The incidence and mortality from cardiovascular disease (CVD) in patients with chronic kidney disease (CKD) far exceeds that seen in the general population. Whilst a number of risk factors and associations have been identified in patients with CKD that may contribute to the increased risk of CVD, our understanding of the underlying pathophysiology remains poor. It has previously been reported that uraemic animals sustain larger myocardial infarcts and that this ‘reduced ischaemia tolerance’ may in part explain the excess mortality from CVD seen in CKD patients. The aim of this work was to establish an in vivo model of uraemic myocardial infarction in order to further explore the pathophysiology of uraemic CVD with particular focus on ameliorating myocardial ischaemia-reperfusion injury using ischaemic and pharmacological preconditioning. An increase in myocardial infarct size was demonstrated in the sub-total nephrectomy model of chronic uraemia, confirming previous reports in the literature. However, infarct size was not found to be increased in adenine diet induced renal failure. In addition, it was demonstrated for the first time, that the techniques of ischaemic preconditioning (IPC) and remote ischaemic preconditioning (RIPC) are both efficacious and not attenuated by chronic uraemia induced by sub-total nephrectomy or adenine diet (IPC only). Investigations were undertaken using an agent (a HIF stabiliser, FG4497) to induce pharmacological preconditioning in both animals with renal insufficiency and those without. These studies demonstrate that stabilisation of hypoxia inducible factor (HIF) may be a promising strategy to induce pharmacological preconditioning. It is hoped that this work may lay the foundations for future investigations to determine why sub-totally nephrectomised rats have larger infarcts whilst those with adenine induced renal failure, with a substantially greater degree of renal dysfunction, do not. Moreover, it is hoped that; by demonstrating that uraemia 3 does not prevent or attenuate the myocardial protection afforded by ischaemic preconditioning, the recruitment of patients with CKD will be encouraged to clinical trials of both ischaemic preconditioning and other therapies to limit myocardial infarction.

Cardiovascular disease is the leading cause of death in patients with underlying chronic kidney disease (CKD). Up to one third of patients presenting with an acute coronary syndrome have CKD stage 3-5. Outcomes following acute myocardial infarction in patients with underlying CKD remain poor. CKD patients are routinely excluded from clinical trials in novel cardioprotective strategies resulting in a paucity of prospective data on which to base guidelines for clinical practice. The aims of this work were to: • Establish and characterise two models of chronic uraemia in rodents: the subtotal nephrectomy model and the adenine diet model. • Determine the effects of underlying chronic uraemia on myocardial ischaemia tolerance. • Examine pharmacological cardioprotective strategies in the context of underlying uraemia using a PARP inhibitor • Investigate the cardioprotective effects of ischaemic conditioning in the context of uraemia. Ischaemic preconditioning and postconditioning protocols were used in both uraemic and non-uraemic animals in a model of acute myocardial infarction. • Preliminary work, using standard molecular biological techniques, was carried out in order to confirm the putative survival pathways responsible for the effect of preconditioning. • Investigate the effect of combining early and late remote ischaemic preconditioning to identify whether summation of these strategies could provide additional tissue protection in a model of acute kidney injury. The results demonstrate that both models develop a uraemic phenotype. Subtotal nephrectomy animals exhibit reduced ischaemia tolerance. PARP inhibition as a pharmacological post conditioning agent was shown to be ineffective at conferring tissue protection, whereas both ischaemic preconditioning and postconditioning were effective cytoprotective strategies in both non-uraemic and uraemic animals. Furthermore, additional benefit was seen when early and late remote preconditioning were summated in a rodent model of acute kidney injury. This work provides a basis for future clinical trials in cardioprotection in the context of underlying CKD.

