Proportionate mortality study of unionized maintenance of way railroad workers.

BACKGROUND: Railroad maintenance of way (MOW) workers are exposed to many workplace hazards, including diesel fuel and exhaust, ballast (silica) dust, asbestos, solvents, herbicides, welding fumes, heavy rolling equipment, vibration and extreme weather. AIMS: Due to the number of excess deaths we found in a companion standardized mortality ratio (SMR) study for union members <65 years, we hypothesized that these workers may have elevated mortality risks among all ages for many chronic conditions. METHODS: Proportionate mortality ratios (PMRs) were calculated for 37 661 male MOW workers ages 20 and older who were members of the Brotherhood of Maintenance of Way Employes Division (BMWED). A data set was submitted to the National Death Index (NDI) to identify decedents and to determine cause of death for workers who died between 1979 and 2014. The CDC WONDER database was used to determine expected mortality for US males. RESULTS: For certain diseases and cancers the SMR and PMR findings have parallel mortality excesses. Examples include septicaemia and anaemia; diabetes; chronic obstructive pulmonary disease (COPD); nephritis; and transportation accidents. Among cancers, we found excess oesophageal, stomach, colorectal, lung, prostate, kidney and in situ cancers. Two excess SMR findings were not replicated in the PMR assessment-Alzheimer's and Parkinson's disease. CONCLUSIONS: The PMR findings suggest that some of the mortality excesses from the SMR study are elevated, which adds support to their being consistently raised among BMWED members. The shared excess causes of death in the PMR and SMR studies should be focused on for future prevention and surveillance activities.

Calibrating the impact of dual RAAS blockade on the heart and the kidney - balancing risks and benefits.

Overactivity of the renin-angiotensin-aldosterone system (RAAS) plays a key role in the pathophysiology of heart failure (HF) and chronic kidney disease (CKD). RAAS antagonists can significantly improve clinical outcomes, but monotherapy blocks but one step of the RAAS and can be bypassed through compensatory mechanisms. Providing more complete RAAS blockade by deploying drugs with complementary actions seemed logical - hence the practice of using dual (or triple) RAAS inhibitors. However, RAAS antagonists also exhibit dose-limiting side effects, including acute kidney injury, hyperkalaemia and hypotension, which blunt their overall effectiveness. Despite achieving better RAAS blockade, several trials failed to show clinical outcome improvements. Patients with concomitant CKD and HF (cardiorenal syndrome) are at the greatest risk of these adverse events and therefore the least able to benefit, yet they also have the worst prognosis. This paradox, where those most in need have fewest therapeutic options, poses three questions which are the focus of this review: whether (i) novel therapies that prevent adverse effects can restore therapeutic benefits to patients who would otherwise be RAAS-therapy intolerant, (ii) there are any validated alternatives to their use and (iii) newer approaches to the detection of fluid congestion are ready for implementation.

Pulmonary Veno-Occlusive Disease: A Newly Recognized Cause of Severe Pulmonary Hypertension in Dogs.

Pulmonary hypertension is a well-known though poorly characterized disease in veterinary medicine. In humans, pulmonary veno-occlusive disease (PVOD) is a rare cause of severe pulmonary hypertension with a mean survival time of 2 years without lung transplantation. Eleven adult dogs (5 males, 6 females; median age 10.5 years, representing various breeds) were examined following the development of severe respiratory signs. Lungs of affected animals were evaluated morphologically and with immunohistochemistry for alpha smooth muscle actin, desmin, CD31, CD3, CD20, and CD204. All dogs had pulmonary lesions consistent with PVOD, consisting of occlusive remodeling of small- to medium-sized pulmonary veins, foci of pulmonary capillary hemangiomatosis (PCH), and accumulation of hemosiderophages; 6 of 11 dogs had substantial pulmonary arterial medial and intimal thickening. Ultrastructural examination and immunohistochemistry showed that smooth muscle cells contributed to the venous occlusion. Increased expression of CD31 was evident in regions of PCH indicating increased numbers of endothelial cells in these foci. Spindle cells strongly expressing alpha smooth muscle actin and desmin co-localized with foci of PCH; similar cells were present but less intensely labeled elsewhere in non-PCH alveoli. B cells and macrophages, detected by immunohistochemistry, were not co-localized with the venous lesions of canine PVOD; small numbers of CD3-positive T cells were occasionally in and around the wall of remodeled veins. These findings indicate a condition in dogs with clinically severe respiratory disease and pathologic features resembling human PVOD, including foci of pulmonary venous remodeling and PCH.

