published_or_final_version / Medicine / Doctoral / Doctor of Philosophy

Background In patients with diabetes mellitus (DM) or chronic kidney disease (CKD), established cardiovascular disease (CVD) is associated with an increased risk of recurrent events and poor outcome. Ischemic stroke after an acute myocardial infarction (AMI) is a devastating event that carries high risks of decreased patient independence and death. Among patients with DM or CKD, the risk of an ischemic stroke within a year following an AMI is not known. Improved risk factor control is required to reduce the likelihood of CVD recurrence. Guidelines recommend target lipid profile and blood pressure values; however, data show that these targets are often not met. Therefore, there remains an urgent need for improved cardiovascular secondary preventive follow- up. Aims The aims of the present studies were to define trends in the incidence and predictors of ischemic stroke after an AMI in patients with DM or CKD. Furthermore to assess whether secondary preventive follow-up with nurse-based telephone follow-up including medication titration after CVD improves risk factor values in patients with DM or CKD and to investigate if this method performs better than usual care to implement a new treatment guideline in diabetic patients. Methods To assess the risk of post-AMI ischemic stroke, patient data were obtained from the Swedish Register of Information and Knowledge about Swedish Heart Intensive Care Admissions (RIKS-HIA). In separate studies, we compared a total of 173 233 AMI patients with and without DM, and 118 434 AMI patients with and without CKD. Within the nurse-based age-independent intervention to limit evolution of disease (NAILED) trial, we investigated a nurse-based cardiovascular secondary preventive follow-up protocol. Patients with acute coronary syndrome, stroke, or transient ischemic attack were randomized to receive either nurse-based telephone follow-up (intervention) or usual care (control). Low-density lipoprotein (LDL-C) levels and blood pressure (BP) were measured at 1 month (baseline) and 12 months post- discharge. Intervention patients with above-target baseline values received medication titration to achieve treatment goals, while the measurements for control patients were forwarded to their general practitioners for assessment. We calculated the changes in LDL-C level and BP between baseline and 12 months post-discharge, and compared  these changes between 225 intervention patients and 215 control patients with concurrent DM or CKD. During the course of the NAILED trial, new secondary preventive guidelines for DM patients were released, including a new LDL-C target value. To assess adherence to the new guidelines within the NAILED trial, we compared LDL-C levels in the 101 intervention patients and 100 control patients with DM. Results Ischemic stroke after AMI The rates of ischemic stroke within one-year after admission for an AMI decreased over time, from 7.1% in 1998–2000 to 4.7% in 2007–2008 among DM patients, and from 4.2% to 3.7% during the same time periods for non-diabetic patients. Lower stroke risk was associated with percutaneous coronary intervention (PCI) and initiation of secondary preventive treatments in-hospital. In-hospital ischemic stroke occurred in 2.3% of CKD patients and 1.2% of non-CKD patients, with no change in these incidences over time. The rates of one-year post- discharge ischemic stroke decreased between 2003–2004 and 2009–2010 from 4.1% to 2.5% among CKD patients, and from 2.0% to 1.3% among non-CKD patients. Lower rates of post-discharge stroke were associated with PCI and statins. Cardiovascular secondary preventive follow-up Among DM and CKD patients with above-target baseline values in the NAILED trial, the median LDL-C value at 12 months was 2.2 versus 3.0 mmol/L (p<0.001) and median systolic BP was 140 versus 145 mmHg (p=0.26) for intervention and control patients, respectively. Before the guideline change, 96% of the intervention and 70% of the control patients reached the target LDL-C value (p<0.001). After the guideline change, the corresponding respective proportions were 65% and 36% (p<0.001). Conclusion Ischemic stroke is a fairly common post-AMI complication among patients with DM and CKD. This risk of stroke has decreased during recent years, possibly due to the increased use of evidence-based therapies. Compared with usual care, cardiovascular secondary prevention including nurse-based telephone follow-up improved LDL-C values at 12 months after discharge in patients with DM or CVD, and led to more efficient implementation of new secondary preventive guidelines.