Cardiovascular disease (CVD) is highly prevalent in chronic kidney disease (CKD) patients. Whilst this can in part be explained by the high incidence of traditional CVD risk factors such as hypertension and diabetes evident in CKD patients, recent focus has been on non-traditional risk factors and their role in CVD progression. These include endothelial dysfunction, arterial stiffness, inflammation and oxidative stress. The potent vasoconstrictor endothelin-1 (ET-1) has been implicated in the pathogenesis of CKD and the CVD associated with it. Further understanding of the mechanisms by which it contributes to CKD and CVD pathogenesis, specifically its interactions with non-traditional risk factors are still required. Additionally, the potential applications of ET antagonists in renal disease have not been fully explored. This thesis aims to investigate the role of ET-1 in the development of renal disease and the associated inflammation, hypertension and vascular dysfunction through a series of in vitro, in vivo and clinical studies. I have demonstrated using in vitro techniques that murine macrophages (Mϕ) express both endothelin A (ETA) and endothelin B (ETB) receptors but that ET-1 does not elicit either a classical pro-inflammatory or alternative anti-inflammatory phenotype in Mϕ. I was however, able to show that M display chemokinesis towards ET-1 and M ETB receptors provide a novel clearance mechanism for ET-1 through receptor mediated dynamin-dependent endocytosis In an in vivo study I investigated whether ET-1 mediates the progressive renal injury after renal ischaemia reperfusion injury (IRI) that leads to the development of CKD. I demonstrated that endothelin A receptor antagonism provided long term beneficial effects reducing blood pressure and preventing progressive kidney injury, inflammation, and the development of fibrosis resulting from an episode of acute kidney injury (AKI). Similar benefits were observed with calcium channel blockade, suggesting hypertension may mediate some of the long term effects of renal IRI and anti-hypertensive treatments could prevent the development of CKD after AKI. Finally, in a clinical study I showed for the first time that CKD patients lack the diurnal variation in arterial stiffness that is seen in matched subjects without CKD. Alteration in the circadian variation of the ET-1 system may contribute to this. In summary, my studies have furthered our understanding of the role of ET-1 in CKD progression and the cardiovascular risk associated with it. Mϕ were shown to express both ET receptors and a novel mechanism of ET-1 clearance was observed in Mϕ. Using an in vivo model of AKI I was able to identify ETA receptor antagonism as a novel therapeutic agent in preventing the development of CKD caused by AKI where data are limited. Finally, alterations in the circadian rhythm of the cardiovascular system is emerging as an important factor in disease pathogenesis. Here the diurnal variation in arterial stiffness was described for the first time in a group of CKD patients and matched controls.

Sushi, von Willebrand factor type A, epidermal growth factor and pentraxin domain containing 1 (SVEP1) is an extracellular matrix protein which may bind to cell surface molecules such as integrins. A non-synonymous single amino acid polymorphism in the Svep1 gene is associated with a 14% increased risk of coronary heart disease, a 13% higher risk of type 2 diabetes and a 1mmHg increase in systolic blood pressure. Expression of the SVEP1 gene is increased in the kidney in the Cyp1a1mRen2 rat model of diabetes and hypertension previously developed in our lab. SVEP1 is also known to be upregulated in human diabetic nephropathy and is upregulated in rodent models of renal fibrosis. I hypothesized that Svep1 played a role in renal fibrosis, diabetes and blood pressure. Hence, the primary goal of this thesis was to investigate the role of SVEP1 and in the pathogenesis of diabetes, hypertension and renal fibrosis. Svep1 gene expression is increased in the kidney in the DOCA-salt-angII-uninephrectomy model of hypertension and following UUO. SVEP1 hemizygous mice showed no differences in expression of pro-fibrotic genes after UUO compared to wildtype littermates. No overt metabolic phenotype was exhibited by the Svep1 hemizygous mice, however there was a significant decrease in fat depot weights after high fat diet (HFD) and a significant increase in blood glucose concentrations during the glucose tolerance test at the 12 week time point in hemizygous Svep1 mice compared with wild-type controls. After telemetry analysis of blood pressure no difference was seen in blood pressure but SVEP1+/-animals had an increased heart rate of 100 beats per minute compared to wildtype animals. Svep1 expression is increased in the kidney in models of hypertension and fibrosis, however loss of one Svep1 allele did not alter the severity of fibrosis in the UUO model or significantly alter glucose tolerance after high fat diet. However, the high fat diet experiment was a pilot study and should be repeated with a larger number of animals. In addition, generation of a mouse with the human point mutation could determine the mechanisms by which this extracellular matrix protein confers risk of diabetes and hypertension.

