<p>Diabetic nephropathy is a chronic kidney disease and one of the more severe complications from diabetes mellitus type 2. The glomerular and tubular dysfunctions usually lead to end stage renal disease and the treatments of these patients (dialysis, kidney transplants) are a huge economic burden for the society. Due to an epidemiologic increase of type 2 diabetes, conventional diagnostic markers like creatinine and albumin are not sufficient, since they are only able to identify already existing kidney damage. With targeted metabolomics, the analysis of small molecules produced from metabolism, this project aimed at finding novel and more sensitive metabolic biomarkers from several different classes of metabolites. The different assays were performed with flow injection analysis, high performance liquid chromatography, gas chromatography and mass spectrometry, and with principal component analysis and discriminant analysis, up-and down-regulated metabolites could be identified and their respective biochemical pathways, if possible, explained. In diabetics significantly elevated concentrations of very long chain fatty acids (impaired peroxisomal β-oxidation), urinary sugars and acylcarnitines in plasma could be recognized. Markers indicating kidney damage included significantly increased plasma concentrations of asymmetric dimethylarginine (inhibition of nitric oxide synthase resulting in decreased endothelial functionality) and histamine (indication of uremic pruritus). Oxidative stress was also found to be a potential prognostic marker as indicated by the raised methionine-sulfoxide to methionine ratio in nephrotic patients. To summarize, this project succeeded in identifying metabolic biomarkers both for diabetes type 2 and nephropathy, which in the future might become important tools in slowing down progression or diagnosing these diseases.</p>

Diss. (sammanfattning) Stockholm : Karol. inst., 2005. / Härtill 4 uppsatser.

Inledning: Mikroskopisk analys av urinsediment anses i dagsläget vara gold standard inom urinsedimentdiagnostik, trots att metoden ofta är otillräckligt standardiserad. En rad automatiserade instrument, såsom UF-5000, finns idag tillgängliga och kompenserar för problematiken med den gamla metoden. Analys av urinsediment är avgörande vid flertal njursjukdomar, där bland annat erytrocyter, leukocyter, epitelceller, cylindrar och kristaller är av stort diagnostiskt värde. Syfte: Syftet var att utvärdera det automatiserade urinpartikelinstrumentet UF-5000 samt att jämföra metoden med manuell ljusmikroskopering av urinsediment. Metod: Vid metodjämförelse analyserades 69 prover med instrumentet UF-5000 samt i mikroskop. Data bearbetades med Passing Bablok-regression, Bland-Altman differensanalys samt Spearmans rangkorrelationkoefficient. Resultat: Statistisk signifikant skillnad förekom vid metodjämförelsen. Utvärderingen av instrumentet visade hög mätnoggrannhet med undantag för variationskoefficienten vid låg leukocytkoncentration samt avvikelser för instrumentets linjäritet. Diskussion: Då ljusmikroskopering av urinsediment är en otillräckligt standardiserad metod kunde statistiskt signifikanta skillnader ses, vilket kan bero på den bristande referensmetoden. Fortsatta studier där automatiserad metod jämförs med en mer standardiserad manuell mikroskopi är av stor vikt. Även reducering av cut-off för diverse parametrar kan vara aktuellt. Instrumentutvärdering visade en generell mätnoggrannhet med enstaka undantag vilket kan bero på felhantering vid analys. För vidare analys av linjäritet skulle ett ytterligare instrument som komplement kunna användas. / Introduction: Microscopy is gold standard for urine sediment analysis, although the method is often insufficiently standardized. Several automated instruments, such as UF-5000, are commercially available on the market. Urine sediment analysis is crucial for diagnosis of kidney and urinary tract diseases where elements such as erythrocytes, leukocytes, epithelial cells, casts and crystals can be identified. Aim: The aim was to evaluate the performance of UF-5000 and compare the method with manual microscopic analysis of urine sediment. Method: Analysis with UF-5000 and microscopy was conducted on 69 samples. Data were processed with Passing Bablok-regression, Bland-Altman bias plot and Spearman's rank order correlation. Result: Comparison showed statistical significance between the two methods. Performance evaluation showed high accuracy apart from the coefficient of variation for low concentration of leukocytes and systematic error for linearity. Discussion: Since microscopy of urine sediment is an insufficiently standardized method, differences were acknowledged caused by discrepancies in the reference method. Further studies where UF-5000 is compared to a more standardized manual microscopy with a larger amount of pathological urine samples is of great importance. Reduction for cut-off may also be relevant. For further analysis of linearity, an additional instrument should be used as a complement.