It is well known that a variety of toxicants can cause damage to the renal proximal tubule. However, the early pathogenesis of these deleterious interactions between a toxicant and this region of the nephron remain poorly understood. Thus, the purpose of this research was to attempt to answer three interrelated questions. First, what are the earliest changes in kidney function and structure after administration of tubule toxicants in vivo? Secondly, how do these structural/functional alterations change over time? Finally, are certain indicators of renal "dysfunction" more sensitive then others to the early stages of proximal tubule injury? The basic experimental approach consisted of injecting laboratory animals with a selective proximal tubule toxicant, and then collecting blood and/or urine at several timepoints after dosing; a variety of renal function indicators were evaluated at each of these timepoints. These included blood urea nitrogen (BUN), the glomerular filtration rate (GFR), and the excretion of glucose, protein, salts, glutathione, enzymes, and other endogenous molecules into the urine. At the termination of the exposure period the kidneys were evaluated histopathologically, and were also assayed for levels of specific enzymes and glutathione. Enzyme histochemistry was used to visualize changes in renal enzyme distribution, and protein electrophoretic methods permitted quantification of urinary proteins. These studies showed that specific markers of renal dysfunction were more sensitive to acute proximal tubule injury than other indicators. Specifically, the urinary excretion of proteins and the brush border membrane marker γ-glutamyl transpeptidase (GGT) were the best indicators of proximal tubule injury. Glucosuria, lysozymuria, and glutathionuria were all less sensitive markers, and changes in BUN or GFR were the poorest indicators of acute proximal tubule injury. These results indicated that the brush border membrane is one of the most susceptible regions of the proximal tubule to acute renal injury. Analysis of urinary protein electrophoresis patterns and kidney histopathology confirmed this hypothesis. This research also demonstrated the progression of the toxicant-tubule interaction over time, and showed that both tubule structure and function may be altered within minutes of administering a nephro-toxicant.

Two accessions of tepary (phaseolus acutifolius Gray var. latifolius) and navy (P. vulgaris L. 'Fleetwood') beans were studied for salt tolerance at several• developmental stages. Genotypes were germinated at 0.0 through -2.5 MPa NaCl at 25°C and 35°C for nine days. Tepary accessions had higher germination percentages and rates than navy for ≤ - 2.0 MPa at 250C and ≤ - 1.5 MPa at 35°C. Fresh weights of root plus hypocotyl decreased severely with the first increment of NaCl (-0.5 MPa) for all genotypes. Fresh weight of navy was reduced more at 35°C than at 25°C. Genotypes were stressed in vermiculite-filled trays with 0.0 through -1.5 MPa NaCl for 14 days. Final growth stage and rates of emergence were reduced at salinities ~ -0.6 MPa NaCl, and were higher in tepary than navy at -1.2 MPa. Tepary beans tended to maintain higher water and osmotic potentials, and at -0.9 MPa had less reduction in leaf area than navy beans. Fresh weights, dry weights and root:shoot ratios declined in all genotypes with increasing salinities. Plants grown hydroponically were stressed with -0.10, -0.25, and -0.50 MPa NaCl during either vegetative or reproductive stages. Navy had equal or greater fresh and dry weights of leaf, stem, and pods at -0.10 MPa, but tepary beans had equal or greater weights at the highest salinity relative to navy. Tepary had the greatest pod weight with -0.50 MPa NaCl applied during the reproductive stage. Carbon exchange rates (CER) were lower in navy than one or both tepary beans at some sampling times. Tepary beans tended to have higher leaf water and osmotic potentials than did navy. Transpiration and stomatal resistance values were similar in all genotypes, while leaf temperatures were different in white tepary versus navy. Tepary beans yielded higher than navy when grown in low and high salinity fields. Transpiration rates, leaf water and osmotic potentials, and CERs were similar or higher, while stomatal resistance and leaf temperatures were similar or lower in tepary than in navy. Plant height and stand count also were measured. Tepary was more salt tolerant than navy, exhibiting greater tolerance to NaCl at every growth stage.

Shoot and root fresh and dry weight, shoot length, leaf area, leaf area index and relative growth rate of 14 day old tepary bean (Phaseolus acutifolis Gray) and navy bean (Phaseolus vulgaris L.) seedlings were reduced following treatment with NaCl solution exhibiting osmotic potential of either -0.25, 0.50, and -0.75 MPa. Salinity reduced the growth of navy bean more than tepary bean. The physiological basis of the adaptive response of tepary bean seedlings to salt stress was explored by determining the water and osmotic potentials, relative water content, free amino acid and sugar concentrations, distribution and levels of inorganic ions within the seedlings and ATPase activity of the root plasma membrane. Salinity led to an osmotic adjustment in the leaves and the proximal part of the root of tepary bean. Turgor remained almost constant whereas osmotic and water potential and relative water content declined following the salt treatments. The osmotic adjustment of the leaves and proximal part of the roots was -1.7 MPa and -1.2 MPa, respectively, in seedlings treated with -0.75 MPa NaCl solution. Free amino acids and sugars increased under salinity stress in both species but they increased more in the tepary bean. Glucose was the most abundant free sugar. The nonstructural carbon solutes contributed -0.15 MPa to the seedling's osmotic adjustment whereas Na, Cl, K and Ca ion levels contributed -0.85 MPa. However, the levels of these solutes were not large enough to account for the total osmotic adjustment observed in the salt treated seedlings. This study shows that tepary bean has specific strategies to overcome the impact of salinity through osmotic adjustment and exclusion of Na and Cl ions from the stems and leaves by retaining these ions in the proximal part of root and stem base. (Abstract shortened with permission of author.)