archives@tulane.edu / Background Ankle brachial index (ABI) is a noninvasive measure of subclinical cardiovascular disease (CVD) and atherosclerosis of the lower extremities. Low and high levels of ABI are associated with cardiovascular mortality and vascular calcification in dialysis chronic kidney disease (CKD) patients. However, the association of the spectrum of vascular calcification with low and high ABI is not well studied in pre-dialysis CKD patients. The purpose of this study is to investigate the association of both low and high ABI with the risk of vascular calcification in CKD patients. Methods We recruited 243 patients with pre-dialysis CKD from the great New Orleans area between 2010 and 2012. Our study used a cross-sectional design with ABI and CAC measured at the same visit. Continuous ABI measurements were taken and further classified into four categories : <=0.9 (low ABI) >0.9-<1.0 (borderline), 1.0-<1.4 (normal), >=1.4 (high). Level of vascular calcification were considered as the outcome and calculated by agatston score. Three categories of CAC is defined as: CAC agaston score=0, 0-100, >100. Three cumulative logit models were applied to the data. The first is an unadjusted univariate model, the second adjusts for baseline demographics, and the third adjusts for baseline demographics and covariates that are associated with CAC. Logistic regression methods were used to calculate the odds ratio of having a higher CAC score for CKD patients. Results We found a significant association between ABI and vascular calcification. All three models returned consistently significant result (p=0.0005, 0.0005, 0.0037, respectively) for the association between ABI and CAC. In addition, low ABI (ABI≤0.9) is also associated with an increased risk of CAC and severe CAC (OR=6.183, 95%CI(1.085, 35.228)). High ABI (>1.4) is also associated with an increase in CAC and severe CAC (OR=5.064, 95%CI (1.696, 15.122)). Borderline ABI (0.9<ABI<1.0) is not associated with an increase in CAC or severe CAC (OR=2.704, 95% CI (0.702, 10.418). Conclusion Compared to normal ABI level, low and high ABIs are both significantly associated with an increased risk of coronary artery calcification and severe coronary artery calcification in CKD patients. / 1 / Shuo Bai

Age-related increases in arterial stiffness are mediated in part by mitochondrial dysfunction. Sirtuin 3 (SIRT3) is a mitochondrial NAD+-dependent deacetylase that regulates mitochondrial function. SIRT3 deficiency contributes to physiological dysfunction in a variety of pathological conditions. Here, we tested the hypothesis that age-associated arterial stiffness, assessed by aortic pulse wave velocity (PWV), would be accompanied with decreased renal and aortic SIRT3 expression and activity due to decreased NAD+ levels. We further tested whether boosting NAD+ concentration with nicotinamide riboside (NR), a NAD+ precursor, for 6 months would reverse the effects of aging. Old (~26 mo, n = 9) C57BL/6 male mice had higher PWV vs. young (6 mo, n = 10) (448 ± 14 vs 382 ± 13, p < 0.005), which was associated with reduced arterial SIRT3 protein (0.365 ± 0.088 AU’s vs 1.000 ± 0.000); p < 0.05). Furthermore, SIRT3 deficient male mice demonstrated higher PWV compared to age-matched control mice (480 ± 21 n = 6 vs. 391 ±12 n = 7, p < 0.005). Aortic SIRT3 protein was negatively correlated with PWV (r=-0.7798, p < 0.005). Old mice also exhibited reduced kidney SIRT3 protein (0.73 ± 0.10 AU’s) compared to young controls (1.00 ± 0.00; p = 0.0192) and reduced NAD+ (918.6 ± 50.5 pmol/mg vs. young 1302.0 ± 56.6 pmol/mg, p = 0.0036). Old mice supplemented with NR had increased NAD+ concentration in kidney tissue (1303.0 ± 90.2 pmol/mg) however, had no effect on normalizing age-associated arterial stiffness (402 ± 18 old with NR vs 418 ± 15 old; p = 0.78). Here we show for that SIRT3 protein correlates with aortic stiffness and may be required for the maintenance of healthy arteries and for the first time that supplementation with NR, a commercially available supplement, ameliorates age-associated decreases in renal NAD+ demonstrating therapeutic potential in kidney disease.