A meta-analysis of blood cytokine network alterations in psychiatric patients: comparisons between schizophrenia, bipolar disorder and depression.

Schizophrenia, bipolar disorder and major depressive disorder (MDD) have all been associated with aberrant blood cytokine levels; however, neither the pattern of cytokine alterations nor the impact of clinical status have been compared across disorders. We performed a meta-analysis of blood cytokines in acutely and chronically ill patients with these major psychiatric disorders. Articles were identified by searching the PubMed, PsycInfo and Web of Science, and the reference lists of these studies. Sixty-eight studies met the inclusion criteria (40 schizophrenia, 10 bipolar disorder and 18 MDD) for acutely ill patients. Forty-six studies met the inclusion criteria (18 schizophrenia, 16 bipolar disorder and 12 MDD) for chronically ill patients. Levels of two cytokines (interleukin-6 (IL-6), tumor necrosis factor-α (TNF-α)), one soluble cytokine receptor (sIL-2R), and one cytokine receptor antagonist (IL-1RA) were significantly increased in acutely ill patients with schizophrenia, bipolar mania and MDD compared with controls (P<0.01). Following treatment of the acute illness, IL-6 levels significantly decreased in both schizophrenia and MDD (P<0.01); sIL-2R levels increased in schizophrenia; and IL-1RA levels in bipolar mania decreased. In chronically ill patients, the levels of IL-6 were significantly increased in schizophrenia, euthymic (but not depressed) bipolar disorder and MDD compared with controls (P<0.01). The levels of IL-1ß and sIL-2R were significantly increased in both chronic schizophrenia and euthymic bipolar disorder. Overall, there were similarities in the pattern of cytokine alterations in schizophrenia, bipolar disorder and MDD during acute and chronic phases of illness, raising the possibility of common underlying pathways for immune dysfunction. Effects of treatment on cytokines were more robust for schizophrenia and MDD, but were more frequently studied than for acute mania. These findings have important implications for our understanding of the pathophysiology and treatment of major psychiatric disorders.

Diabetic nephropathy: What does the future hold?

The consensus management of diabetic nephropathy (DN) in 2015 involves good control of glycaemia, dyslipidaemia and blood pressure (BP). Blockade of the renin-angiotensin-aldosterone system using angiotensin-converting enzyme inhibitors, angiotensin-2 receptor blockers or mineralocorticoid inhibitors are key therapeutic approaches, shown to be beneficial once overt nephropathy is manifest, as either, or both, of albuminuria and loss of glomerular filtration rate. Some significant additional clinical benefits in slowing the progression of DN was reported from the Remission clinic experience, where simultaneous intensive control of BP, tight glycaemic control, weight loss, exercise and smoking cessation were prioritised in the management of DN. This has not proved possible to translate to more conventional clinical settings. This review briefly looks over the history and limitations of current therapy from landmark papers and expert reviews, and following an extensive PubMed search identifies the most promising clinical biomarkers (both established and proposed). Many challenges need to be addressed urgently as in order to obtain novel therapies in the clinic; we also need to examine what we mean by remission, stability and progression of DN in the modern era.

The uses and abuses of Vitamin D compounds in chronic kidney disease-mineral bone disease (CKD-MBD).

