Effects of chronic exposure to low-level cadmium on renal tubular function and CYP2A6-mediated coumarin metabolism in healthy human subjects

Relationships between cadmium (Cd) body burden, kidney function and coumarin metabolism were investigated using two groups of 197 and 200 healthy Thais with men and women in nearly equal numbers. A mean age of one group was 30.5 years and it was 39.3 years for the other group. Of 397, 20 subjects (5%) excreted urine Cd between 1.4 mug/g and 3.8 mug/g creatinine and these subjects faced 10-15% increase in the probability of having abnormal urinary excretion of N-acetyl-beta-D-glucosaminidase (NAG-uria). The prevalence of NAG-uria varied with Cd body burden in a dose-dependent manner (chi(2) = 22, P < 0.008). Also NAG-nuria was one of the three kidney effect markers tested that showed the greatest strength of correlation with urine Cd in both men and women (r = 0.48 P < 0.001). In addition, urine Cd excretion of men and women showed a positive correlation (r = 0.46 to 0.54. P < 0.001) with urine 7-hydroxycoumarin (7-OHC) excretion which was used as a marker of liver cytochrome P450 2A6 (CYP2A6) enzyme activity. Urinary CA excretion accounted for 25% of the total variation in urine 7-OHC excretion (P < 0.001). These data suggest that Cd may increase the expression of CYP2A6 in liver, resulting in enhanced coumarin metabolism in subjects with high Cd body burden. (C) 2003 Elsevier Ireland Ltd. All rights reserved.

Effects of cigarette smoking and exposure to cadmium and lead on phenotypic variability of hepatic CYP2A6 and renal function biomarkers in men

Effects of cigarette smoking and exposure to dietary cadmium (Cd) and lead (Pb) on urinary biomarkers of renal function and phenotypic variability of cytochrome P450 2A6 (CYP2A6) were investigated in a group of 96 healthy Thai men with mean age of 36.7 year (19-57 years). In non-smokers, Cd burden increased with age (r = 0.47, P < 0.001). In current smokers, Cd burden increased with both age (r = 0.45, P = 0.01) and number of cigarettes smoked per day (r = 0.32, P = 0.05). Cd-linked renal tubular dysfunction was seen in both smokers and non-smokers, but Pb-linked glomerular dysfunction was seen in smokers only, possibly due to more recent exposure to high levels of Cd and Pb, as reflected by 30-50% higher serum Cd and Pb levels in smokers than non-smokers (P < 0.05). Exposure to dietary Cd and Pb appeared to be associated with mild tubular dysfunction whereas dietary exposure plus cigarette smoking was associated with tubular plus glomerular dysfunction. Hepatic CYP2A6 activity in non-smokers showed a positive association with Cd burden (adjusted P = 0.38, P = 0.006), but it showed an inverse correlation with Pb (adjusted beta = -0.29, P = 0.003), suggesting opposing effects of Cd and Pb on hepatic CYP2A6 phenotype. In contrast, CYP2A6 activity in current smokers did not correlate with Cd or Pb, but it showed a positive correlation with serum ferritin levels (r = 0.45, P = 0.01). These finding suggest that Pb concentrations in the liver probably were too low to inhibit hepatic synthesis of heme and CYP2A6 and that the concurrent induction of hepatic CYP2A6 and ferritin was probably due to cigarette smoke constituents other than the Cd and Pb. (C) 2004 Elsevier Ireland Ltd. All rights reserved.

Evidence for Concurrent Effects of Exposure to Environmental Cadmium and Lead on Hepatic CYP2A6 Phenotype and Renal Function Biomarkers in Non Smokers