PhD / Introduction Kidney transplantation confers both survival and quality of life advantages over dialysis for most people with end-stage kidney disease (ESKD). The mortality rate on dialysis is 10-15% per year, compared with 2-4% per year post-transplantation. Short-term graft survival is related to control of the acute rejection process, requiring on-going immunosuppression. Most current immunosuppressive algorithms include one of the calcineurin inhibitors (CNI: cyclosporin or tacrolimus), an anti-metabolite (azathioprine or mycophenolate) and corticosteroids, with or without antibody induction agents (Ab) given briefly peri-transplantation. Despite this approach, between 15-35% of recipients undergo treatment for an episode of acute rejection (AR) within one year of transplantation. Transplantation is not without risk, and relative mortality rates for kidney recipients after the first post-transplant year remain 4-6 times that of the general population. Longer-term transplant and recipient survival are related to control of chronic allograft nephropathy (rooted in the interplay of AR, non-immunological factors, and the chronic nephrotoxicity of CNI) and limitation of the complications of chronic ESKD and long-term immunosuppression: cardiovascular disease, cancer and infection, which are responsible for 22%, 39% and 21% of deaths respectively. This thesis is presented as published works on the theme of immunosuppression and cancer after kidney transplantation. The work presented in the first chapters of this thesis has striven to identify, evaluate, synthesise and distil the entirety of evidence available of new and established immunosuppressive drug agents through systematic review of randomised trial data, with particular emphasis on quantifying harms of treatment. The final chapters use inception cohort data from the Australian and New Zealand Dialysis and Transplant Registry (ANZDATA), which is first validated then used to explore the risk of cancer in more detail than was possible from trial data alone. Interleukin 2 receptor antagonists Interleukin-2 receptor antagonists (IL2Ra, commercially available as basiliximab and daclizumab) are humanised or chimeric IgG monoclonal antibodies to the alpha subunit of the IL2 receptor present only on activated T lymphocytes, and the rationale for their use has been as induction agents peri-transplantation. Introduced in the mid-1990s, IL2Ra use has increased globally, and by 2003 38% of new kidney transplant recipients in the United States and 25% in Australasia received an IL2Ra. This study aimed to systematically identify and synthesise the evidence of effects of IL2Ra as an addition to standard therapy, or as an alternative to other induction agents. We identified 117 reports from 38 randomised trials involving 4893 participants. Where IL2Ra were compared with placebo (17 trials; 2786 patients), graft loss was not different at one (Relative Risk -RR 0.84; 0.64 to 1.10) or 3 years (RR 1.08; 0.71 to1.64). AR was reduced at 6 months (RR 0.66; 0.59 to 0.74) and at 1 year (RR 0.66; 0.59 to 0.74) but cytomegalovirus (CMV) disease (RR 0.82; CI 0.65 to 1.03) and malignancy (RR 0.67; 0.33 to1.36) were not different. Where IL2Ra were compared with other antibody therapy no significant differences in treatment effects were demonstrated, but IL2Ra had significantly fewer side effects. Given a 40% risk of rejection, 7 patients would need treatment with IL2Ra in addition to standard therapy, to prevent 1 patient having rejection, with no definite improvement in graft or patient survival. There was no apparent difference between basiliximab and daclizumab. Tacrolimus versus cyclosporin for primary immunosuppression There are pronounced global differences in CNI use; 63% of new kidney transplant recipients in the USA but only 22% in Australia receive tacrolimus as part of the initial immunosuppressive regimen. The side effects of CNI differ: tacrolimus is associated more with diabetes and neurotoxicity, but less with hypertension and dyslipidaemia than cyclosporin, with uncertainty about equivalence