body surface area, respectively). Salt and water iodine concentrations were satisfactory. Conclusions: Sri Lanka has safely and effectively implemented USI with good sources of iodine, leading to sustained iodine sufficiency over more than two decades. The early postiodization TgAb surge (42.1%) has settled (6.4%), and despite a persistently high TPOAb prevalence (10.3%), SCH prevalence remains low (3%). Further studies should be undertaken to monitor thyroid autoimmune dysfunction in Sri Lankan children, using age-specific, population-derived reference ranges.

The impact of pre-registration education on the motivation and preparation of midwifery students to work in continuity of midwifery care: An integrative review.

Access to continuity of midwifery care (CoMC) models in Australia is increasing but the capacity of the emerging midwifery workforce to provide this care remains largely unknown. The aim of this integrative literature review is to discover how well pre-registration midwifery education prepares and motivates Australian midwifery students to work in CoMC models when they enter practice. Following title review of 432 papers, removal of duplicates and review against the inclusion and exclusion criteria, nine papers were included for review. The results show that access to CoMC is a crucial component of midwifery education, equipping students with knowledge, skills, confidence and motivation to work in this way upon graduation. Existing methods of program delivery and institutional structures often present students with challenges that detract from the value of their CoMC experiences. A focus on CoMC placement - particularly with a continuity of midwifery mentor - may motivate graduates to work in this model of care. This strategy is recommended to better align Australian midwifery education with maternity care reform.

Long-term cardiovascular effects of vandetanib and pazopanib in normotensive rats.

Vandetanib and pazopanib are clinically available, multi-targeted inhibitors of vascular endothelial growth factor (VEGF) and platelet-derived growth factor (PDGF) receptor tyrosine kinases. Short-term VEGF receptor inhibition is associated with hypertension in 15%-60% of patients, which may limit the use of these anticancer therapies over the longer term. To evaluate the longer-term cardiovascular implications of treatment, we investigated the "on"-treatment (21 days) and "off"-treatment (10 days) effects following daily administration of vandetanib, pazopanib, or vehicle, in conscious rats. Cardiovascular variables were monitored in unrestrained Sprague-Dawley rats instrumented with radiotelemetric devices. In Study 1, rats were randomly assigned to receive either daily intraperitoneal injections of vehicle (volume 0.5 mL; n = 5) or vandetanib 25 mg/kg/day (volume 0.5 mL; n = 6). In Study 2, rats received either vehicle (volume 0.5 mL; n = 4) or pazopanib 30 mg/kg/day (volume 0.5 mL; n = 7), dosed once every 24 hours for 21 days. All solutions were in 2% Tween, 5% propylene glycol in 0.9% saline solution. Vandetanib caused sustained increases in mean arterial pressure (MAP), systolic blood pressure (SBP), and diastolic blood pressure (DBP) compared to baseline and vehicle. Vandetanib also significantly altered the circadian cycling of MAP, SBP, and DBP. Elevations in SBP were detectable 162 hours after the last dose of vandetanib. Pazopanib also caused increases in MAP, SBP, and DBP. However, compared to vandetanib, these increases were of slower onset and a smaller magnitude. These data suggest that the cardiovascular consequences of vandetanib and pazopanib treatment are sustained, even after prolonged cessation of drug treatment.

Symmetric dimethylarginine is a stronger predictor of mortality risk than asymmetric dimethylarginine among older people with kidney disease.

