Chronic kidney disease (CKD) is a worldwide health problem with rising incidence and high cardiovascular mortality. CKD compromises cardiovascular function, in part, characterized by vascular calcification (VC), elevated pulse wave velocity (PWV) and pulse pressure (PP). Through manipulation of dietary adenine, we produced a model characterized by graded severity of CKD, VC and hyperphosphatemia. To our knowledge, we are the first to explore the relationship between aortic calcium content and changes in circulatory function in rodents with CKD. Fourteen-week old Sprague-Dawley rats received a diet containing an adenine concentration (0.25-0.75%) plus high-normal dietary phosphate (1%), for up to 10 weeks. Circulatory changes were determined by arterial radiotelemetry (n=6) and by assessment of aortic pulse wave velocity (PWV, n=32). VC was assessed using the calcium-O-cresophthalein-complexone assay. At sacrifice, kidney function (creatinine (µmol/L)) was worst in the group with VC (251.3±60.2 µmol/L), compared to non-calcifying CKD (200.3±68.8 µmol/L) or control (50.0±16.2 µmol/L). PWV (cm/s) adjusted for blood pressure (BP) was markedly elevated in animals with VC (3.23±0.33 log(cm/s)) versus non-calcifying CKD (2.85± 0.12 log(cm/s)) or control (2.96±0.08 log(cm/s)). Arterial pressure radiotelemetry revealed that there was an increase in pulse pressure (38±4.7 mmHg to 58 ±15.2 mmHg) during the development of VC. Systolic pressure remained relatively stable throughout (129±8.7 mmHg), diastolic pressure fell during weeks 9 and 10 of the study (91±6.0 mmHg down to 74±9.1 mmHg), a fall that almost fully accounted for the changes in pulse pressure. The calcifying CKD animals also exhibited left ventricular hypertrophy (LVH) compared to CKD or control animals (2.32±0.3 vs 2.03±0.2, 1.80±0.1 g/kg respectively). Manipulating dietary adenine produces a graded severity of CKD with calcification which impact circulatory changes (PP and PWV). These altered circulatory functions are likely to be key factors in the enhanced LVH. This model appears to be a useful for the study of CKD-associated VC. / Thesis (Master, Pharmacology & Toxicology) -- Queen's University, 2009-12-16 15:10:49.384

Background: High serum phosphorus (hPhos) is common in chronic kidney disease (CKD) and increases the risk of metastatic calcification. Guidelines advise patients with hPhos to restrict dietary phoshorus intake to 800-1000mg/day, and compliance with this diet can be challenging. Innovative education may improve compliance. Hypothesis: Intensive dietary education using the Phosphorus Point System Tool© (PPS) will result in lower serum phosphorus levels compared to standard education (SE). Methods: This study compared the effectiveness of the PPS to SE on 1) serum phosphorus, 2) dietary phosphate intake, knowledge and satisfaction in pre-dialysis CKD. Results: The PPS reduced 12 week serum phosphorus by 0.16 mmol/L (95% CI 0.37 to -0.05, p=0.130) when controlling for baseline. Dietary phosphorus and protein intake decreased significantly at week 6 on PPS compared to SE (p= 0.026, p=0.050; respectively). Summary: Although there was a trend indicating the tool may reduce serum phosphorus levels, further research is needed.

Background: High serum phosphorus (hPhos) is common in chronic kidney disease (CKD) and increases the risk of metastatic calcification. Guidelines advise patients with hPhos to restrict dietary phoshorus intake to 800-1000mg/day, and compliance with this diet can be challenging. Innovative education may improve compliance. Hypothesis: Intensive dietary education using the Phosphorus Point System Tool© (PPS) will result in lower serum phosphorus levels compared to standard education (SE). Methods: This study compared the effectiveness of the PPS to SE on 1) serum phosphorus, 2) dietary phosphate intake, knowledge and satisfaction in pre-dialysis CKD. Results: The PPS reduced 12 week serum phosphorus by 0.16 mmol/L (95% CI 0.37 to -0.05, p=0.130) when controlling for baseline. Dietary phosphorus and protein intake decreased significantly at week 6 on PPS compared to SE (p= 0.026, p=0.050; respectively). Summary: Although there was a trend indicating the tool may reduce serum phosphorus levels, further research is needed.