<p>Psykisk ohälsa ökar i samhället, 20 % av Sveriges befolkning riskerar att någon gång i livet drabbas av depression. 600 personer varje år drabbas av kronisk njursvikt vilket innebär att dialysbehandling kan bli aktuellt. Att leva med en livslång sjukdom, som det innebär när man behandlas med dialys, och samtidigt drabbas av psykisk ohälsa innebär ett stort lidande för den enskilda individen. Genom att sjuksköterskan bemöter patienterna med empati och medmänsklighet så skapar denne goda förutsättningar för att relationen ska präglas av tillit och ärlighet. Syftet med denna litteraturstudie var att belysa hur sjuksköterskan kan identifiera och förebygga depression hos människor som behandlas med dialys. Resultatet visar att depression är vanligt förekommande bland dialyspatienter. Depression hos dessa människor kan leda till sömnproblem, nutritionsproblem, känsla av förlust och social isolering. Identifiering av depression kan ske genom användning av bedömningsformulär, detta kan även användas som en åtgärd för att förebygga depression. Mer kvalitativ forskning inom ämnet hade varit ett bra sätt för att öka förståelsen för denna patientgrupps situation. Genom att öka kunskapen ökar också förståelsen för depression och vad det innebär att leva med en livslång sjukdom och denna komplexa situation.</p> / <p>Mental illness is increasing in society, 20% of Sweden's population is at risk to suffer some from depression at some point in their lives. 600 people each year suffer from chronic kidney failure, which can lead to the need for dialysis treatment. To live with a lifelong disease and suffer from mental illness at the same time exposes the individual for a great suffering. By responding to the patients with empathy and compassion the nurse creates good conditions for the relationship, to be able to be characterized by trust and honesty. The purpose of this literature study was to elucidate how the nurse can identify and prevent depression for people treated with dialysis. The results show that depression is common among dialysis patients. For these people, depression can lead to sleeping problems, nutritional problems, feelings of loss, and social isolation. Identification of depression can be done through the use of evaluation forms; this can also be used as a measure to prevent depression. More qualitative research on the subject would be a good method to increase the understanding of the situation these patients are in. Raising awareness also increases the understanding of depression and what it means to live with a lifelong disease, and the complex situation it means.</p>

Diabetic long-term complications, despite intensive treatment, cause serious handicaps at relatively young age in diabetic patients. Diabetic nephropathy (DN) develops in up to 30% of patients with type 1 diabetes (T1D). Besides the eventual loss of kidney function, with need for dialysis treatment and transplantation, this complication also increases the risk of early death from cardiovascular disease. In addition to hyperglycaemia, the risk of developing DN is influenced by a number of life-style related factors, such as smoking and diet, but the mechanisms of action of these factors are largely unknown. The incidence of DN is not linearly related to diabetes duration. There is a peak incidence of DN at 15-20 years and this, together with results from family studies, shows that genetic factors are important contributors. Possible candidate genes are those involved in regulation of intraglomerular pressure and blood pressure, oxidative stress and inflammation. The main aims of this thesis were: ● To investigate the risk of DN associated with polymorphisms in; A) the endothelial NO-synthase gene (NOS3) and genes in the renin-angiotensin-system (RAAS) (all involved in the regulation of intraglomerular pressure). B) the manganese superoxide dismutase gene (SOD2) (involved in the regulation of oxidative stress). C) the ICAM1 gene (involved in activation and migration of lymphocytes) ● To investigate gene-smoking interactions ● To investigate the influence of normal diet on risk of microalbuminuria. The aims were addressed in different case-control settings, including 347 T1D patients from Sweden and 1163 patients from Finland, with or without DN, defined as; overt DN – having albumin excretion rate (AER) ≥200 μg/min, incipient DN – AER between 20 and 200 μg/min, non-DN controls – having AER &lt;20 μg/min and at least 20 years of diabetes duration. In one study also non-diabetic healthy individuals were included to asses the risk of T1D associated with the ICAM1 gene. Results: The RAAS genes were investigated in the Swedish sample set and there was an association between a polymorphism in the angiotensin II type 1 receptor (AGTR1) gene and overt DN, when adjusting for age, duration of diabetes, HbA1c, sex and smoking (adjusted OR=3.04, 99% CI=1.02-9.06). Also a synergistic interaction with smoking was indicated. The ICAM1 gene was investigated in the Swedish sample set, but no association with DN was found. There were, however, associations between T1D and two polymorphisms in this gene, rs281432 (OR=1.64, 95% CI=1.14-2.38) and rs5498 (OR=2.46, 95% CI=1.59-3.80). In the combined Swedish/Finnish sample set, the Glu/Glu genotype of the Glu298Asp polymorphism in the NOS3 gene was associated with DN when age at diabetes onset, duration of diabetes, HbA1c, blood pressure, sex and smoking were taken into account (adjusted OR=1.46, 95% CI=1.12-1.91). There was also association between a polymorphism in the MnSOD gene and DN in this sample set. Homozygosity for the valine-allele of the Val16Ala polymorphism was associated with increased risk of DN in a model including age at diabetes onset, duration of diabetes, HbA1c, sex and smoking (adjusted OR=1.32, 95% CI=1.00-1.74). Smoking was associated with DN (OR=2.00, 95% CI=1.60-2.50) and in the Swedish sample set there were indications of interactions between smoking and the NOS3 and SOD2 genes, but these results could not be confirmed in the Finnish sample set. A high protein intake can enhance glomerular filtration rate and accelerate progression to DN, also other dietary components such as fat, fibres, vitamins and the ratio red/white meat have been discussed as important for DN development. In a nested case-control study including young T1D patients, the normal dietary intakes of protein and other nutrients were assessed using a semiquantitative questionnaire. The results showed that T1D patients consuming more than 6.5 g fish protein (&gt;75th percentile) per day were at slightly lower risk to have microalbuminuria in both crude (OR=0.49, 95% CI=0.25-0.97) and adjusted analyses (OR=0.26, 95% CI=0.09-0.76, adjusted for age, duration of diabetes, sex, HbA1c, mean arterial pressure, BMI, region, smoking, energy intake and fish fat intake). Conclusions: The risk of having diabetic nephropathy is influenced by at least two genes controlling blood pressure and one gene protecting against oxidative stress. Smoking also increases the risk of DN and our findings indicate that smoking may accentuate the effect of the AGTR1, NOS3 and SOD2 genes. Normal dietary intake of protein was not associated with risk of having microalbuminuria in young T1D patients, on the other hand, an intake of fish protein above the 75th percentile decreased the risk of microalbuminuria.