BACKGROUND: Circulating asymmetric dimethylarginine and symmetric dimethylarginine are increased in patients with kidney disease. Symmetric dimethylarginine is considered a good marker of glomerular filtration rate, while asymmetric dimethylarginine is a marker of cardiovascular risk. However, a link between symmetric dimethylarginine and all-cause mortality has been reported. In the present study, we evaluated both dimethylarginines as risk and glomerular filtration rate markers in a cohort of elderly white individuals, both with and without chronic kidney disease. METHODS: Glomerular filtration rate was measured in 394 individuals aged >74 years using an iohexol clearance method. Plasma asymmetric dimethylarginine, symmetric dimethylarginine and iohexol were measured simultaneously using isotope dilution tandem mass spectrometry. RESULTS: Plasma asymmetric dimethylarginine concentrations were increased ( P < 0.01) in people with glomerular filtration rate <60 mL/min/1.73 m2 compared with those with glomerular filtration rate ≥60 mL/min/1.73 m2, but did not differ ( P > 0.05) between those with glomerular filtration rate 30-59 mL/min/1.73 m2 and <30 mL/min/1.73 m2. Plasma symmetric dimethylarginine increased consistently across declining glomerular filtration rate categories ( P < 0.0001). Glomerular filtration rate had an independent effect on plasma asymmetric dimethylarginine concentration, while glomerular filtration rate, gender, body mass index and haemoglobin had independent effects on plasma symmetric dimethylarginine concentration. Participants were followed up for a median of 33 months. There were 65 deaths. High plasma asymmetric dimethylarginine ( P = 0.0412) and symmetric dimethylarginine ( P < 0.0001) concentrations were independently associated with reduced survival. CONCLUSIONS: Among elderly white individuals with a range of kidney function, symmetric dimethylarginine was a better marker of glomerular filtration rate and a stronger predictor of outcome than asymmetric dimethylarginine. Future studies should further evaluate the role of symmetric dimethylarginine as a marker of outcome and assess its potential value as a marker of glomerular filtration rate.

Thyrotrophin receptor antibody concentration and activity, several years after treatment for Graves' disease.

OBJECTIVE: TSH receptor antibodies (TRAb) are responsible for autoimmune hyperthyroid disease (Graves' disease; GD) with TRAb levels tending to decrease following treatment. Measurement of TRAb activity during follow-up could prove valuable to better understand treatment effectiveness. STUDY DESIGN: TRAb concentration and stimulating (TSAb) and blocking (TSBAb) activity of patient serum were assessed following different treatment modalities and follow-up length. METHODS: Sixty-six subjects were recruited following treatment with carbimazole (n = 26), radioiodine (n = 27) or surgery (n = 13). TRAb, TPOAb, TgAb and GADAb were measured at a follow-up visit as well as bioassays of TSAb and TSBAb activity. RESULTS: Forty-five per cent of all patients remained TRAb-positive for more than one year and 23% for more than 5 years after diagnosis, irrespective of treatment method. Overall, TRAb concentration fell from a median (IQR) of 6.25 (3.9-12.7) to 0.65 (0.38-3.2) U/L. Surgery conferred the largest fall in TRAb concentration from 11.4 (6.7-29) to 0.58 (0.4-1.4) U/L. Seventy per cent of TRAb-positive patients were positive for TSAb, and one patient (3%) was positive for TSBAb. TRAb and TSAb correlated well (r = 0.83). In addition, 38/66 patients were TgAb-positive, 47/66 were TPOAb-positive and 6/66 were GADAb-positive at follow-up. CONCLUSIONS: TRAb levels generally decreased after treatment but persisted for over 5 years in some patients. TRAb activity was predominantly stimulatory, with only one patient demonstrating TSBAb. A large proportion of patients were TgAb/TPOAb-positive at follow-up. All treatment modalities reduced TRAb concentrations; however, surgery was most effective.

Effects of 4 multitargeted receptor tyrosine kinase inhibitors on regional hemodynamics in conscious, freely moving rats.

VEGF inhibitors, including receptor tyrosine kinase inhibitors, are used as adjunct therapies in a number of cancer treatments. An emerging issue with these drugs is that most cause hypertension. To gain insight into the physiological mechanisms involved, we evaluated their regional hemodynamic effects in conscious rats. Male Sprague Dawley rats (350-450 g) were chronically implanted with pulsed Doppler flow probes (renal and mesenteric arteries, and the descending abdominal aorta) and catheters (jugular vein, peritoneal cavity, and distal abdominal aorta). Regional hemodynamics were measured over 4 d, before and after daily administration of cediranib (3 and 6 mg/kg, 3 and 6 mg/kg/h for 1 h, i.v.), sorafenib (10 and 20 mg/kg, 10 and 20 mg kg/h for 1 h, i.v.), pazopanib (30 and100 mg/kg, i.p.), or vandetanib (12.5 and 25 mg/kg, i.p.). All drugs evoked significant increases (P < 0.05; n = 7-8) in mean arterial pressure, which were generally accompanied by significant mesenteric and hindquarters, but not renal, vasoconstrictions. The hypertensive effects of cediranib were unaffected by losartan (10 mg/kg/h), bosentan (20 mg/kg/h), or a combination of phentolamine and propranolol (each 1 mg/kg/h), suggesting a need for new strategies to overcome them.-Carter, J. J., Fretwell, L. V., Woolard, J. Effects of 4 multitargeted receptor tyrosine kinase inhibitors on regional hemodynamics in conscious, freely moving rats.