Vitamin D is of paramount importance to skeletal development, integrity and health. Vitamin D homeostatis is typically deranged in a number of chronic conditions, of which chronic kidney disease is one of the most important. The use of vitamin D based therapy to target secondary hyperparathyroidism is now several decades old, and there is a large body of clinical practice, experience, guidelines and research to underpin this. However, there are many unknowns, of significant clinical relevance. Amongst which is what "species" of vitamin D we should be using, in what patient, and, under what conditions. Sadly, there has been a real dearth of randomised controlled trials, and trials with outputs of clinical relevance, which means our clinical practice has not developed and refined adequately ove the last 4 decades. This article will discuss the vexed but critical questions of which vitamin D therapies might suit which kidney patients, and will high-light the many important clinical questions which urgently require answering.

Uric acid as a cardiorenal risk factor - ready for prime-time?

Patients with cardiac morbidity are known to have increased risk of developing renal disease, and vice versa. Cardiorenal syndrome is a general term describing concomitant cardiac and renal dysfunction, and recently there has been renewed interest in the role of uric acid (UA) in its pathophysiology and management. There is evidence to suggest that UA-lowering drugs, such as the xanthine oxidase (XO) inhibitors allopurinol and Febuxostat, may not only retard deteriorating renal function in the context of chronic kidney disease (CKD) but also confer protective cardiovascular effects. As these diseases represent considerable health burdens, this evidence merits evaluation to determine whether or not hyperuricaemia is a cardiorenal risk factor that necessitates intervention and if existing pharmacological agents are sufficiently efficacious.

Vitamin D in renal transplantation - from biological mechanisms to clinical benefits.

Recent developments in our understanding of vitamin D show that it plays a significant role in immunological health, uniquely occupying both an anti-microbial and immunoregulatory niche. Vitamin D deficiency is widespread amongst renal transplant recipients (RTRs), thus providing one patho-mechanism that may influence the achievement of a successful degree of immunosuppression. It may also influence the development of the infectious, cardiovascular and neoplastic complications seen in RTRs. This review examines the biological roles of vitamin D in the immune system of relevance to renal transplantation (RTx) and evaluates whether vitamin D repletion may be relevant in determining immunologically-related clinical outcomes in RTRs, (including graft survival, cardiovascular disease and cancer). While there are plausible biological and epidemiological reasons to undertake vitamin D repletion in RTRs, there are few randomized-controlled trials in this area. Based on the available literature, we cannot at present categorically make the case for routine measurement and repletion of vitamin D in clinical practice but we do suggest that this is an area in urgent need of further randomized controlled level evidence.

The EVOLVE study is negative, so what does this 'bitter pill' of disappointment mean now for renal patients?

The extremely high morbidity and mortality experienced by subjects with chronic kidney disease (CKD) has often been described and reviewed, but this familiarity should not breed indifference to the huge burden of premature cardiovascular disease ­ something which becomes more obvious, but increasingly challenging to treat, as GFR declines, or proteinuria increases. The health outcomes for a middle-aged person entering renal replacement therapy are as bad as those seen with a major solid organ malignancy; while there has been modest progress in improving outcomes over the last two decades, the diagnosis of significant or progressive CKD should and thus still does continue to cast a shadow over patients, carers and healthcare professionals alike.

Vitamin D metabolites and/or analogs: which D for which patient?