We examined the interrelationships between phenotype of hepatic cytochrome P450 2A6 (CYP2A6), nephropathy, and exposure to cadmium and lead in a group of 118 healthy Thai men and women who had never smoked. Their urinary Cd excretion ranged from 0.05 to 2.36 mug/g creatinine, whereas their urinary Pb excretion ranged from 0.1 to 12 mug/g creatinine. Average age and Cd burden of women and men did not differ. Women, however, on average showed a 46% higher urinary Pb excretion (p < 0.001) and lower zinc status, suggested by lower average serum Zn and urinary Zn excretion compared with those in men. Cd-linked nephropathy was detected in both men and women. However, Pb-linked nephropathy was seen only in women, possibly because of higher Pb burden coupled with lower protective factors, notably of Zn (P < 0.001), in women compared with men. In men, Pb burden showed a negative association with CYP2A6 activity (adjusted beta = -0.29, p = 0.003), whereas Cd burden showed a positive association with CYP2A6 activity (adjusted beta = 0.38, p = 0.001), suggesting opposing effects of Cd and Pb on hepatic CYP2A6 phenotype. The weaker correlation between Cd burden CYP2A6 activity in women despite similarity in Cd burden between men and women is consistent with opposing effects of Pb and Cd on hepatic CYP2A6 phenotypic expression. A positive correlation between Cd-linked nephropathy (urinary N-acetyl-beta-D-glucosaminidase excretion) and CYP2A6 activity in men (r = 0.39, p = 0.002) and women (r = 0.37, p = 0.001) suggests that Cd induction of hepatic CYP2A6 expression and Cd-linked nephropathy occurred simultaneously.

Renal and hepatic accumulation of cadmium and lead in the expression of CYP4F2 and CYP2E1

The present study examined accumulation of the metal toxins cadmium (Cd) and lead (Pb) in relation to the abundance of cytochrome P450 4F2 (CYP4F2), CYP2E1 and concentrations of zinc and copper in liver and kidney samples using immunoblotting coupled with metal analysis. The post mortem liver and kidney cortex samples were from 23 males and 8 females aged 3-89 years. All were Caucasians who had not been exposed to metals in the workplace. Average kidney cortex Cd load of 17.4 mu g/g w.w. was 17 times greater than average liver Cd load (1.1 mu g/g w.w.). In contrast, average kidney cortex Ph load of 0.09 mu g/g w.w. was two times lower than liver Pb load of 0.19 mu g/g w.w. Average Zn and Cu concentrations in the kidney cortex samples were 67% and 33% lower than those in the liver. Liver and kidney Cd loads, but not liver or kidney Ph loads, correlated positively with donors' age. After controlling for liver Cd load, an inverse correlation was seen between Zn and age (partial r = -0.39, P = 0.02), suggesting reduction in liver Zn levels in old age. Liver CYP2E1 protein abundance correlated with age-adjusted Cd load (partial r = 0.37, P = 0.02) whereas kidney CYP4172 protein abundance showed a positive correlation with age-adjusted Cd loads (partial r = 0.40, P = 0.02). These findings suggest that Cd may be an inducer of renal CYP4172 and hepatic CYP2E1 and that increased renal CYP4172 expression may implicate in Cd-linked renal tubular dysfunction and high blood pressure, involving CYP4F2-dependent arachidonic acid metabolism. (c) 2005 Elsevier Ireland Ltd. All rights reserved.

Neonatal calyceal dilation and renal fibrosis resulting from loss of Adamts-1 in mouse kidney is due to a developmental dysgenesis

Background. A disintegrin and metalloproteinase with thrombospondin motifs 1, Adamts-1, is important for the development and function of the kidney. Mice lacking this protein present with renal lesions comprising enlarged calyces, and reduced cortex and medulla layers. Our current findings are consistent with the defect occurring due to a developmental dysgenesis. Methods. We generated Adamts-1 null mice, and further investigated their kidney phenotype in a time course study ranging from E18.5 to 12 months of age. Immunohistochemistry was used to assess the localization of type IV collagen, TGF-beta and F4/80-positive macrophages in the kidneys of Adcants-1 null mice compared to wild-type control animals. The expression of Adamts-1 mRNA was determined in metanephric kidney explants by in situ hybridization. Results. Adamts-1 null mice have a gross kidney defect. At day 18.5 of gestation, the Adcants-1 null kidney has a normal appearance but at birth when the kidney begins to function, the defect becomes evident. During development of the kidney Adamts-1 expression was specifically detected in the developing loops of Henle, as well as in the proximal and distal convoluted tubules. Expression was not detected in the ureter, ureteric bud or its derivatives as had been previously suggested. At 6 months and I year of age, the Adamts-1 null mice displayed interstitial fibrosis in the cortical and medullary regions of the kidney. At I year of age, the Adamts-1 null mice displayed mild interstitial matrix expansion associated with increased collagen type IV expression, without apparent tubular dilatation, compared to wild-type animals. Immunohistochemical analysis demonstrated TGF-beta protein localized to infiltrating macrophages and glomeruli of Adamts-1 null mice. Conclusions. Adamts-1 is required for the normal development of the kidney. The defect observed in its absence results from a dysgenic malformation affecting the medulla that becomes apparent at birth, once the kidneys start to function.