Biological Variation of Plasma and Urinary Markers of Acute Kidney Injury in Patients with Chronic Kidney Disease.

BACKGROUND: Identification of acute kidney injury (AKI) is predominantly based on changes in plasma creatinine concentration, an insensitive marker. Alternative biomarkers have been proposed. The reference change value (RCV), the point at which biomarker change can be inferred to have occurred with statistical certainty, provides an objective assessment of change in serial tests results in an individual. METHODS: In 80 patients with chronic kidney disease, weekly measurements of blood and urinary biomarker concentrations were undertaken over 6 weeks. Variability was determined and compared before and after adjustment for urinary creatinine and across subgroups stratified by level of kidney function, proteinuria, and presence or absence of diabetes. RESULTS: RCVs were determined for whole blood, plasma, and urinary neutrophil gelatinase-associated lipocalin (111%, 59%, and 693%, respectively), plasma cystatin C (14%), creatinine (17%), and urinary kidney injury molecule 1 (497%), tissue inhibitor of metalloproteinases 2 (454%), N-acetyl-ß-d-glucosaminidase (361%), interleukin-18 (819%), albumin (430%), and α1-microglobulin (216%). Blood biomarkers exhibited lower variability than urinary biomarkers. Generally, adjusting urinary biomarker concentrations for creatinine reduced (P < 0.05) within-subject biological variability (CVI). For some markers, variation differed (P < 0.05) between subgroups. CONCLUSIONS: These data can form a basis for application of these tests in clinical practice and research studies and are applicable across different levels of kidney function and proteinuria and in the presence or absence of diabetes. Most of the studied biomarkers have relatively high CVI (noise) but also have reported large concentration changes in response to renal insult (signal); thus progressive change should be detectable (high signal-to-noise ratio) when baseline data are available.

Serum Cystatin C Does Not Predict Mortality or Treatment Failure in Peritoneal Dialysis: A Prospective Study.

UNLABELLED: ♦ BACKGROUND: Small solute clearance, especially that derived from residual renal function (RRF), is an independent risk factor for death in peritoneal dialysis (PD) patients. Assessment of solute clearance is time-consuming and prone to multiple errors. Cystatin C is a small protein which has been used as a glomerular filtration rate (GFR) marker. We investigated whether serum cystatin C concentrations are related to mortality in patients receiving PD. ♦ METHODS: New and prevalent PD patients (n = 235) underwent assessment of Kt/Vurea, RRF, weekly creatinine clearance (CCr), normalized protein catabolic rate (nPCR) and a peritoneal equilibration test (PET) at intervals. Blood was collected simultaneously for cystatin C measurement. Patients were followed for a median of 1,429 days (range 12 to 2,964 days) until death or study closure. Cause of death was recorded where given. Cox regression was performed to determine whether cystatin C had prognostic value either independently or with adjustment for other factors (age, sex, dialysis modality, diabetic status, cardiovascular comorbidity, Kt/V, CCr, RRF, nPCR or 4 h dialysate to plasma creatinine ratio (4 h D/Pcr) during the PET). The primary outcomes were all-cause mortality and treatment failure. ♦ RESULTS: There were 93 deaths. Increasing age and 4 h D/Pcr ratio, decreased RRF and presence of diabetes were significantly [p < 0.05] negatively associated with survival and treatment failure. Serum cystatin C was not related to either outcome. ♦ CONCLUSIONS: Serum cystatin C concentration does not predict mortality or treatment failure in patients receiving PD.

Effects of receptor tyrosine kinase inhibitors on VEGF165 a- and VEGF165 b-stimulated gene transcription in HEK-293 cells expressing human VEGFR2.