Numerous drugs with vitamin D activity are available for clinical use and it may not be easy for the nonspecialist to select the most suitable for the individual patient. In this paper we review the main characteristics of the available drugs and provide evidence about any potential specific clinical indications, with special emphasis on renal patients, in order to facilitate the optimal choice. Natural vitamin D products (i.e. those identical to natural metabolites) are first examined, followed by the most frequently used synthetic molecules (i.e. bioengineered molecules not-existing in nature), which are generally indicated as " analogs". Either cholecalciferol, ergocalciferol or calcifediol can be employed in subjects with normal renal function and in CKD stage 3-5 patients to correct vitamin D deficiency and improve, respectively, age- or growth-related bone disease and secondary hyperparathyroidism. Calcifediol can be considered more rapid and effective. In all cases, especially with increasing doses, the risk of hypercalcemia must be taken into account. Calcitriol, which can be regarded as the active hormonal form of vitamin D, has the most potent hypercalcemic effect in both normal and renal failure patients. In renal patients calcitriol is a potent inhibitor of parathyroid activity, but the risk of hypercalcemia, now regarded as harmful, is evident whenever pharmacologic doses are used. Alfacalcidol, requiring 25-hydroxylation to become the active hormonal form of vitamin D3, is prescribed in normal subjects to treat osteoporosis and in renal patients to cure hyperparathyroidism and renal bone disease. Doxercalciferol, transformed into the active hormonal form of vitamin D2 following 25-hydroxylation, is mostly studied in renal patients in whom it cures secondary hyperparathyroidism, possibly with a lower calcemic effect than calcitriol. Paricalcitol, a vitamin D2 analog not requiring activation, has been specifically developed to suppress PTH in renal patients with a limited calcemic effect. As such it is now regarded as a powerful drug useful to treat even severe cases of secondary hyperparathyroidism. Importantly, reno-protective and cardio-protective effects of this analog have been recently evaluated by means of randomized clinical trials in renal patients with partially positive renal effects and negative cardiac results, thus additional studies are needed for confirmation. 22-oxacalcitriol, a vitamin D3 analog with a limited calcemic effect available in Japan, is mostly used in renal patients affected by secondary hyperparathyroidism. The clinical activity of some vitamin D analogs is such that they can be employed in diseases like cancer and autoimmunity. The clinical activity of some vitamin D analogs is such that they can be employed in diseases like cancer and autoimmunity. In summary, available drugs with vitamin D like activity are not all the same either in terms of pharmacological actions, and side-effects. They have specific characteristics that may be useful to know in order to operate the best choice in the individual patient.

Prevalence and predictors of abdominal aortic calcification in healthy living kidney donors.

BACKGROUND: Vascular calcification (VC) is common and is both a marker and a cause of increased cardiovascular morbidity and mortality, especially so in chronic kidney disease (CKD) patients. Renal transplantation is the cornerstone of the successful long-term management of CKD, and in order to satisfy transplantation needs, more use is made now of living kidney donors (LKD). Prior to selection for transplantation, much screening of potential LKD takes place, including for cardiovascular issues. It is not known; however, how much these potentially healthy LKD may be prone to clinically silent VC. METHODS: We identified 103 living kidney donors from 2011 renal transplant records. Abdominal aortic calcification (AAC) was assessed using existing abdominal CT imaging using multi-channel CT aortograms (used primarily to assess renal vascular anatomy). Using these CT scans, manual calcium scoring was undertaken to calculate total aortic calcium load (AAC severity score). The prevalence, severity and associations of AAC between calcified and non-calcified donors were then compared. RESULTS: A total of 103 donors were identified from records. Ninety three of these had detailed clinical records to complement their CT scans. Fifty of ninety-three donors were male, and the mean age was 45.9 ± 1.8 years. Mean MDRD eGFR was 88.73 ± 2.97 ml/min/1.73 m(2). 7.14 ± 3.07 % of the aorta in these donors was calcified with a mean AAC severity score of 0.98 ± 0.56. In kidney donors >50 years of age, there was significantly more AAC than in those <50: 2.47 ± 1.56 versus 0.31 ± 0.29, p < 0.001. There was no relationship between the presence or severity of aortic VC and donor GFR, systolic blood pressure, pulse pressure, calcium-phosphate product or smoking. CONCLUSIONS: AAC prevalence, patterns and severity in this important donor population have not previously been described in the literature. There was relatively little VC in what would be regarded as a "healthy" donor population. VC was more common with age, but the other possible risk factors for the presence or severity of VC did not impact on overall AAC scores. VC did not influence vascular stiffness as represented by pulse pressure. Following the evolution of AAC over time in those who have donated a kidney, and lost some global renal function as a consequence, would be of considerable interest.

Implementation of a pharmacist-driven pain management consultation service for hospitalised adults with a history of substance abuse.