of nephrotoxicity or how these relate to patient and graft survival, or impact on patient compliance and quality of life. This study aimed to systematically review and synthesise the positive and negative effects of tacrolimus and cyclosporin as initial therapy for renal transplant recipients. We identified 123 reports from 30 randomised trials involving 4102 participants. At 6 months graft loss was reduced in tacrolimus-treated recipients (RR 0•56; 0•36 to 0•86), and this effect persisted for 3 years. The relative reduction in graft loss with tacrolimus diminished with higher levels of tacrolimus (P=0.04), but did not vary with cyclosporin formulation (P=0.97) or cyclosporin level (P=0.38). At 1 year, tacrolimus patients suffered less AR (RR 0•69; 0•60 to 0•79), and less steroid-resistant AR (RR 0•49; 0•37 to 0•64), but more insulin-requiring diabetes (RR 1•86; 1•11 to 3•09), tremor, headache, diarrhoea, dyspepsia and vomiting. The relative excess in diabetes increased with higher levels of tacrolimus (P=0.003). Cyclosporin-treated recipients experienced significantly more constipation and cosmetic side-effects. We demonstrated no differences in infection or malignancy. Treating 100 recipients with tacrolimus instead of cyclosporin for the 1st year post-transplantation avoids 12 suffering acute rejection and 2 losing their graft but causes an extra 5 to become insulin dependent diabetics, thus optimal drug choice may vary among patients. Target of rapamycin inhibitors for primary immunosuppression Target of rapamycin inhibitors (TOR-I) are among the newest immunosuppressive agents and have a novel mode of action but uncertain clinical role. Sirolimus is a macrocyclic lactone antibiotic and everolimus is a derivative of sirolimus. Both prevent DNA synthesis resulting in arrest of the cell cycle. Animal models suggested TOR-I would provide synergistic immunosuppression when combined with CNI, but early clinical studies demonstrated synergistic nephrotoxicity. Since then diverse trials have explored strategies that avoid this interaction and investigated other potential benefits. The aim of this study was to systematically identify and synthesise available evidence of sirolimus and everolimus when used in initial immunosuppressive regimens for kidney recipients. We identified 142 reports from 33 randomised trials involving 7114 participants, with TOR-I evaluated in four different primary immunosuppressive algorithms: as replacement for CNI, as replacement for antimetabolites, in combination with CNI at low and high dose, and with variable dose of CNI. When TOR-I replaced CNI (8 trials, 750 participants), there was no difference in AR (RR 1.03; 0.74 to 1.44), but creatinine was lower (WMD -18.31 umol/l; -30.96 to -5.67), and bone marrow more suppressed (leucopoenia RR 2.02; 1.12 to 3.66, thrombocytopenia RR 6.97; 2.97 to 16.36, anaemia RR 1.67; 1.27 to 2.20). When TOR-I replaced antimetabolites (11 trials, 3966 participants), AR and CMV were reduced (RR 0.84; 0.71 to 0.99 and RR 0.49; 0.37 to 0.65) but hypercholesterolaemia was increased (RR 1.65; 1.32 to 2.06). When low was compared to high-dose TOR-I, with equal CNI dose (10 trials, 3175 participants), AR was increased (RR 1.23; 1.06 to 1.43) but GFR higher (WMD 4.27 ml/min; 1.12 to 7.41). When low-dose TOR-I and standard-dose CNI were compared to higher-dose TOR-I and reduced CNI AR was reduced (RR 0.67; 0.52 to 0.88), but GFR also reduced (WMD -9.46 ml/min; -12.16 to -6.76). There was no significant difference in mortality, graft loss or malignancy risk demonstrated for TOR-I in any comparison. Generally surrogate endpoints for graft survival favoured TOR-I (lower risk of acute rejection and higher GFR) and surrogate endpoints for patient outcomes were worsened by TOR-I (bone marrow suppression, lipid disturbance). Long-term hard-endpoint data from methodologically robust randomised trials are still needed. Monoclonal and polyclonal antibody therapy for treating acute rejection Strategies for treating AR include pulsed steroids, an antibody (Ab) preparation, the alteration of background