A population based cross-sectional time series analysis was conducted using three Ontario administrative databases, to assess trends over time in the surgical management of kidney stone disease. All kidney stone treatments performed with extracorporeal shockwave lithotripsy (SWL), ureteroscopy (URS) and percutaneous nephrolithotomy between July 1, 1991 and December 31, 2010, were included. Time series modeling with exponential smoothing and autoregressive integrated moving average models demonstrated a significant increase in the utilization of URS over time (23.69% to 59.98%, p<0.0001), with a reciprocal significant decrease in the utilization of SWL (68.77% to 33.36%, p<0.0001). As a result of this shift in treatment paradigm, time series modeling also demonstrated an associated significant decrease in the need for ancillary treatment over time (22.12% to 16.01%, p<0.0001) and a significant increase in the need for hospital readmission (8.01% to 10.85%, p<0.0001) or emergency room visit (7.58% to 9.95%, p=0.0024) within 7 days following treatment.

A population based cross-sectional time series analysis was conducted using three Ontario administrative databases, to assess trends over time in the surgical management of kidney stone disease. All kidney stone treatments performed with extracorporeal shockwave lithotripsy (SWL), ureteroscopy (URS) and percutaneous nephrolithotomy between July 1, 1991 and December 31, 2010, were included. Time series modeling with exponential smoothing and autoregressive integrated moving average models demonstrated a significant increase in the utilization of URS over time (23.69% to 59.98%, p<0.0001), with a reciprocal significant decrease in the utilization of SWL (68.77% to 33.36%, p<0.0001). As a result of this shift in treatment paradigm, time series modeling also demonstrated an associated significant decrease in the need for ancillary treatment over time (22.12% to 16.01%, p<0.0001) and a significant increase in the need for hospital readmission (8.01% to 10.85%, p<0.0001) or emergency room visit (7.58% to 9.95%, p=0.0024) within 7 days following treatment.

The objective of this PhD research was the development of novel 3D interactive medical platforms for medical image analysis, simulation and visualisation, with a focus on oncology images to support clinicians in managing the increasing amount of data provided by several medical image modalities. DoctorEye and Automatic Tumour Detector platforms were developed through constant interaction and feedback from expert clinicians, integrating a number of innovations in algorithms and methods, concerning image handling, segmentation, annotation, visualisation and plug-in technologies. DoctorEye is already being used in a related tumour modelling EC project (ContraCancrum) and offers several robust algorithms and tools for fast annotation, 3D visualisation and measurements to assist the clinician in better understanding the pathology of the brain area and define the treatment. It is free to use upon request and offers a user friendly environment for clinicians as it simplifies the implementation of complex algorithms and methods. It integrates a sophisticated, simple-to-use plug-in technology allowing researchers to add algorithms and methods (e.g. tumour growth and simulation algorithms for improving therapy planning) and interactively check the results. Apart from diagnostic and research purposes, it supports clinical training as it allows an expert clinician to evaluate a clinical delineation by different clinical users. The Automatic Tumour Detector focuses on abdominal images, which are more complex than those of the brain. It supports full automatic 3D detection of kidney pathology in real-time as well as 3D advanced visualisation and measurements. This is achieved through an innovative method implementing Templates. They contain rules and parameters for the Automatic Recognition Framework defined interactively by engineers based on clinicians’ 3D Golden Standard models. The Templates enable the automatic detection of kidneys and their possible abnormalities (tumours, stones and cysts). The system also supports the transmission of these Templates to another expert for a second opinion. Future versions of the proposed platforms could integrate even more sophisticated algorithms and tools and offer fully computer-aided identification of a variety of other organs and their dysfunctions.