BACKGROUND: Pain management in adult patients with concomitant substance use disorders (SUDs) presents a clinical challenge in the absence of objective assessment criteria. Effective pain management is dependent on the clinician's ability to differentiate true pain symptoms from manipulative behaviours. Successful strategies for achieving effective pain control in these patients include implementing a multidisciplinary team approach, use of non-opioid and non-pharmacologic alternatives, and judicious use of opioid analgesics. OBJECTIVE: To describe the implementation of a pharmacist-driven pain management service for patients with concomitant SUDs. METHODS: In an urban teaching hospital located in Trenton, New Jersey, United States, a clinical pharmacist-led pain management service evolved to provide formal consultation. Standardised assessment and treatment approaches were developed to assure consistency. Multidisciplinary education was provided to the medical staff. MAIN OUTCOME MEASURE: The study describes a variety of patterns associated with the program from its pilot period through the first 6 years of service, including opioid utilisation, volume and source of consultations, and multidisciplinary perceptions regarding the program's impact. RESULTS: The establishment of a pharmacist-led pain management consult service successfully addressed patient's needs while modifying drug-seeking behaviours. A significant decrease in opioid usage was noted during the program's pilot period and sustained over time. The program's success has extended the pharmacist's role beyond the program's initial scope to address general pain management needs and to address educational needs of the medical staff. Today, clinical pharmacists are utilised most often for refractory cases for which the most appropriate method of pain management may not be clear.

Thiopurine toxicity.

Thiopurines are a class of immunosuppressant and antineoplastic drugs developed by Gertrude Elion and George Hitchings and patented in 1953 for use to treat leukaemia, then used to prevent transplant rejection (Marx, 2005).

The relationship between intact PTH and biointact PTH (1-84) with bone and mineral metabolism in pre-dialysis chronic kidney disease (CKD).

OBJECTIVES: Abnormalities in PTH are implicated in the pathogenesis of bone abnormalities in chronic kidney disease (CKD)-mineral bone disorder (CKD-MBD). PTH concentrations are important in clinical decision and management. This emphasises the importance of providing an assay which measures biologically active PTH. We compared concentrations of intact PTH with biointact PTH (1-84) in CKD and end stage renal disease (ESRD) and investigated the relationship between the 2 PTH assays with bone and mineral laboratory parameters and bone mineral density (BMD) in CKD. DESIGN AND METHODS: We assessed 140 patients (61 in ESRD and 79 with CKD stages 1-4) in this cross-sectional study. We measured biointact PTH (1-84) as well as routine biochemical parameters on all subjects. In the CKD cohort, bone turnover markers; bone alkaline phosphatase (BAP) and tartrate resistant acid phosphatase (TRACP)-5b and bone mineral density (BMD) were also determined. RESULTS: In ESRD, intact PTH concentration was significantly higher compared to biointact PTH (1-84) (422 [443] v/s 266 [251] pg/mL, (p<0.001) with an average bias of 60%. In CKD, intact PTH concentration was also higher compared to biointact PTH (1-84) (79[55] v/s 68[49] pg/mL p<0.001) with an average bias of 18%. Only the biointact PTH (1-84) assay showed any significant correlation with serum calcium concentrations (r=-0.26, p<0.05) and phosphate (r=0.25, p<0.05) in CKD. Following multilinear regression analysis and adjustment for all significant co-variables, only eGFR, BAP and 25 (OH)vitamin remained significantly associated with intact PTH and biointact PTH (1-84). The strength of association was stronger between BAP and biointact PTH (1-84) (biointact PTH (1-84): p=0.007, intact PTH: p=0.01). In adjusted analyses, only biointact PTH (1-84) was significantly associated with BMD at the fore-arm (FARM) (p=0.049). CONCLUSIONS: The study confirms the differences between intact PTH and biointact PTH (1-84) in ESRD. Whilst there may be similarities in the diagnostic ability of both intact and biointact PTH (1-84), our data suggest that biointact PTH (1-84) assay may better reflect bone metabolism and BMD in CKD. Further longitudinal studies are needed.

Treating stones in transplanted kidneys.