Meeting the health care needs of people with chronic conditions presents one of the greatest challenges for 21st century health care system renewal. Appropriate redesign of health care delivery with this complex patient population in mind requires information from many sources. Although much is known about the patient experience of chronic illness much less is understood about how patients navigate their health care delivery context. The purpose of this qualitative study was to examine the point of view of patients dealing with multi-morbidity. These people have a unique understanding of how health care delivery links across time, place, and settings because of the care they require for their multiple chronic conditions. An interpretive descriptive design was used to examine patient navigation from the perspective of 20 adult patients with chronic kidney disease, and co-existing diagnoses of diabetes mellitus and/or cardiovascular disease. The findings generated from iterative, constant comparative analysis add important patient perspectives about health care system navigation. From the consumer perspective health care navigation is challenging, requiring (a) ongoing discovery about the complex social structures that make up the health care system, and (b) learning how to strategically use this knowledge to manage the health care system. The findings highlight the disjunctures and misalignments in the health care delivery system, the cumulative health care-related burden of multiple chronic conditions for consumers, and consumer concerns about subtle inequities in the health care system. As health care renewal efforts gain momentum new knowledge from the perspective of consumers, such as that captured in this research, is important. The consumer perspective provides a valuable opportunity for stakeholders in health care policy- and decision-making to contextualize and make greater sense of the information used in making decisions about health care service delivery for vulnerable populations, like patients with multiple chronic conditions.