Psykisk ohälsa ökar i samhället, 20 % av Sveriges befolkning riskerar att någon gång i livet drabbas av depression. 600 personer varje år drabbas av kronisk njursvikt vilket innebär att dialysbehandling kan bli aktuellt. Att leva med en livslång sjukdom, som det innebär när man behandlas med dialys, och samtidigt drabbas av psykisk ohälsa innebär ett stort lidande för den enskilda individen. Genom att sjuksköterskan bemöter patienterna med empati och medmänsklighet så skapar denne goda förutsättningar för att relationen ska präglas av tillit och ärlighet. Syftet med denna litteraturstudie var att belysa hur sjuksköterskan kan identifiera och förebygga depression hos människor som behandlas med dialys. Resultatet visar att depression är vanligt förekommande bland dialyspatienter. Depression hos dessa människor kan leda till sömnproblem, nutritionsproblem, känsla av förlust och social isolering. Identifiering av depression kan ske genom användning av bedömningsformulär, detta kan även användas som en åtgärd för att förebygga depression. Mer kvalitativ forskning inom ämnet hade varit ett bra sätt för att öka förståelsen för denna patientgrupps situation. Genom att öka kunskapen ökar också förståelsen för depression och vad det innebär att leva med en livslång sjukdom och denna komplexa situation. / Mental illness is increasing in society, 20% of Sweden's population is at risk to suffer some from depression at some point in their lives. 600 people each year suffer from chronic kidney failure, which can lead to the need for dialysis treatment. To live with a lifelong disease and suffer from mental illness at the same time exposes the individual for a great suffering. By responding to the patients with empathy and compassion the nurse creates good conditions for the relationship, to be able to be characterized by trust and honesty. The purpose of this literature study was to elucidate how the nurse can identify and prevent depression for people treated with dialysis. The results show that depression is common among dialysis patients. For these people, depression can lead to sleeping problems, nutritional problems, feelings of loss, and social isolation. Identification of depression can be done through the use of evaluation forms; this can also be used as a measure to prevent depression. More qualitative research on the subject would be a good method to increase the understanding of the situation these patients are in. Raising awareness also increases the understanding of depression and what it means to live with a lifelong disease, and the complex situation it means.

This thesis is comprised of four studies and concerns haemodialysis patients’ confidence in being able to manage fluid intake between treatment sessions, and whether the fluid intake is influenced by certain modifiable characteristics of the persons in question. The overall aim was to study aspects of excessive fluid overload and haemodialysis patients’ self-regulation of fluid allotment from a bio-psychosocial and behavioural medicine perspective. The extent of non-adherence to fluid allotment was described in Study I. National registry data were used. Three out of ten Swedish haemodialysis patients had excessive fluid overload and one out of five was at risk for treatment related complications due to too rapid ultrafiltration rate. The objective in Study II was to develop and psychometrically evaluate a self-administered scale to measure situation-specific self-efficacy to low fluid intake. The measure (the Fluid Intake Appraisal Inventory) was found to be reliable and valid in haemodialysis settings. Subgroups based on individual profiles of self-efficacy, attentional style and depressive symptoms were explored in Study III using a cluster analytic approach. Three distinct subgroups were found and the subgroup structure was validated for clinical relevance. The individuals’ profile concerning self-efficacy, attentional style and depressive symptoms has to be taken into account in nursing interventions designed to reduce haemodialysis patients’ fluid intake. In Study IV, an intervention designed to reduce haemodialysis patients’ fluid intake was introduced and its acceptability, feasibility and efficacy were evaluated and discussed. Acceptability of such an intervention was confirmed. Addressing beliefs, behaviours, emotions and physical feelings is clinically feasible and may reduce haemodialysis patient’s excessive fluid overload. This thesis indicates that there is a potential for improvement in the fluid management care of haemodialysis patients. Behavioural nursing strategies that aim to assist patients to achieve fluid control should be applied more extensively. Cognitive profiles of the patients should be taken into account when targeted nursing intervention aiming to encourage and maintain the patient’s fluid control is introduced.