immunosuppression, or combinations of these options. In 2002, in the USA 61.4% of patients with AR received steroids, 20.4% received Ab and 18.2% received both. The Ab available for AR are not new: horse and rabbit derived polyclonal antibodies (ATG and ALG) have been used for 35 years, and a mouse monoclonal antibody (muromonab-CD3) became available in the late 1980s. These preparations remove the functional T-cell population from circulation, producing powerful saturation immunosuppression which is useful for AR but which may be complicated by immediate toxicity and higher rates of infection and malignancy. The aim of this study was to systematically evaluate and synthesise all evidence available to clinicians for treating AR in kidney recipients. We identified 49 reports from 21 randomised trials involving 1394 participants. Outcome measures were inconsistent and incompletely defined across trials. Fourteen trials (965 patients) compared therapies for 1st AR episodes (8 Ab versus steroid, 2 Ab versus another Ab, 4 other comparisons). In treating first rejection, Ab was better than steroid in reversing AR (RR 0.57; CI 0.38 to 0.87) and preventing graft loss (RR 0.74; CI 0.58 to 0.95) but there was no difference in preventing subsequent rejection (RR 0.67; CI 0.43 to 1.04) or death (RR 1.16; CI 0.57 to 2.33) at 1 year. Seven trials (422 patients) investigated Ab treatment of steroid-resistant rejection (4 Ab vs another Ab, 1 different doses Ab, 1 different formulation Ab, 2 other comparisons). There was no benefit of muromonab-CD3 over ATG or ALG in reversing rejection (RR 1.32; CI 0.33 to 5.28), preventing subsequent rejection (RR 0.99; CI 0.61 to 1.59), graft loss (RR 1.80; CI 0.29 to 11.23) or death (RR 0.39; CI 0.09 to 1.65). Given the clinical problem caused by AR, comparable data are sparse, and clinically important differences in outcomes between widely used interventions have not been excluded. Standardised reproducible outcome criteria are needed. Validity of cancer data in an end stage kidney disease registry Registries vary in whether the data they collect are given voluntarily or as a requirement of law, the completeness of population coverage, the breadth of data collected and whether data are assembled directly or indirectly through linkage to other databases. Data quality is crucial but difficult to measure objectively. Formal audit of ANZDATA cancer records has not previously taken place. The aim of this study was to assess agreement of records of incident cancer diagnoses held in ANZDATA (voluntary reporting system) with those reported under statute to the New South Wales (NSW) state Central Cancer Registry (CCR), to explore the strengths and weaknesses of both reporting systems, and to measure the impact of any disagreement on results of cancer analyses. From 1980-2001, 9453 residents received dialysis or transplantation in NSW. Records from ANZDATA registrants were linked to CCR using probabilistic matching and agreement between registries for patients with 1 or more cancers, all cancers and site-specific cancer was estimated using the kappa-statistic (κ). ANZDATA recorded 867 cancers in 779 (8.2%) registrants; CCR 867 cancers in 788 (8.3%), with κ =0.76. ANZDATA had sensitivity 77.3% (CI 74.2 to 80.2), specificity 98.1% (CI 97.7 to 98.3) if CCR records were regarded as the reference standard. Agreement was similar for diagnoses whilst receiving dialysis (κ =0.78) or after transplantation (κ =0.79), but varied by cancer type. Melanoma (κ =0.61) and myeloma (κ =0.47) were less good; lymphoma (κ =0.80), leukaemia (κ =0.86) and breast cancer (κ =0.85) were very good. Artefact accounted for 20.8% non-concordance but error and misclassification did occur in both registries. Cancer risk did not differ in any important way whether estimated using ANZDATA or CCR records. Quality of cancer records in ANZDATA are high, differences largely explicable, and seem unlikely to alter results of analyses. Risk of cancer after kidney transplantation Existing data on the magnitude of excess risk of cancer across different kidney recipient