BACKGROUND AND PURPOSE: Receptor tyrosine kinase inhibitors (RTKIs) targeted at VEGF receptor 2 (VEGFR2) have proved to be attractive approaches to cancer therapy based on their ability to reduce angiogenesis. Here we have undertaken a quantitative analysis of the interaction of RTKIs and two VEGF splice variants, VEGF(165)a and VEGF(165)b, with VEGFR2 by studying nuclear factor of activated T-cells (NFAT) reporter gene activity in live HEK-293 cells. EXPERIMENTAL APPROACH: HEK-293 cells expressing the human VEGFR2 and a firefly luciferase reporter gene regulated by an NFAT response element were used for quantitative analysis of the effect of RTKIs on VEGF(165)a- and VEGF(165)b-stimulated luciferase gene expression. KEY RESULTS: VEGF(165)a produced a concentration-dependent activation of the NFAT-luciferase reporter gene in living cells that was inhibited in a non-competitive fashion by four different RTKIs (cediranib, pazopanib, sorafenib and vandetanib). The potency obtained for each RTKI from this analysis was similar to those obtained in binding studies using purified VEGFR2 kinase domains. VEGF(165)b was a lower-efficacy agonist of the NFAT-luciferase response when compared with VEGF(165)a. Analysis of the concentration-response data using the operational model of agonism indicated that both VEGF(165) isoforms had similar affinity for VEGFR2. CONCLUSIONS AND IMPLICATIONS: Quantitative pharmacological analysis of the interaction of VEGF(165) isoforms and RTKIs with VEGFR2 in intact living cells has provided important insights into the relative affinity and efficacy of VEGF(165)a and VEGF(165)b for activation of the calcineurin- NFAT signalling pathway by this tyrosine kinase receptor.

Accuracy of the MDRD (Modification of Diet in Renal Disease) study and CKD-EPI (CKD Epidemiology Collaboration) equations for estimation of GFR in the elderly.

BACKGROUND: Glomerular filtration rate (GFR) is a measure of kidney function, commonly estimated using equations that adjust serum creatinine concentration for age, race, and sex. The Modification of Diet in Renal Disease (MDRD) Study equation is widely used, but underestimates GFR at higher levels. The serum creatinine-based Chronic Kidney Disease-Epidemiology Collaboration (CKD-EPI(cr)) equation generally provides more accurate estimation at GFR >60 mL/min/1.73 m(2). Newer equations have been reported using cystatin C concentration either alone (CKD-EPI(cys)) or in combination with creatinine concentration (CKD-EPI(cr-cys)). None of these equations has been well validated in older people. We tested the accuracy of these equations in people 74 years or older compared with GFR measured by a reference method. STUDY DESIGN: Diagnostic test evaluation in a prospective cohort. SETTING & PARTICIPANTS: Participants (n = 394; median age, 80 [range, 74-97] years) recruited from nephrology clinics and the community. INDEX TEST: GFR estimated using the MDRD Study, CKD-EPI(cr), CKD-EPI(cys) and CKD-EPI(cr-cys) equations. REFERENCE TEST: GFR measured using an iohexol clearance method. RESULTS: Median measured GFR was 53.4 (range, 7.2-100.9) mL/min/1.73 m(2). MDRD Study-, CKD-EPI(cr)-, and CKD-EPI(cr-cys)-estimated GFRs overestimated GFR (median differences of 3.5 [P< 0.001], 1.7 [P < 0.001], and 0.8 [P = 0.02] mL/min/1.73 m(2), respectively); the CKD-EPI(cys) equation was unbiased. Accuracy (percentage of estimates within 30% of measured GFR [P(30)]) was 81%, 83%, 86%, and 86% for the MDRD Study, CKD-EPI(cr), CKD-EPI(cys), and CKD-EPI(cr-cys) equations, respectively. Accuracy of the MDRD Study equation was inferior (P = 0.004) to the CKD-EPI(cr) equation at GFR >60 mL/min/1.73 m(2). LIMITATIONS: Those of non-European ancestry were not included. For practical reasons, only a 4-hour sampling protocol was used for iohexol clearance. CONCLUSIONS: The CKD-EPI(cr) equation appeared less biased and was more accurate than the MDRD Study equation. No equation achieved an ideal P(30) in the overall population. Our data suggest that GFR estimation is as satisfactory in older people of European ancestry as it has been reported to be in younger individuals.

