京都大学 / 0048 / 新制・課程博士 / 博士(医学) / 甲第21256号 / 医博第4374号 / 新制||医||1029(附属図書館) / 京都大学大学院医学研究科医学専攻 / (主査)教授 中山 健夫, 教授 小川 修, 教授 川村 孝 / 学位規則第4条第1項該当 / Doctor of Medical Science / Kyoto University / DFAM

No / ß2-Microglobulin (ß2m) is one of over 20 proteins known to be involved in human amyloid disease. Peptides equivalent to each of the seven ß-strands of the native protein, together with an eighth peptide (corresponding to the most stable region in the amyloid precursor conformation formed at pH 3.6, that includes residues in the native strand E plus the eight succeeding residues (named peptide E¿)), were synthesised and their ability to form fibrils investigated. Surprisingly, only two sequences, both of which encompass the region that forms strand E in native ß2m, are capable of forming amyloid-like fibrils in vitro. These peptides correspond to residues 59¿71 (peptide E) and 59¿79 (peptide E¿) of intact ß2m. The peptides form fibrils under the acidic conditions shown previously to promote amyloid formation from the intact protein (pH <5 at low and high ionic strength), and also associate to form fibrils at neutral pH. Fibrils formed from these two peptides enhance fibrillogenesis of the intact protein. No correlation was found between secondary structure propensity, peptide length, pI or hydrophobicity and the ability of the peptides to associate into amyloid-like fibrils. However, the presence of a relatively high content of aromatic side-chains correlates with the ability of the peptides to form amyloid fibrils. On the basis of these results we propose that residues 59¿71 may be important in the self-association of partially folded ß2m into amyloid fibrils and discuss the relevance of these results for the assembly mechanism of the intact protein in vitro.

Everyday life can be complex when next of kin of haemodialysis patients are preoccupied with taking care of the patient and his/her health, which implies the difficulties and requirements needed. The general aim of this thesis was to explore and describe everyday life among next of kin of haemodialysis patients with focus on the life situation, health, time and professional support. Two perspectives of the thesis was applied: a holistic perspective on the everyday life of next of haemodialysis patient and a social perspective with focus on human communication and understanding of next of kin’s experience of everyday life. A qualitative descriptive and explorative design, comprising a phenomenographic and content analysis was used in Studies I-IV. The data collected in the studies consisted of interviews with next of kin to haemodialysis patient and analysis of professional support for next of kin to chronic haemodialysis patients in nursing documentation from two hospitals in Sweden. The experience of time in everyday life among next of kin of haemodialysis patients demonstrated that time for them is minimised and life space contracted. Next of kin experienced ambivalence towards their own health, especially in cases of patients’ spouses When next of kin of haemodialysis patient’s became involved in the patients’ care, they experienced arduousness in relation to their own health as well as less uninterrupted time for themselves in everyday life, and their life situation was characterised by confinement and social isolation. They were aware of the prognosis of renal disease and the fact that haemodialysis is a life-sustaining treatment, which forced them to live for the moment. The everyday life among the next of kin changed when the family became involved in the care, which in turn lead to a changed life situation and restrictions in everyday life. Lack of knowledge in nursing documentation of professional support revealed necessity of the readiness of next of kin. It is therefore important to be familiar with this in the nursing process, especially when the patient and their next of kin need support and attention in everyday life. Original papers not included. / <p>Linköping University Medical Dissertation, 926, I. Ziegert K. &amp; Fridlund B. Conceptions of life situation among next of kin of haemodialysis patients. Journal of Nursing Management 2001; (9) 231-239. doi:10.1046/j.1365-2834.2001.00233.x, II. Ziegert K., Fridlund B. &amp; Lidell E. Health in everyday life among spouses of patients on haemodialysis; a content analysis. Scandinavian Journal of Caring Sciences, Volume 20, Number 2, June 2006, pp. 223-228(6). DOI: 10.1111/j.1471-6712.2006.00400.x, III. Ziegert K., Fridlund B. &amp; Lidell E. Time in everyday life as experienced by next of kin of haemodialysis patients (Submitted for publication)., IV. Ziegert K., Fridlund B. &amp; Lidell E. Professional support for next of kin of patients receiving chronic haemodialysis treatment. A content analysis study of nursing documentation. Journal of Clinical Nursing, Volume 16, Number 2, February 2007, pp. 353-361(9). DOI: 10.1111/j.1365-2702.2006.01597.x,</p>