Fibroblast growth factor-23 (FGF23) was initially identified as the causative factor of autosomal dominant hypophosphatemic rickets. Further studies confirmed that FGF23 is predominantly expressed in the osteocytes and osteoblasts of bone and that circulating FGF23 acts on the kidney to inhibit renal phosphate reabsorption and 1,25(OH)2D3 hydroxylation. With the progression of chronic kidney disease (CKD), the kidneys become insufficient to maintain a normal systemic mineral homeostasis, resulting in various abnormalities of bone and mineral metabolism, generally referred to as Chronic Kidney Disease – Mineral and Bone Disorders (CKD-MBD). FGF23 increases early in the course of CKD in order to maintain normal serum phosphate levels; long before a significant increase in serum phosphate can be detected. Recent studies suggest that increased FGF23 levels are associated with progression of CKD, mortality, and the development of refractory secondary hyperparathyroidism. Because FGF23 is the very earliest marker of CKD-MBD, it is of particular interest to evaluate the relation between FGF23 and CKD-MBD abnormalities, in the setting of early CKD and also in individuals with normal renal function. In the present work, we show that FGF23 is linked to several dynamic measurements of vascular function, including endothelial dysfunction, arterial stiffness, and atherosclerosis. FGF23 is also positively associated with left ventricular mass index and an increased risk of having left ventricular hypertrophy. All associations were independent of serum phosphate and were strengthened in subjects with diminished renal function. Furthermore, we found significant evidence for an association between higher FGF23 and increased fat mass and dyslipidemia, which could represent a novel pathway linking FGF23 to cardiovascular disease. Finally, we show that FGF23 is a significant predictor of future fracture risk. Although these associations could be reflecting the increased risk associated with hyperphosphatemia and calcitriol deficiency, current evidence points towards FGF23 being more than an innocent bystander. At the very least, FGF23 holds promise of being a bio-marker of cardiovascular status and phosphate-related toxicity both in CKD and in the general population, and might be a therapeutic target that could improve the fatal prognosis in CKD patients.

This thesis is comprised of four studies and concerns haemodialysis patients’ confidence in being able to manage fluid intake between treatment sessions, and whether the fluid intake is influenced by certain modifiable characteristics of the persons in question. The overall aim was to study aspects of excessive fluid overload and haemodialysis patients’ self-regulation of fluid allotment from a bio-psychosocial and behavioural medicine perspective. The extent of non-adherence to fluid allotment was described in Study I. National registry data were used. Three out of ten Swedish haemodialysis patients had excessive fluid overload and one out of five was at risk for treatment related complications due to too rapid ultrafiltration rate. The objective in Study II was to develop and psychometrically evaluate a self-administered scale to measure situation-specific self-efficacy to low fluid intake. The measure (the Fluid Intake Appraisal Inventory) was found to be reliable and valid in haemodialysis settings. Subgroups based on individual profiles of self-efficacy, attentional style and depressive symptoms were explored in Study III using a cluster analytic approach. Three distinct subgroups were found and the subgroup structure was validated for clinical relevance. The individuals’ profile concerning self-efficacy, attentional style and depressive symptoms has to be taken into account in nursing interventions designed to reduce haemodialysis patients’ fluid intake. In Study IV, an intervention designed to reduce haemodialysis patients’ fluid intake was introduced and its acceptability, feasibility and efficacy were evaluated and discussed. Acceptability of such an intervention was confirmed. Addressing beliefs, behaviours, emotions and physical feelings is clinically feasible and may reduce haemodialysis patient’s excessive fluid overload. This thesis indicates that there is a potential for improvement in the fluid management care of haemodialysis patients. Behavioural nursing strategies that aim to assist patients to achieve fluid control should be applied more extensively. Cognitive profiles of the patients should be taken into account when targeted nursing intervention aiming to encourage and maintain the patient’s fluid control is introduced.