Estimation of residual glomerular filtration rate in peritoneal dialysis patients using cystatin C: comparison with 51Cr-EDTA clearance.

BACKGROUND: Measuring glomerular filtration rate (GFR) is an important assessment in peritoneal dialysis patients. In clinical practice, it is commonly measured by calculating the mean of the urinary clearance of urea and creatinine (GFR(UrCl)) but this process is time consuming and unreliable. We wished to compare several estimates of GFR including residual GFR estimated from cystatin C (GFR(CysC)) using a published equation (Hoek), GFR(UrCl) and (51)Cr-ethylenediaminetetraacetic acid (EDTA) clearance, in peritoneal dialysis patients. METHODS: GFR(CysC), GFR(UrCl) and (51)Cr-EDTA clearance were measured in 28 patients undergoing peritoneal dialysis in a single dialysis unit. RESULTS: GFR(CysC) was related to GFR(UrCl) (Spearman's rank correlation coefficient r(s) = 0.44; P = 0.0185) and to (51)Cr-EDTA clearance (r(s) = 0.48; P = 0.0099). GFR(CysC) values were significantly (P = 0.0077) lower than (51)Cr-EDTA clearance results (mean bias -19.7%). However, GFR(CysC) did not differ significantly (P > 0.05) from GFR(UrCl). CONCLUSIONS: GFR(CysC) is related to GFR(UrCl) but has a significant negative bias against (51)Cr-EDTA. Given the known limitations of (51)Cr-EDTA in estimating GFR in renal failure, this study provides additional validation suggesting that cystatin C-estimated rGFR (GFR(CysC)) gives a reasonable estimation of GFR without the clinical problems associated with 24 h urine collections.

A first-in-man phase i and pharmacokinetic study on CHR-2797 (Tosedostat), an inhibitor of M1 aminopeptidases, in patients with advanced solid tumors.

PURPOSE: To determine the maximum tolerated dose, dose-limiting toxicity, pharmacokinetics, and preliminary therapeutic activity profile of CHR-2797 (tosedostat), a novel, orally bioavailable inhibitor of the M1 family of aminopeptidases with antiproliferative and antiangiogenic activity in vitro. EXPERIMENTAL DESIGN: A phase I study of accelerated titration design that escalated through nine doses (10-320 mg) in patients (Eastern Cooperative Oncology Group performance status, < or =2) with advanced solid tumors. CHR-2797 was administered once daily. RESULTS: Forty patients (median age, 60 years; range, 24-80 years; male, 27; female, 13) were treated in 12 cohorts with once daily doses (10-320 mg). Dose-limiting toxicities were thrombocytopenia, dizziness, and visual abnormalities in one patient, and anemia, blurred vision, and vomiting in a second patient at 320 mg, resulting in an inability to complete 28 days of study drug. The most commonly observed toxicities were fatigue, diarrhea, peripheral edema, nausea, dizziness, and constipation. One patient had a partial response (renal cell carcinoma) and four patients had stable disease for >6 months. CHR-2797 and its active metabolite, CHR-79888, show dose-proportional increases in plasma AUC and C(max). The terminal half-life for CHR-2797 is approximately 1 to 3.5 hours and between 6 and 11 hours for CHR-79888. Intracellular (packed blood cells) exposure to CHR-79888 is consistent with intracellular levels that proved to be efficacious in xenograft models. CONCLUSION: CHR-2797 is well tolerated and can be safely administered at doses that result in intracellular levels of CHR-79888 that are associated with activity in preclinical models. The recommended dose for single agent therapy in solid tumors is 240 mg/d.

Bone mineral metabolism and its relationship to kidney disease in a residential care home population: a cross-sectional study.