groups are sparse. Quantifying an individual transplant candidate’s cancer risk informs both pre-transplant counselling, treatment decisions and has implications for monitoring, screening and follow-up after transplantation. The aims of this study were firstly to establish the risk of cancer in the post-transplant population compared to that experienced by the general population, and secondly to quantify how excess risk varied within the transplanted population, seeking to establish meaningful absolute risk estimates for post-transplant cancer based on unalterable recipient characteristics known a priori at the time of transplantation. 15,183 residents of Australia and New Zealand had a transplant between 1963 and 2004, and were followed for a median of 7.2 years (130,186 person-years), with 1642 (10.8%) developing cancer. Overall, kidney recipients had 3 times the cancer risk, with risk inversely related to age (Standardised Incidence Ratio of 15 to 30 in children reducing to 2 in people > 65 years). Female recipients aged 25 -29 had rates of cancer (779.2/100,000) equivalent to women aged 55 - 59 from the general population. The risk pattern of lymphoma, colorectal and breast cancer was similar to the overall age trend, melanoma showed less variability across ages and prostate cancer showed no risk increase. Within the transplanted population cancer risk was affected by age differently for each sex (P=0.007), and was elevated for recipients with prior non-skin malignancy (Hazard Ratio: HR 1.40; 1.03 to 1.89), of white race (HR 1.36; 1.12 to 1.89), but reduced for those with diabetic ESKD (HR 0.67; 0.50 to 0.89) Rates of cancer in kidney recipients were similar to non-transplanted people 20 -30 years older, but risk differed across patient groups. Men aged 45 - 54 at transplantation with graft function at 10 years had a risk of cancer that varied from 1 in 13 (non-white, diabetic ESKD, no prior cancer) to 1 in 5 (white, prior cancer, ESKD from other causes).

Bone disease and fractures are common in men and women with chronic kidney disease (CKD). The etiology of fractures in CKD is multi-factorial; identifying risk factors for fracture is important in CKD, so that patients who are at high risk can be treated before they fracture. The majority of studies have focused on risk factors associated with fracture in patients with stage 5 CKD on dialysis–there is a need for studies in pre-dialysis CKD. Three novel, non-radiological factors were assessed in 211 men and women with stage 3-5 CKD: cytokines osteoprotegerin (OPG) and receptor activator of nuclear factor kappa beta ligand (RANKL); tests of neuromuscular function including the timed up and go (TUG), 6 minute walk (6MW), and grip strength; and daily activity levels by accelerometry. Fractures were defined as self-reported low-trauma fractures since the age of 40 and/or prevalent vertebral fractures identified by morphometry. Logistic regression and receiver operating characteristic curves (ROC) were performed using STATA version 11.0. Those with fractures had elevated OPG compared to those without fractures (9.37±4.23 vs. 8.13±3.04 pmol/L, p=0.03), however, after adjusting for age OPG did not differ by fracture status. After adjusting for age, weight, and sex, impairments in both the TUG and 6MW tests were associated with fractures (TUG odds ratio (OR): 1.68, 95% confidence interval (CI): 1.40-2.02; 6MW OR: 0.53, 95% CI: 0.52-0.54). The diagnostic tests characteristics of the TUG and 6MW tests were excellent; both could discriminate fracture status (TUG AUROC: 0.90, 95% CI: 0.84-0.95; 6MW AUROC: 0.87, 95% CI: 0.84-0.95). Overall, subjects were primarily sedentary. After adjusting for stage of CKD, increased sedentary activity and decreased light intensity activity could discriminate fracture status (sedentary AUROC: 0.72, 95% CI: 0.56 to 0.87; light activity AUROC: 0.71, 95% CI: 0.55 to 0.87). In conclusion, non-radiological, novel factors including the TUG, the 6MW, and daily activity, but not OPG or RANKL were able to discriminate fracture status in men and women with stage 3-5 CKD.