The formation of calculi in renal allografts is an uncommon complication in renal transplant recipients, with a reported incidence of 0.2-1.7% according to retrospective studies. Although the majority of these stones appear to form de novo following renal transplantation (RTX), there is a growing body of evidence suggesting that more often than previously thought they may be transplanted with the donor graft itself. The etiology and pathophysiology of renal graft stones is multifactorial. A combination of metabolic and urodynamic factors predispose to stone formation and these are generally found more frequently in allograft rather than native kidneys. In addition tertiary hyperparathyroidism (following RTX) plays an important role. Renal allograft stones can pose significant challenges for the clinician. The diagnosis requires a high index of suspicion and must be prompt, as these patients' reliance on a solitary kidney for their renal function leaves them susceptible to significant morbidity. However, reports in the literature come largely from anecdotal experience and case reports, meaning that there is a limited consensus regarding how best to manage the condition. We suggest that interventional treatment should be guided primarily by stone size and individual patient presentation. Good outcomes have been reported with shockwave lithotripsy (SWL), percutaneous nephrolithotomy (PCNL) and ureteroscopy, but optimal management of the risk factors leading to calculi formation (i.e., prevention) will remain the most cost-effective management.

Cardiovascular disease in chronic kidney disease: untying the Gordian knot.

Chronic kidney disease (CKD) affects around 10-13% of the general population, with only a small proportion in end stage renal disease (ESRD), either on dialysis or awaiting renal transplantation. It is well documented that CKD patients have an extremely high risk of developing cardiovascular disease (CVD) compared with the general population, so much so that in the early stages of CKD patients are more likely to develop CVD than they are to progress to ESRD. Various pathophysiological pathways and explanations have been advanced and suggested to account for this, including endothelial dysfunction, dyslipidaemia, inflammation, left ventricular hypertrophy and cardiac autonomic dysfunction. In this review, we try to understand and further explore the link between CKD and CVD, as well as offering interventional advice where available, while exposing the current lack of RCT-based research and trial evidence in this area. We also suggest pragmatic Interim measures we could take while we wait for definitive RCTs.

Vascular and arterial calcification in peritoneal dialysis patients--state-of-the-art 2012.

Vascular calcification is a major challenge to the long-term health of many patients with chronic kidney disease, and patients receiving peritoneal dialysis therapy are no exception to this. The mechanisms behind vascular calcification are complex and diverse. There are several different imaging techniques that can be used to interrogate the vasculature in these patients, and the relative merits of these as research and screening tools we discuss. There are some recent epidemiological studies which throw fresh light on the implications of the development or progression of vascular calcification. Finally, an animal model experiment is reported which one day may open up the possibility of a successful therapeutic intervention.

Circulating sclerostin and Dickkopf-1 (DKK1) in predialysis chronic kidney disease (CKD): relationship with bone density and arterial stiffness.

Abnormalities of bone metabolism and increased vascular calcification are common in chronic kidney disease (CKD) and important causes of morbidity and mortality. The Wnt signaling pathway may play a role in the bone and vascular disturbances seen in CKD, termed collectively "CKD-MBD." The aim of the study was to investigate the possible association of circulating concentrations of the secreted Wnt signaling inhibitors DKK1 and sclerostin with BMD and arterial stiffness in predialysis CKD. Seventy-seven patients (48 M, 29 F), mean age 57 (SD = 14) years with CKD stages 3B (n = 32) and 4 (n = 45) were studied. Sclerostin, DKK1, PTH, and 1,25(OH)(2)D were analyzed. BMD was measured at the lumbar spine (LS), femoral neck (FN), total hip (TH), and forearm (FARM). Arterial stiffness index was determined by contour analysis of digital volume pulse (SI(DVP)). There was a positive correlation between sclerostin and age (r = 0.47, p < 0.000). Sclerostin was higher in men than women (p = 0.013). Following correction for age and gender, there was a negative association between GFR and sclerostin (p = 0.002). We observed a positive association between sclerostin and BMD at the LS (p = 0.0001), FN (p = 0.004), and TH (p = 0.002). In contrast, DKK1 was negatively associated with BMD at the FN (p = 0.038). A negative association was seen between DKK1 and SI(DVP) (p = 0.027). Our data suggest that the Wnt pathway may play a role in CKD-MBD. Prospective studies are required to establish the clinical relevance of sclerostin and DKK1 as serological markers in CKD.