Protein-energy wasting (PEW) is commonly seen in patients with chronic kidney disease (CKD). The condition is characterised by chronic, systemic low-grade inflammation which affects nutritional status by a variety of mechanisms including reducing appetite and food intake and increasing muscle catabolism. PEW is linked with co-morbidities such as cardiovascular disease, and is associated with lower quality of life, increased hospitalisations and a 6-fold increase in risk of death1. Significant gender differences have been found in the severity and effects of several markers of PEW. There have been limited studies testing the ability of anti-inflammatory agents or nutritional interventions to reduce the effects of PEW in dialysis patients. This thesis makes a significant contribution to the understanding of PEW in dialysis patients. It advances understanding of measurement techniques for two of the key components, appetite and inflammation, and explores the effect of fish oil, an anti-inflammatory agent, on markers of PEW in dialysis patients. The first part of the thesis consists of two methodological studies conducted using baseline data. The first study aims to validate retrospective ratings of hunger, desire to eat and fullness on visual analog scales (VAS) (paper and pen and electronic) as a new method of measuring appetite in dialysis patients. The second methodological study aims to assess the ability of a variety of methods available in routine practice to detect the presence of inflammation. The second part of the thesis aims to explore the effect of 12 weeks supplementation with 2g per day of Eicosapentaenoic Acid (EPA), a longchain fatty acid found in fish oil, on markers of PEW. A combination of biomarkers and psychomarkers of appetite and inflammation are the main outcomes being explored, with nutritional status, dietary intake and quality of life included as secondary outcomes. A lead in phase of 3 months prior to baseline was used so that each person acts as their own historical control. The study also examines whether there are gender differences in response to the treatment. Being an exploratory study, an important part of the work is to test the feasibility of the intervention, thus the level of adherence and factors associated with adherence are also presented. The studies were conducted at the hemodialysis unit of the Wesley Hospital. Participants met the following criteria: adult, stage 5 CKD on hemodialysis for at least 3 months, not expected to receive a transplant or switch to another dialysis modality during the study, absence of intellectual impairment or mental illness impairing ability to follow instructions or complete the intervention. A range of intermediate, clinical and patient-centred outcome measures were collected at baseline and 12 weeks. Inflammation was measured using five biomarkers: c-reactive protein (CRP), interleukin-6 (IL6), intercellular adhesion molecule (sICAM-1), vascular cell adhesion molecule (sVCAM-1) and white cell count (WCC). Subjective appetite was measured using the first question from the Appetite and Dietary Assessment (ADAT) tool and VAS for measurements of hunger, desire to eat and fullness. A novel feature of the study was the assessment of the appetite peptides leptin, ghrelin and peptide YY as biomarkers of appetite. Nutritional status/inflammation was assessed using the Malnutrition-Inflammation Score (MIS) and the Patient-Generated Subjective Global Assessment (PG-SGA). Dietary intake was measured using 3-day records. Quality of life was measured using the Kidney Disease Quality of Life Short Form version 1.3 (KDQOL-SF™ v1.3 © RAND University), which combines the Short-Form 36 (SF36) with a kidney-disease specific module2. A smaller range of these variables was available for analysis during the control phase (CRP, ADAT, dietary intake and nutritional status). Statistical analysis was carried out using SPSS version 14 (SPSS Inc, Chicago IL, USA). Analysis of the first part of the thesis involved descriptive and bivariate statistics, as well as Bland-Altman plots to assess agreement between methods, and sensitivity analysis/ROC curves to test the ability of methods to predict the presence of inflammation. The unadjusted (paired ttests) and adjusted (linear mixed model) change over time is presented for the main outcome variables of inflammation and appetite. Results are shown for the whole group followed by analyses according to gender and adherence to treatment. Due to the exploratory nature of the study, trends and clinical significance were considered as important as statistical significance. Twenty-eight patients (mean age 61±17y, 50% male, dialysis vintage 19.5 (4- 101) months) underwent baseline assessment. Seven out of 28 patients (25%) reported sub-optimal appetite (self-reported as fair, poor or very poor) despite all being well nourished (100% SGA A). Using the VAS, ratings of hunger, but not desire to eat or fullness, were significantly (p<0.05) associated with a range of relevant clinical variables including age (r=-0.376), comorbidities (r=-0.380) nutritional status (PG-SGA score, r=-0.451), inflammatory markers (CRP r=-0.383; sICAM-1 r=-0.387) and seven domains of quality of life. Patients expressed a preference for the paper and pen method of administering VAS. None of the tools (appetite, MIS, PG-SGA, albumin or iron) showed an acceptable ability to detect patients who are inflamed. It is recommended that CRP should be tested more frequently as a matter of course rather than seeking alternative methods of measuring inflammation. 27 patients completed the 12 week intervention. 20 patients were considered adherent based on changes in % plasma EPA, which rose from 1.3 (0.94)% to 5.2 (1.1)%, p<0.001, in this group. The major barriers to adherence were forgetting to take the tablets as well as their size. At 12 weeks, inflammatory markers remained steady apart from the white cell count which decreased (7.6(2.5) vs 7.0(2.2) x109/L, p=0.058) and sVCAM-1 which increased (1685(654) vs 2249(925) ng/mL, p=0.001). Subjective appetite using VAS increased (51mm to 57mm, +12%) and there was a trend towards reduction in peptide YY (660(31) vs 600(30) pg/mL, p=0.078). There were some gender differences apparent, with the following adjusted change between baseline and week 12: CRP (males -3% vs females +17%, p=0.19), IL6 (males +17% vs females +48%, p=0.77), sICAM-1 (males -5% vs females +11%, p=0.07), sVCAM-1 (males +54% vs females +19%, p=0.08) and hunger ratings (males 20% vs females -5%, p=0.18). On balance, males experienced a maintainence or reduction in three inflammatory markers and an improvement in hunger ratings, and therefore appeared to have responded better to the intervention. Compared to those who didn’t adhere, adherent patients maintained weight (mean(SE) change: +0.5(1.6) vs - 0.8(1.2) kg, p=0.052) and fat-free mass (-0.1 (1.6) vs -1.8 (1.8) kg, p=0.045). There was no difference in change between the intervention and control phase for CRP, appetite, nutritional status or dietary intake. The thesis makes a significant contribution to the evidence base for understanding of PEW in dialysis patients. It has advanced knowledge of methods of assessing inflammation and appetite. Retrospective ratings of hunger on a VAS appear to be a valid method of assessing appetite although samples which include patients with very poor appetite are required to confirm this. Supplementation with fish oil appeared to improve subjective appetite and dampen the inflammatory response. The effectiveness of the intervention is influenced by gender and adherence. Males appear to be more responsive to the primary outcome variables than females, and the quality of response is improved with better adherence. These results provide evidence to support future interventions aimed at reducing the effects of PEW in dialysis patients.

Chronic kidney disease is a substantial health problem effecting a large portion of the US population. Presence of excess protein, particularly albumin, in the urine of patients with chronic kidney disease is an independent risk factor for cardiovascular disease and progression to end stage renal disease. In addition, excess protein reabsorption in the proximal tubule is sufficient to cause damage to the proximal tubule independent of the initial condition that lead to chronic disease. In the last decade, excess protein reabsorption by the proximal tubule as a result of chronic kidney damage has been shown to cause oxidative and ER stress, cell death, as well as tubule inflammation and fibrosis in the proximal tubule cell. Only recently have two studies investigated the role of autophagy in protein-induced tubule damage. Autophagy is a dynamic catabolic mechanism used to degrade cytosolic elements in times of cell starvation and is an important process in the cell's response to stress. The results of the studies by Wei Jin Liu et al. and Yamahara et. al. provide important first steps to determine whether autophagy of excess protein in proteinuric states prevents proximal tubule cell toxicity and potentially slow the progression of chronic kidney disease (CKD). This thesis will explore the results of these two studies in the context of proximal tubule damage in chronic kidney disease, and discuss the potential for protein autophagy to improve our understanding and treatment of chronic kidney disease.