Bone disease and fractures are common in men and women with chronic kidney disease (CKD). The etiology of fractures in CKD is multi-factorial; identifying risk factors for fracture is important in CKD, so that patients who are at high risk can be treated before they fracture. The majority of studies have focused on risk factors associated with fracture in patients with stage 5 CKD on dialysis–there is a need for studies in pre-dialysis CKD. Three novel, non-radiological factors were assessed in 211 men and women with stage 3-5 CKD: cytokines osteoprotegerin (OPG) and receptor activator of nuclear factor kappa beta ligand (RANKL); tests of neuromuscular function including the timed up and go (TUG), 6 minute walk (6MW), and grip strength; and daily activity levels by accelerometry. Fractures were defined as self-reported low-trauma fractures since the age of 40 and/or prevalent vertebral fractures identified by morphometry. Logistic regression and receiver operating characteristic curves (ROC) were performed using STATA version 11.0. Those with fractures had elevated OPG compared to those without fractures (9.37±4.23 vs. 8.13±3.04 pmol/L, p=0.03), however, after adjusting for age OPG did not differ by fracture status. After adjusting for age, weight, and sex, impairments in both the TUG and 6MW tests were associated with fractures (TUG odds ratio (OR): 1.68, 95% confidence interval (CI): 1.40-2.02; 6MW OR: 0.53, 95% CI: 0.52-0.54). The diagnostic tests characteristics of the TUG and 6MW tests were excellent; both could discriminate fracture status (TUG AUROC: 0.90, 95% CI: 0.84-0.95; 6MW AUROC: 0.87, 95% CI: 0.84-0.95). Overall, subjects were primarily sedentary. After adjusting for stage of CKD, increased sedentary activity and decreased light intensity activity could discriminate fracture status (sedentary AUROC: 0.72, 95% CI: 0.56 to 0.87; light activity AUROC: 0.71, 95% CI: 0.55 to 0.87). In conclusion, non-radiological, novel factors including the TUG, the 6MW, and daily activity, but not OPG or RANKL were able to discriminate fracture status in men and women with stage 3-5 CKD.

Due to high frequency and occurrence of chronic kidney diseases in Taiwan, as well as the low public awareness, this research aims to explore the knowledge construction process of Hemodialysis in health broadcasting programs from a health communication point of view. This research intended to answer the following questions: 1) What are health radio program audience types? 2) How does the knowledge on hemodialysis differ among audiences? 3) What is the knowledge construction process among audience in regards to hemodialysis? Data were collected by ten episodes of the Kaohsiung Police Ration Station¡¦s ¡§Medical Network¡¨ program for a six month period (January ~ June 2011). This research has utilized content analysis method on the audience type, quantitative description on questions identified by the audience and qualitative methods to summarize and interpret the audience¡¦s knowledge construction process on hemodialysis. The results showed that the main audiences for health broadcast programs are mostly male, age 31 to 50 years, holding profession as drivers, service personnel and potential patients. Among them, the potential patients and their family members most often times ask diagnostic questions, falling into the compelled group in seek of knowledge. Those who have not been diagnosed with the disease often times bring up knowledge confirmation questions, belonging to the proactive knowledge chaser group. These two groups also demonstrated different hemodialysis knowledge construction processes. While the radio program host plays the role of knowledge enhancer to the diagnostic-need group (potential patients), the role transfers to a knowledge transformation model for the knowledge confirmation group (non-patients). Participating physicians follow the treatment process of ¡V examination, diagnosis and treatment to deliver information. The research process shall provide broadcasters or other media professionals a best practice on how the audience absorbs information - to study the distribution and motives of the audience and to deliver the knowledge of health and illnesses.