Background and aim: There had been no randomized end-point studies with statins for patients with severe renal failure. The purpose of this prospective, open, randomized, controlled study was to investigate whether atorvastatin (10 mg/day) would alter cardiovascular end-points and the overall mortality rate of patients with chronic kidney disease stage 4 or 5 (creatinine clearance&lt;/30 ml/min) and to influence risk factors. Material &amp; Methods: This was an open, prospective, randomized study. A total of 143 patients were included: 73 were controls and 70 were prescribed 10 mg/day of atorvastatin. As efficacy variables, total cholesterol, low-density lipoprotein cholesterol, high-density lipoprotein cholesterol and triglyceride levels were determined at the start of the study and at 1, 3, 6, 12, 18, 24, 30 and 36 months. The primary end-points were all cause of mortality, non-lethal acute myocardial infarction, and coronary artery intervention. Various risk factors were studied. In the 97 patients on haemodialysis inter dialysis weight gain (IDWG) was calculated as ultrafiltration in kg/body weight in kg given in percentage of the weight. The burden of IDWG was analyzed. Results: In the atorvastatin group, total cholesterol and low-density lipoprotein cholesterol were significantly reduced, the latter by 35% at 1 month and then sustained. Atorvastatin was withdrawn in 23% of patients due to unacceptable side effects, most frequent complaints being gastrointestinal discomfort and headache. Primary end-points occurred in 74% of the subjects. There was no difference in cardiovascular endpoint and survival between the control and atorvastatin groups. The 5-year end-point-free survival rate from study entry was 20%. There was no evidence of more benefit of atorvastatin for patients with diabetes mellitus and chronic kidney disease versus the other patients; instead plasma fibrinogen increased. The IDWG was significantly larger in patients who suffered from end-points due to cardiovascular reasons, cardiac reasons, congestive heart failure, aortic aneurysm, and intracerebral bleeding. Conclusion: These data showed that in contrast to other patient groups, patients with severe chronic kidney disease 4 and 5, including those with diabetes mellitus, seem to have no benefit from 10mg/day of atorvastatin. Instead we found a high IDWG to be an important risk factor that should be prevented. There was no evident connection between atorvastatin medication and IDWG.

Introduction: Forty years ago the life saving and life prolonging therapy of dialysis was rationed. It was extremely unlikely that people aged over 50 years would be offered treatment. Today, those aged over 65 years are becoming the fastest growing group of patients on dialysis. Changing population demographics and referral patterns, the opening up of eligibility for dialysis to high risk individuals, refinement and developments in dialysis technology and its ‘success’ in keeping more patients alive for longer periods, along with rising public expectation, are just some of the reasons behind this change in the age profile of those being currently treated for kidney failure. Older people are likely to have multiple co-morbidities and decreased functional status that may complicate their decision-making about dialysis and limit their treatment options. / Enhancing choice and involvement in treatment decision-making to the patient’s satisfaction is a central theme of health care ethics. Current national and international ethical guidelines about the initiation of dialysis recommend shared or joint decision-making and discuss patient ‘benefit’ and patient ‘need’. This project sought to determine how these recommendations, and other ethical issues related to informed consent, possible withdrawal of treatment and quality of life, were embodied in the personal experiences of a group of older people facing dialysis decisions. / Aim: The general aim of this research was to follow the dialysis decision-making process over time amongst a group of people aged 65 years and older. More specifically, this research sought to explore with the participants the following issues: what factors impacted on their dialysis decision-making; how they understood both what was happening to them and the goals of treatment; their preferences for information seeking; how they perceived any future decision-making; how or whether the commencement and experience of dialysis influenced their decision-making; and once treatment had been initiated, how they felt about their initial decisions. / Method: A predominantly longitudinal qualitative study was undertaken. Meetings were conducted prior to the potential initiation of dialysis with 21 participants. These meetings involved a semi-structured interview and the administration of three questionnaires focusing on preferences for decision-making, information seeking and quality of life. Data was also collected from the participants’ health records. For those participants who commenced dialysis a further two meetings were undertaken one month and then six months after treatment was instigated. The qualitative data was analysed thematically using concepts that had either been pre-determined and explored within the interviews or, had emerged from the participants’ stories. / Findings: Findings from this study include: participants not feeling that they had a choice about dialysis; a mismatch between theoretical expectations of informed consent and shared decision-making and the ‘actor centred experiential’ model of decision-making adopted by participants; a need to re-evaluate the balance and relationships between physiological measures of effectiveness emphasised by health professionals, and psychosocial and functional markers valued by participants; and treatment goals not being individually negotiated. / Conclusion: An interest in remaining alive was the driving force behind why participants chose to have dialysis. Other factors impacting on decisions about dialysis were multi-faceted and were based on priorities other than what health professionals consider important. Shared decision-making, as described in the literature, is not unproblematic. However, health professionals need to accept the underlying premises on which shared decision-making is based so that they can find out what expectations patients have of treatment, beyond that of saving life. Such expectations need to be discussed with patients and the various treatment options need to be negotiated in an attempt to achieve patients’ goals. Patients should be encouraged however to be involved in decision-making to the extent to which they desire.