Conselho Nacional de Desenvolvimento CientÃfico e TecnolÃgico / A doenÃa renal crÃnica (DRC) à caracterizada pela perda normalmente lenta, progressiva e irreversÃvel da funÃÃo renal. Sugere-se que, nesta patologia, a resposta natriurÃtica do organismo à ingestÃo de sal e a expansÃo de volume encontra-se reduzida em consequÃncia da lesÃo dos nÃfrons. Nesse contexto, mostram-se necessÃrios estudos que estabeleÃam uma relaÃÃo entre a DRC e a regulaÃÃo de peptÃdeos natriurÃticos, como guanilina (Gn), uroguanilina (UGn) e peptÃdeo natriurÃtico atrial (PNA), e o efeito da angiotensina II (AngII) sobre a regulaÃÃo destes peptÃdeos. Assim, buscou-se avaliar uma possÃvel modulaÃÃo da via das guanilinas pelo enalapril no modelo de nefrectomia 5/6 (nx5/6). Utilizou-se ratos Wistar, machos, com peso entre 250-300g. Os animais foram divididos em 4 grupos (n=8): grupos controle sem tratamento ou tratado com enalapril (10mg/kg v.o.) (SHAM e SHAM+E) e grupos submetidos à nx 5/6 sem tratamento ou tratado com enalapril (10 mg/kg v.o.) (Nx e Nx+E). Ao final da 10 semana apÃs a cirurgia, foram determinados alguns marcadores de funÃÃo renal. As amostras de rim foram encaminhadas para anÃlise histolÃgica e avaliaÃÃo expressÃo de RNAm para Gn, UGn, PNA e dos receptores da guanilato ciclase de membrana, GC-A e GC-C e do receptor de clearence (NPR-C). No intestino, determinou-se a expressÃo de RNAm para Gn, UGn e G-C. Nx apresentou os nÃveis sÃricos de creatinina (Nx= 1.28  0.07; SHAM= 0.67  0.02 mg/dL), urÃia (Nx=108.0  5.57; SHAM=96.83  4.08 mg/dL), proteinÃria (Nx=129.10  13.87 SHAM=96.83  4.07; mg/24hrs) e FENa+ (Nx=3.552  0.56; SHAM=1.43  0.16) aumentados, e a TFG (Nx=0.44  0.10  0.04; SHAM=0.97  0.07 mL/min) diminuÃda. Nx+E, quando comparado a Nx, apresentou nÃveis reduzidos de creatinina (Nx+E= 0.97  0.08; Nx=1.28  0.07 mg/dL), de proteinÃria (Nx+E=31.94  6.46 Nx= 129.10  13.87 mg/24hrs) e da FENa+ (Nx+E= 2.02  0.28; Nx=3.55  0.56), alÃm elevar a TFG (Nx+E=0.70  0.08; Nx=0.44  0.10 mL/min). Nx apresentou aumento da expressÃo gÃnica intra-renal de Gn (Nx=13.92  5.13; SHAM=1.08  0.20), UGn (Nx=12.77  7.00; SHAM=1.04  0.13), GC-A (Nx=5.91  1.36; SHAM=1.06  0.17) e NPR-C (Nx=7.835  1.72; SHAM=1.15  0.27), e Nx+E teve genes reduzidos para UGn (Nx+E=0.10  0.03; Nx=1.75  0.96), GC-A (Nx+E=0.031  0.01; Nx=1.18  0.27) e NPR-C (Nx+E=0.03  0.01; Nx=1.08  0.24) quando comparados a Nx. No intestino, houve uma reduÃÃo da transcriÃÃo de GC-C (Nx=0,22Â0,04; SHAM=1.12  0.22) em Nx, e o enalapril aumentou os nÃveis de expressÃo deste gene (Nx+E=3.94  0.57; Nx=1.15  0.22). Em conjunto, estes dados sugerem uma hiperativaÃÃo na via das guanilinas na DRC, alÃm de modulaÃÃo dessa classe de peptÃdeos por parte da AngII.