BACKGROUND: Institutionalized older people have a high risk of bone fractures due to osteoporosis. In addition, chronic kidney disease (CKD) is highly prevalent in older people living in residential homes. Secondary hyperparathyroidism, poor calcium intake and deficiency of 1,25-dihydroxyvitamin D may lead to decreased bone mass in people with CKD. The present cross-sectional study assessed the relationship between markers of bone mineral metabolism and kidney function in a residential care home population. METHODS: Older subjects were recruited from residential care homes and kidney function stratified by the estimated glomerular filtration rate (GFR). Parathyroid hormone (PTH), 25-hydroxyvitamin D and 1,25-dihydroxyvitamin D were measured in 188 residents not receiving vitamin D/calcium treatment [mean age 85 (range 68- 100) years, 75% female] and in 52 residents receiving vitamin D/calcium supplementation. RESULTS: Amongst those not receiving vitamin D/calcium, median PTH increased with declining GFR (P < 0.0001), particularly as GFR (mL/min/1.73 m(2)) fell below 45. PTH concentration was suppressed by increasing 25-hydroxyvitamin D (P < 0.0001), but not 1,25-dihydroxyvitamin D (P > 0.05) concentration. Nearly all residents (92%) had 25-hydroxyvitamin D deficiency or insufficiency and this was uninfluenced by kidney function (P > 0.05). Concentration of 1,25-dihydroxyvitamin D declined with worsening renal function (P < 0.0004) but 1,25-dihydroxyvitamin D deficiency was prevalent at all stages of kidney disease, including amongst residents receiving vitamin D/calcium supplementation. CONCLUSION: Vitamin D deficiency and secondary hyperparathyroidism are common in this population irrespective of renal function. However, as GFR falls below 45, the prevalence of secondary hyperparathyroidism and 1,25-dihydroxyvitamin D deficiency increases. Unidentified CKD appears to exacerbate secondary hyperparathyroidism in this at risk population.

Chronic kidney disease prevalence in a UK residential care home population.

BACKGROUND: Chronic kidney disease (CKD) is common ( approximately 30%) in non-institutionalized older people but little is known about the prevalence of CKD amongst older people living in residential care. METHODS: An observational study of older subjects [n = 250, median age 86 (range 67-100) years, 79% female, 100% Caucasian, 16% diabetic, 48% hypertensive, 5% known renal disease, mean number of medications 7] who were recruited over a 9-month period from 155 residential care homes in east Kent (total population 3811) using a randomization process. The estimated glomerular filtration rate (eGFR, ml/min/1.73 m(2)) was calculated using the Cockcroft and Gault equation corrected for the body surface area and the simplified Modification of Diet in Renal Disease (MDRD) Study equation. Serum cystatin C concentration was also measured. RESULTS: Using the MDRD equation 18% had eGFR >/=60, 39% stage 3A CKD (eGFR 45-59), 34% stage 3B CKD (eGFR 30-44) and 10% stage 4 CKD (eGFR 15-29). By the Cockcroft-Gault equation the equivalent figures were 3%, 18%, 48% and 31%, respectively. Agreement between the equations for staging of CKD was poor (kappa = 0.07). However, >80% of residents were categorized as having stage 3 CKD (>40% stage 3B) or worse whichever equation was used. Serum cystatin C concentration was increased in 92% of the population. Increasing age and higher body mass index were predictive of decreased renal function. CONCLUSION: Significant CKD is prevalent and unrecognized in this population. This may have important management implications particularly for treatment with renally excreted drugs, fracture prevention or managing cardiovascular risk.

Involvement of redox events in caspase activation in zinc-depleted airway epithelial cells.

Airway epithelial cells (AEC) contain both pro- and anti-apoptotic factors but little is known about mechanisms regulating apoptosis of these cells. In this study we have examined the localization of pro-caspase-3 and Zn(2+), a cellular regulator of pro-caspase-3, in primary sheep and human AEC. Zn(2+) was concentrated in both cytoplasmic vesicles and ciliary basal bodies, in the vicinity of both pro-caspase-3 and the antioxidant Cu/Zn superoxide dismutase (Cu/Zn SOD). Depletion of intracellular Zn(2+) in sheep AEC, using the membrane permeant Zn(2+) chelator TPEN, increased lipid peroxidation in the apical cell membranes (as assessed by immunofluorescence with anti-hydroxynonenal) as well as increasing activated pro-caspase-3 and apoptosis. There were smaller increases in caspase-2 and -6 but not other caspases. Activation of caspase-3 in TPEN-treated AEC was inhibited strongly by N-acetylcysteine and partially by vitamin C and vitamin E. These findings suggest that cytoplasmic pro-caspase-3 is positioned near the lumenal surface of AEC where it is under the influence of Zn(2+) and other anti-oxidants.