Thesis (MNutr (Interdisciplinary Health Sciences. Human Nutrition))--University of Stellenbosch, 2008. / BACKGROUND: Although hypoglycaemia is a known complication of haemodialysis, there is little information about its prevalence among patients on maintenance haemodialysis. OBJECTIVE: To determine the prevalence of hypoglycaemia in patients on maintenance haemodialysis in Kenyatta National Hospital (Nairobi, Kenya) and to identify potential nutritionrelated causes of hypoglycaemia. METHODS: A cross-sectional, descriptive and observational study design was followed. Patients who had been on chronic maintenance haemodialysis for 3 months or longer were included in the study which was carried out from May 8 through to June 30, 2006. Random blood glucose levels were determined at baseline, 15 minutes, 30 minutes and 45 minutes, and at hourly intervals thereafter until the end of the dialysis session. The prevalence of hypoglycaemia (a blood glucose level less than 3.9 mmol/L) was then determined for the duration of haemodialysis. The relationship between minimum blood glucose levels and dietary intake, anthropometric status, primary diagnosis, co-morbid and socio-demographic factors, prescribed medication and dialysis related factors was determined. RESULTS: Among the 51 haemodialysis patients who participated in the study, the prevalence of hypoglycaemia was 16% (n=8). Eight percent (n=4) of these patients were however already hypoglycaemic on initiation of dialysis. Dietary intake of niacin ((r=0.31; p=0.02), riboflavin (r=0.30; p=0.03) and vitamin B6 (r=0.30; p=0.03) showed a significant relationship with blood glucose levels. The relationships between hypoglycaemic episodes and insulin administration (p=0.06), and between blood glucose levels and BMI (r=0.25; p=0.08 and protein intake (r=0.26; p=0.07) approached significance. There was no significant relationship between blood glucose levels and the duration of haemodialysis (p=0.942), hours of haemodialysis (p=0.27) and the dialysate solution used (p=0.12). CONCLUSIONS: Hypoglycaemia was present in 16% of patients on maintenance haemodialysis. Potential nutritional parameters which may have contributed to lower blood glucose levels in this study include a lower dietary intake of niacin, riboflavin, and vitamin B6. Lower protein intake and lower BMI was marginally associated with low blood glucose levels.

The dissertation entitled ?Health Related Quality of Life (HRQoL) in Dialysed Patients with Respect to Age? contains a theoretical and practical part. The theoretical part describes chronic kidney disorder and the treatment of this disease. It mentions the causes, repercussions and complications of this disease. It also suggests the form of treatment as the method of replacing the function of the kidneys which includes haemodialysis, peritoneal dialysis and transplantation. I have attempted to elaborate their principle, history and current form, benefits, negative aspects and complications. The practical part describes the actual research. Health Related Quality of Life (HRQoL) was ascertained in a group of patients undergoing haemodialysis at one dialysis centre. Questionnaire SF 36 was used which allows for a quantified assessment of the quality of life in eight domains. The results were statistically assessed and clearly depicted using tables and graphs. The quality of life was compared in the monitored group with the general population and also based on age and gender. The results found show a reduced quality of life of dialysed patients compared with the standard population. A difference was also found in the assessment of the quality of life in some age groups. No difference in results was proved with regard to gender.

End stage renal disease (ESRD) patients have an excess cardiovascular risk, above that predicted by traditional risk factor models. Despite the advances in both Cardiovascular disease (CVD) management and renal replacement therapy (RRT), there still is a major burden of cardiovascular mortality and morbidity in the chronic kidney disease (CKD) population. Declining renal function itself represents a continuum of cardiovascular risk and in those individuals who survive to reach ESRD, the risk of suffering a cardiac event is uncomfortably and unacceptably high. Pro-thrombotic status may contribute to this increased risk. Global thrombotic status assessment, including measurement of occlusion time (OT) the time taken to form an occlusive platelet rich thrombus and thrombolytic status (time taken to lyse such thrombus) as assessed by measuring Lysis Time (LT), may identify vulnerable patients. The aim of this study was to assess overall thrombotic status in ESRD and relate this to cardiovascular and peripheral thrombotic risk. Small sub studies were also planned to establish the effect of RRT modality on the thrombotic status.