The development, evaluation and use of freshly isolated renal proxinal tubule systems in the fischer rat

The investigation of renal pathophysiology and toxicology has traditionally been advanced by the development of increasingly defined and refined in vitro preparations. This study has sought to develop and evaluate various methods of producing pure samples of renal proximal tubules (PTs) from the Fischer rat. The introduction summarised the most common in vitro preparations together with the parameters used to monitor viability - particularly with regard to toxic events. The most prevalent isolation methods have involved the use of collagenase to produce dissociation of the cortex. However, the present study has shown that even the mildest collagenase treatment caused significant structural damage which resulted in a longevity of only 3hr in suspension. An alternative mechanical isolation technique has been developed in this study that consists of perfusion loading the renal glomeruli with Fe304 followed by disruption of the cortex by homogenisation and sequential sieving. The glomeruli are removed magnetically and the PTs then harvested by a 64μM sieve. PTs isolated in this way showed a vastly superior structural preservation over their collagenase isolated counterparts; also oxygen consumption and enzyme leakage measurements showed a longevity in excess of 6hr when incubated in a very basic medium. Attempts were then made to measure the cytosolic calcium levels in both mechanical and collagenase isolated PTs using the fluorescent calcium indicator Fura. However results were inconclusive due to significant binding of the Fura to the external PT surfaces. In conclusion, PTs prepared by the present mechanical isolation technique exhibit superior preservation and longevity compared with even the mildest collagenase isolation technique and hence appear to offer potential advantages over collagenase isolation as an in vitro renal system.

Compliance in peritoneal dialysis : a qualitative study of renal nurses

End-stage renal failure is a life-threatening condition, often treated with home-based peritoneal dialysis (PD). PD is a demanding regimen, and the patients who practise it must make numerous lifestyle changes and learn complicated biomedical techniques. In our experience, the renal nurses who provide mostPDeducation frequently express concerns that patient compliance with their teaching is poor. These concerns are mirrored in the renal literature. It has been argued that the perceived failure of health professionals to improve compliance rates with PD regimens is because ‘compliance’ itself has never been adequately conceptualized or defined; thus, it is difficult to operationalize and quantify. This paper examines how a group of Australian renal nurses construct patient compliance with PD therapy. These empirical data illuminate how PD compliance operates in one practice setting; how it is characterized by multiple and often competing energies; and how ultimately it might be pointless to try to tame ‘compliance’ through rigid definitions and measurement, or to rigidly enforce it in PD patients. The energies involved are too fractious and might be better spent, as many of the more experienced nurses in this study argue, in augmenting the energies that do work well together to improve patient outcomes.

Developing a model of care to improve the health and well-being for Indigenous people receiving renal dialysis treatment

The high levels of end-stage renal disease among Indigenous Australians, particularly in remote areas of the country, are a serious public health concern. The magnitude of the problem is reflected in figures from the Australian and New Zealand Transplant and Dialysis Registry that show that Indigenous Australians experience end-stage renal disease at a rate almost 9–10 times higher than other non-Indigenous Australians. A majority of Indigenous Australians have to relocate to receive appropriate renal dialysis treatment. In some Australian states, renal treatment is based on self-care dialysis which allows those Indigenous Australians to be treated back in their community. Evidence clearly shows that reuniting renal patients with community and family improves overall health and well-being for those Indigenous Australians. With the appropriate resources, training, and support, self-care management of renal dialysis treatment is an effective way for Indigenous people with end-stage renal failure to be treated at home. In this context, the study was used to gain insight and further understanding of the impact that end-stage renal disease and renal dialysis treatment has had on the lives of Indigenous community members. The study findings are from 14 individually interviewed people from South East Queensland. Data from the interviews were analysed using a combination of thematic and content analysis. The study methodology was based on qualitative data principles where the Indigenous community members were able to share their experiences and journeys living with end-stage renal disease. Many of the experiences and understanding closely relate to the renal disease pattern and the treatment with other outside influences, such as social, cultural, and environmental influences, all having an equal impact. Each community member’s experience with end-stage renal disease is unique; some manage with family and medical support, while others try to manage independently. From the study, community members who managed their renal dialysis treatment independently were much more aware of their renal health status. The study provides recommendations towards a model of care to improve the health and well-being is based on self-care and self-determination principles.