Bakgrund: När njurfunktionen blir försämrad bör dialysbehandling påbörjas. I Sverige får ungefär 2700 patienter hemodialysbehandling och 800 patienter behandlas med peritonealdialys. Vid dialysbehandling uppstår svårigheter som kan påverka patientens liv på flera olika sätt. För att patienten ska kunna hantera den svåra tiden med dialysbehandling kan copingstrategier användas. Det har visat sig att sjuksköterskan spelar en viktig roll för att stödja och uppmuntra patienter under den svåra tiden med dialysbehandling. Syfte: Att beskriva patienters upplevelser av dialysbehandling samt att granska valda artiklars datainsamlingsmetod. Metod: En beskrivande design och 13 vetenskapliga artiklar med kvalitativ ansats har använts i denna litteraturstudie. Databaserna CINAHL, Medline via PubMed och PsycINFO användes vid sökning av artiklar. Huvudresultat: Att vara beroende av långvarig dialysbehandling gjorde att patienterna var tvungna att spendera mycket tid på sjukhuset. Detta begränsade deras frihet att utföra dagliga aktiviteter, resa eller arbeta. Patienternas självbild påverkades negativt på grund av kroppsliga förändringar relaterade till sjukdomen och behandlingen. Känslomässiga reaktioner såsom rädsla, depression och oro inför framtiden var de vanligaste förekommande upplevelserna hos patienterna. För att övervinna dessa svåra situationer använde patienterna sig av copingstrategier. De inkluderade 13 artiklarna i denna litteraturstudie hade en kvalitativ ansats och intervjuer användes som datainsamlingsmetod. Slutsatser: Den svåra tiden med dialysbehandling påverkade patienterna fysiskt, psykiskt och socialt. För att klara av negativa och krävande omständigheter som sjukdomen och behandlingen medförde behövde patienterna olika strategier. Det krävdes även att sjuksköterskor gav stöd och information som kunde underlätta för patienter att hantera situationer som kunde uppstå relaterat till dialysbehandlingen / Background: When renal function is impaired should dialysis treatment start. In Sweden, there are about 2700 people have hemodialysis treatment and 800 individuals on peritoneal dialysis. On dialysis treatment, there are many difficulties that affect the patient's life in several ways. To handle the tough times with the dialysis treatment can patient use coping strategies. In addition it has been shown that the nurse plays an important role in supporting and encouraging patients during the difficult period of dialysis treatment. Aim: To describe patients' experiences of dialysis treatment and to review data collection method of the included articles. Method: A descriptive design and 13 scientific articles with qualitative approach were used in this study. The databases CINAHL, MEDLINE though PubMed and PsycINFO were used for searching articles. Results: To be depended on the long-term dialysis treatment made the patients had to spend a lot of time in the hospital. This limited the patient's freedom to perform daily activities, to travel or to work. There was a negative impact on patients' self-image because of bodily changes related to the disease and treatment. Emotional reactions such as fear, depression and anxiety about the future were the common experiences of the patients. One way to overcome these difficult situations, patients used coping strategies. The included 13 articles in this study had a qualitative approach and interviews were used as data collection method. Conclusion: During the difficult period of dialysis treatment, the patient was affected physically, psychologically and socially. To cope with the adverse and demanding circumstances that the disease and treatment caused, patients needed different strategies. It also requires that nurses provide support and information that can help patients to handle these situations.