Tryptophan is metabolised along the kynurenine pathway under the influence of tryptophan 2,3 dioxygenase and indoleamine 2,3 dioxygenase. Quinolinic acid and kynurenine, two neuroactive metabolites of the kynurenine pathway are, in chronic renal failure patients, considered as uraemic toxins. Related research is generally hampered by the non-availability of relevant analytical techniques. The primary aim of this study was, therefore, to develop and validate suitable methods for the determination of tryptophan, kynurenine and quinolinic acid. The second aim was to quantify the levels of these substances in the blood of chronic renal failure patients on renal replacement therapies and to compare the levels of haemodialysis patients to those on peritoneal dialysis. Patients’ quality of life was investigated relative to disturbances in tryptophan metabolism. Gas chromatography coupled to mass spectrometry (GC-MS) gave the best results for the analysis of tryptophan, kynurenine and quinolinic acid. A Hewlett Packard HP GC 6890 series gas chromatographer was coupled to a MS 5973 series mass spectrometer. Analytes were separated on a DB-5MS column with a nominal length of 30 metres, a diameter of 250.0 µm and film thickness of 0.10 µm. Helium was used as carrier gas, and the chromatographic analysis run time 12.5 minutes. The validation results were within the acceptance criteria for newly developed methods. The linear calibration curves constructed for all of the analytes gave r2 correlation coefficients >0.99. Other validation data such as precision, bias, accuracy and stability all fell within acceptable validation limits. In the study on chronic renal failure patients significant differences were seen between patients and controls. Tryptophan levels were 5.34 SD 5.04 µM for the haemodialysis group, 6.73 SD 3.18 µM for the peritoneal dialysis group and 28.4 SD 4.31 µM for the control group. Kynurenine levels were 4.7 SD 1.9 µM for the haemodialysis group, 2.9 SD 2.0 µM for the peritoneal dialysis group and 2.1 SD 0.6 µM for the control group. Quinolinic acid levels were 4.9 SD 2.0 µM for the haemodialysis group, 2.8 SD 2.0 µM for the peritoneal dialysis group and 0.3 SD 0.1 µM for the control group. Tryptophan was lower for the total patient group than for controls with significantly lower levels for haemodialysis versus control (p<0.05) and peritoneal dialysis versus control (p<0.05). Kynurenine levels were higher in the total patient group with significantly higher levels for the haemodialysis versus control group (p=0.0001). The patient groups had higher quinolinic acid levels with significantly higher levels for the haemodialysis versus control (p<0.05) and peritoneal dialysis versus control (p<0.05) groups. This study was the first to determine the three substances simultaneously in both haemodialysis and peritoneal dialysis patients. The study showed significant tryptophan depletion, as well as kynurenine and quinolinic acid accumulation for both groups. No significant differences were found between the patient groups other than higher kynurenine levels in the haemodialysis group. The quality of life (SF-36) was largely similar in the two patient groups. This decrease in the quality of life strongly correlated with the degree of tryptophan depletion. / Dissertation (MSc)--University of Pretoria, 2008. / Chemical Pathology / unrestricted

Patients with end-stage renal disease frequently suffer from cardiovascular complications. Many factors contribute to their development: hyperkinetic circulation caused by anaemia, fluid retention and by presence of dialysis arteriovenous access; metabolic changes leading to acceleration of atherosclerosis and increase of vascular stiffness and also fluctuation of blood pressure and organ perfusion during haemodialysis, that cause repeated tissue hypoxia. We performed our research on patients in chronic haemodialysis programme. The project studying long-term patency of dialysis access showed that dialysis graft patency is negatively influenced by presence of coronary artery disease and low serum concentrations of cholesterol. In our studies about tissue hypoxia we proved that haemodialysis patients suffer from hypoxia of cerebral tissue and muscle tissue of the dialysis access arm, and that the hypoxia worsens during dialysis. Factors associated with brain hypoxia are presence of heart failure, higher BNP levels and higher erythrocyte distribution width. One of the serious consequences of brain hypoxia is development of cognitive deficit. Among the negative impact of haemodialysis on the heart, we observed left atrial dysfunction, which is a consequence of long-term remodelling and cannot be...