Climate variability and hemorrhagic fever with renal syndrome transmission in northeastern China

Background: The transmission of hemorrhagic fever with renal syndrome (HFRS) is influenced by climatic variables. However, few studies have examined the quantitative relationship between climate variation and HFRS transmission. ---------- Objective: We examined the potential impact of climate variability on HFRS transmission and developed climate-based forecasting models for HFRS in northeastern China. ---------- Methods: We obtained data on monthly counts of reported HFRS cases in Elunchun and Molidawahaner counties for 1997–2007 from the Inner Mongolia Center for Disease Control and Prevention and climate data from the Chinese Bureau of Meteorology. Cross-correlations assessed crude associations between climate variables, including rainfall, land surface temperature (LST), relative humidity (RH), and the multivariate El Niño Southern Oscillation (ENSO) index (MEI) and monthly HFRS cases over a range of lags. We used time-series Poisson regression models to examine the independent contribution of climatic variables to HFRS transmission. ----------- Results: Cross-correlation analyses showed that rainfall, LST, RH, and MEI were significantly associated with monthly HFRS cases with lags of 3–5 months in both study areas. The results of Poisson regression indicated that after controlling for the autocorrelation, seasonality, and long-term trend, rainfall, LST, RH, and MEI with lags of 3–5 months were associated with HFRS in both study areas. The final model had good accuracy in forecasting the occurrence of HFRS. ---------- Conclusions: Climate variability plays a significant role in HFRS transmission in northeastern China. The model developed in this study has implications for HFRS control and prevention.

Palliative care challenges : implications for nurses' practice in renal settings

The very act of withdrawing dialysis places renal nurses in a unique practice setting requiring a sudden shift in care delivery from one of providing Ife-sustaining, active treatment to that of palliation. The impact of this act on the renal nurse remains largely invisible. Minimal research has been conducted that explores the significant issues and challenges that exist for renal nurses in the delivery of palliation following withdrawal of dialysis treatment. This paper attempts to highlight the issues and challenges that do exist for renal nurses in providing palliation and the subsequent lack of available research knowledge to inform practice in the renal setting. It recommends further research be conducted into the renal setting so as to inform the development of appropriate education to support renal nurses practice in the future.

What information counts at the moment of practice? Information practices of renal nurses

Aims. This article is a report of a study done to identify how renal nurses experience information about renal care and the information practices that they used to support everyday practice. Background. What counts as nursing knowledge remains a contested area in the discipline yet little research has been undertaken. Information practice encompasses a range of activities such as seeking, evaluation and sharing of information. The ability to make informed judgement is dependent on nurses being able to identify relevant sources of information that inform their practice and those sources of information may enable the identification of what knowledge is important to nursing practice. Method. The study was philosophically framed from a practice perspective and informed by Habermas and Schatzki; it employed qualitative research techniques. Using purposive sampling six registered nurses working in two regional renal units were interviewed during 2009 and data was thematically analysed. Findings. The information practices of renal nurses involved mapping an information landscape in which they drew on information obtained from epistemic, social and corporeal sources. They also used coupling, a process of drawing together information from a range of sources, to enable them to practice. Conclusion. Exploring how nurses engage with information, and the role the information plays in situating and enacting epistemic, social and corporeal knowledge into everyday nursing practice is instructive because it indicates that nurses must engage with all three modalities in order to perform effectively, efficiently and holistically in the context of patient care. © 2011 The Authors. Journal of Advanced Nursing © 2011 Blackwell Publishing Ltd.

Lessons learnt : complementing good clinical renal questions with an appropriate research strategy

The purpose of this article is to present lessons learnt by nurses when conducting research to encourage colleagues to ask good clinical research questions. This is accomplished by presenting a study designed to challenge current practice which included research flaws. The longstanding practice of weighing renal patients at 0600 hours and then again prior to receiving haemodialysis was examined. Nurses believed that performing the assessment twice, often within a few hours, was unnecessary and that patients were angry when woken to be weighed. An observational study with convenience sampling collected data from 46 individuals requiring haemodialysis, who were repeatedly sampled to provide 139 episodes of data. Although the research hypotheses were rejected, invaluable experience was gained, with research and clinical practice lessons learnt, along with surprising findings.