Background: Chronic Kidney Disease (CKD) is a worldwide public health problem. There are few studies in Latin America, especially in primary care settings. Our objective was to determine the prevalence, stages, and associated factors of CKD in primary care setting. Methods: We did a retrospective secondary analysis of a database from the Diabetes and Hypertension Primary Care Center of the Peruvian Social Security System (EsSalud) in Lima, Peru. We defined CKD as the presence of eGFR <60 mL/min and/or albuminuria >30 mg/day in 24 h, according to Kidney Disease: Improving Global Outcomes (KDIGO). Factors associated with CKD were evaluated with Poisson Regression models; these factors included age, gender, type 2 diabetes mellitus (DM2), hypertension (HTN), body mass index (BMI), and uric acid. Associations were described as crude and adjusted prevalence ratios (PR) and their 95% confidence intervals (95% CI). Results: We evaluated 1211 patients (women [59%], mean age 65.8 years [SD: 12.7]). Prevalence of CKD was 18%. Using the estimated glomerular filtration rate (eGFR), the prevalence was 9.3% (95% CI 5.3 – 13.3) in patients without HTN or DM2; 20.2% (95% CI 17.6 – 22.8) in patients with HTN, and 23.9% (95% CI 19.4 – 28.4) in patients with DM2. The most common stages were 1 and 2 with 41.5% and 48%, respectively. Factors associated with CKD in the adjusted analysis were: age in years (PR = 1.03, 95% CI 1.01 – 1.04), DM2 (PR = 3.37, 95% CI 1.09 – 10.39), HTN plus DM2 (PR = 3.90, 95% CI 1.54 – 9.88), and uric acid from 5 to <7 mg/dL (PR = 2.04, 95% CI 1.31 – 3.19) and ≥7 mg/dL (PR = 5.19, 95% CI 3.32 – 8.11). Conclusions: Prevalence of CKD in the primary care setting population was high. CKD is more frequent in the early stages of the disease, and individuals with hypertension, DM2, older age and hyperuricemia have higher prevalence of CKD.

INTRODUCTION Chronic kidney disease (CKD) affects 50 million people globally. Several studies show the importance of implementing interventions that enhance patients’ knowledge about their disease. In 2011 the Kidney Disease Knowledge Survey (KiKS) was developed: a questionnaire that assesses the specific knowledge about chronic kidney disease in pre-dialysis patients. OBJECTIVE To translate to Spanish, culturally adapt and validate the Kidney Disease Knowledge Survey questionnaire in a population of patients with pre-dialysis chronic kidney disease. METHODS We carried out a Spanish translation and cross-cultural adaptation of the Kidney Disease Knowledge Survey questionnaire. Subsequently, we determined its validity and reliability. We determined the validity through construct validity; and reliability by evaluating its internal consistency and its intra- observer reliability (test-retest). RESULTS We found a good internal consistency (Kuder-Richardson = 0.85). The intra-observer reliability was measured by the intra-class correlation coefficient that yielded a value of 0.78 (95% CI: 0.5-1.0). This value indicated a good reproducibility; also, the mean difference of -1.1 test-retest SD 6.0 (p = 0.369) confirms this finding. CONCLUSION The translated Spanish version of the Kidney Disease Knowledge Survey is acceptable and equivalent to the original version; it also has a good reliability, validity and reproducibility. Therefore, it can be used in a population of patients with pre-dialysis chronic kidney disease.

Introduction—Chronic kidney disease (CKD) affects 50 million people globally. Several studies show the importance of implementing interventions that enhance patients' knowledge about their disease. In 2011, the Kidney Disease Knowledge Survey (KiKS) was developed, a questionnaire that assesses the specific knowledge about CKD in pre-dialysis patients. Objective—To translate to Spanish, culturally adapt and validate the questionnaire KiKS in a population of patients with pre-dialysis CKD. Methods—The translation and cultural adaptation of KiKS was performed. Subsequently, its validity and reliability were determined. The validity was evaluated by construct validity; and the reliability by its internal consistency and its intra-observer reliability (test-retest). Results—A good internal consistency was found (Kuder-Richardson = 0.85). Regarding intraobserver reliability, the intraclass correlation coefficient with a value of 0.78 (95% CI: 0.5–1.0) indicated a good reproducibility; the mean difference of −1.1 test-retest S.D. 6.0 (p = 0.369) confirm this.