Percutaneous kidney biopsies have been performed since 1944 to establish diagnoses and treatment. Risk factors based on a limited amount of data have shown age, blood pressure, kidney function and needle size as some risk factors for biopsy complications. Although the techniques of biopsy have improved over the years, it is still an invasive procedure and serious complications can occur. The overall aim of this thesis was to obtain a large series of data from biopsy procedures and to use these to bring further light on risk factors to help minimize the risk for patients and to optimize diagnostics. Specific aims were to clarify if different factors, such as gender, diagnoses, localization of biopsies, needle types and sizes, could be useful to help minimize complication risks in native kidney biopsies (Nkb) and transplant kidney biopsies (Txb). Another point to investigate was the value of the Resistive Index (RI) obtained at ultrasound before performing Txb. Materials and methods: A protocol for prospective multicentre registration of various factors and complications associated with Nkb and Txb was designed. Consecutive data were obtained from seven hospitals. All biopsies, except one computer tomography-guided Nkb, were performed using real-time ultrasound guidance and an automated spring-loaded biopsy device. For the biopsies 14- to 20- Gauge (G) needles were used. The kidney function level, i.e. estimated glomerular filtration rate (eGFR), was calculated using the Modification of Diet in Renal Disease (MDRD) formula (GFR in mL/min per 1.73m2). For statistical analyses the IBM SPSS Statistic 22 (Armonk, NY, USA) and OpenEpi (Open Source Epidemiologic Statistics for Public Health, www.OpenEpi.com) were used. Data were presented as Odds Ratio (OR), Risk Ratio (RR) and Confidence Intervals (CI). A two sided p-value of &lt;0.05 was considered significant. In total 1299 consecutive biopsies (1039 native and 260 transplant kidneys) in 1178 patients (456 women and 722 men) were used for investigation. The median age of patients was 55 years (range 16 to 90 years). Major (require an intervention) and minor biopsy complications (no need of intervention) were registered. Results: The overall frequency of biopsy complications for Nkb was 8.8% (major 6.7%, minor 2.1%) and for Txb was 6.5% (major 3.8%, minor 2.7%); no death. Women had a higher risk for development of major (10.7% versus 4.7%, OR 2.4, CI 1.4-4.2) and overall biopsy complications (13.2% versus 6.5%, OR 2.2, CI 1.4-3.5) compared to men in Nkb. In Nkb, major complications were more common after biopsies from the right kidney in women versus men (10.8% vs 3.1%, OR 3.7, CI 1.5–9.5), in patients with lower versus higher BMI (25.5 vs 27.3, p=0.016) and for younger versus older age (44.8 vs 52.3 years, p=0.002). Lower (90 mmHg) compared to higher (98 mmHg) mean arterial pressure in Txb indicated a risk of major complications (p=0.039). Factors such as number of passes and kidney function did not influence complication rates. Biopsy needles of 16 G compared to 18 G showed more glomeruli per pass in Nkb (11 vs 8, p&lt;0.001) and in Txb (12 vs 8, p&lt;0.001). Sub-analysis revealed that 18 G 19 mm side-notch needles in Nkb resulted in more major (11.3% vs 3%, OR 4.1, CI 1.4-12.3) and overall complications (12.4% vs 4.8%, OR 2.8, CI 1.1-7.1) in women than in men. If the physician had performed less compared to more than four Nkb per year, minor (3.5% vs 1.4%, OR 2.6, CI 1.1-6.2) and overall complications (11.5% vs 7.4%, OR 1.6, CI 1.1-2.5) were more common. The localization of biopsy within the kidney (Nkb and Txb) was not a risk factor for complications. Patients with IgA-nephritis compared to patients with other diseases had a higher risk of major complications (11.7% vs 6.4 %, OR 1.8, CI 1.1–3.2). More major complications were found in Nkb if they had higher versus lower degree of glomerulosclerosis (31% vs 20 %, p=0.008) and in Txb if there was a higher versus lower degree of interstitial fibrosis (82% vs 33%, p&lt;0.001). Re-biopsies (Nkb) were more common in patients with IgA-nephritis than those with other diseases (4.7% vs 1.3 %, OR 4, CI 1.5–11), in younger versus older age (42.6 vs 52.3 years, p=0.031), and in those with a higher versus lower degree of interstitial fibrosis (63% vs 34 %, p=0.046). In Txb, a RI≥0.8 compared to RI&lt;0.8 predicted major (13.3% vs 3.2%, RR 4.2, CI 1.3-14.1) and overall biopsy complications (16.7% vs 5.3%, RR 3.2, CI 1.2-8.6). In the group &lt;0.8, RI correlated with age (rs=0.28, p&lt;0.001) and systolic blood pressure (rs=0.18, p=0.02). In the group ≥0.8, RI correlated with degree of interstitial fibrosis (rs=0.65, p=0.006) and systolic blood pressure (rs=0.40, p=0.03). The multiple regression analysis showed that the &lt;0.8 RI group correlated only with age (p&lt;0.001), whereas the ≥0.8 RI group correlated only with the degree of interstitial fibrosis (p=0.003). Conclusions: The present results motivate greater attention to be paid to the possibility of major side-effects after Nkb in women and biopsies from their right side, but as well in younger patients, and in those with lower BMI. This also applies for patients with presumptive IgA-nephritis and higher degree of glomerulosclerosis. In Txb, patients with higher degree of interstitial fibrosis had a greater risk of major complications. Moreover, the present data indicate that Nkb and Txb should be preferably taken with 16 G needles with 20 mm sample size. This results in better histological quality and there is a lower risk for major complications as compared to 18 G needles. The localization of biopsy within the kidney (Nkb and Txb) does not alter complication rates. For Nkb there were fewer complications if the physician had performed at least four biopsies per year. A RI≥0.8 in Txb indicates a greater risk for major and overall complications.