| 1. |
- Venetsanos, Dimitrios
(författare)
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Improving management of STEMI patients treated with primary PCI : Pharmacotherapy, renal function estimation and gender perspective
- 2017
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- This thesis focused on the acute management of patients with ST-segment elevation myocardial infarction (STEMI) in an effort to provide information that may improve outcome. The aim was to evaluate the efficacy and safety of bivalirudin versus unfractionated heparin (UFH) in STEMI patients during primary PCI. Furthermore, to provide pharmacodynamic data of novel ways of ticagrelor administration compared to standard tivcagrelor. Additionally, to identify subgroups of patients, such as women who may derive greater benefit from specific antithrombotic strategies due to their risk/benefit profile. Finally, to evaluate current formulas for estimation of renal function in the acute phase of STEMI.In Paper I, all STEMI patients in Sweden between 2008 and 2014, treated with primary PCI and UFH or bivalirudin were included in our analysis. Of the total population of 23 800 patients, 8 783 (36.9%) were included in the UFH group and 15 017 (63.1%) in the bivalirudin group. Concomitant GPI administration was 68.5% in the UFH arm compared to 3.5% in the bivalirudin arm (p<0.01).The adjusted incidence of 30-day mortality was not significant different between the two groups (UFH vs bivalirudin, adjusted HR 0.94; 95% CI 0.82 -1.07). The adjusted risk for 1-year mortality, 30-day and 1-year stent thrombosis and re-infarction did not differ significantly between the two groups. In contrast, patients treated with UFH had a significantly higher incidence of major in-hospital bleeding (adjusted OR 1.62; 95%CI 1.30 -2.03).In Paper II pharmacodynamic data of chewed or crushed ticagrelor compared to standard ticagrelor loading dose (LD) was assessed in 99 patients with stable angina. Platelet reactivity (PR) was assessed with VerifyNow before, 20 and 60 minutes after LD. High Residual platelet reactivity (HRPR) was defined as > 208 P2Y12 reaction units (PRU). Chewed ticagrelor tablets resulted in significantly lower PRU values compared to crushed or integral tablets at 20 and 60 minutes. Crushed ticagrelor LD resulted in significantly lower PRU values compared to integral tablets at 20 minutes whereas no difference was observed at 60 minutes. At 20 minutes, no patients had HRPR with chewed ticagrelor compared to 68% with integral and 30% with crushed ticagrelor LD (p<0.01).In Paper III we presented a pre-specified gender analysis of the ATLANTIC trial including 1 862 STEMI patients that were randomly assigned to pre-hospital versus in-hospital administration of 180mg ticagrelor. Women were older and had higher TIMI risk score. Women had a 3-fold higher risk for all-cause mortality compared to men (5.7% vs 1.9%, HR 3.13, 95% CI 1.78 – 5.51). However, after adjustment for baseline characteristics, the difference was lesser and no longer significant (HR 1.98, 95% CI 0.97 – 4.04). Female gender was not an independent predictor of risk for bleeding after multivariable adjustments (BARC type 3-5 HR 1.52, 95% CI 0.74-3.09). There was no interaction between gender and efficacy or safety of randomised treatment.In Paper IV, forty patients with PCI- treated STEMI were included between November 2011 and February 2013. We validated the performance of the Cockcroft-Gault (CG), the Modification of Diet in Renal Disease (MDRD-IDMS), the Chronic Kidney Disease Epidemiology (CKD-EPI) and the Grubb relative cystatin C (rGCystC) equations for estimation of GFR against measured GFR (mGFR) during the index hospitalisation for STEMI.MDRD-IDMS and CKD-EPI demonstrated a good performance to estimate GFR with accuracy within 30% (P30) 82.5% vs 82.5%, respectively. CKD was best classified by CKD-EPI (Kappa 0.83). CG showed the worst performance with the lowest P30. The rG-CystC equation had a marked bias of -17.8% and significantly underestimated mGFR (p=0.03).Conclusions – In STEMI patients treated with primary PCI, bivalirudin should be preferred in patient at high risk for bleeding. With crushed or chewed ticagrelor tablets a more rapid platelet inhibition may be achieved, compared with standard integral tablets. In STEMI patients, fast and potent platelet inhibition with chewed ticagrelor may reduce the risk of early stent thrombosis and patients treated with a less aggressive antithrombotic strategy, such as UFH or bivalirudin monotherapy, may derive a greater benefit. Although gender differences in adverse outcomes could mainly be explained by older age and clustering of comorbidities in women, a bleedreduction strategy in women with high risk characteristics is warranted in order to improve their outcome. Regardless the choice of antithrombotic strategy, dose adjustment of drugs cleared by kidneys based on GFR estimation is of crucial importance. MDRD and CKD-EPI should be the formulas used for estimation of GFR in STEMI patients
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| 2. |
- Klaff, Rami, 1971-
(författare)
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Disease-Specific Survival in Prostate Cancer Patients : Results from the Scandinavian Prostate Cancer Group (SPCG) Trial No. 5 and Regional Cancer Register Data
- 2016
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- IntroductionProstate cancer (PCa) is the most common cancer among men in Sweden. The clinical course varies considerably, which makes it difficult to predict the prognosis in the individual case. In order to explore the early as well as the late course of the disease, large study groups and population-based cohorts are necessary.AimsTo explore factors that influence the long-term outcome of men with low-risk tumours in a population-based register, to predict the long-term course, and to assess the mortality rate for men with prostate cancer (Paper I)To analyse long-term outcome and to investigate factors associated with long-term survival in patients with metastases to the skeleton (Paper II)To analyse early androgen deprivation treatment (ADT) failure and to define clinical predictors associated with short survival due to early ADT failure in prostate cancer patients with bone metastases (Paper III)To analyse the prognostic significance of the extent of bone metastases in relation to other pretreatment variables in prostate cancer patients, and to explore the impact of bone metastases on quality-of-life (Paper IV)Material and methodsThe study groups were assembled from The South East Region Prostate Cancer Register (SERPCR), and The Scandinavian Prostate Cancer Group (SPCG) Trial No. 5. In the first study, prognostic factors and long-term disease-specific mortality rates of low-risk prostate cancer patients from the early PSA era were analysed. In the second study, patient-related factors, quality-of-life (QoL) and long-term survival in 915 PCa patients with bone metastases (M1b) under ADT, were analysed. In Study III factors predicting primary failure to respond to ADT were identified. Study IV explored the impact of the extent of bone metastases on survival and QoL for these men.Result and conclusionsThe long-term disease-specific mortality of low-risk localised PCa is low, but the annual mortality rate gradually increases. This indicates that some tumours slowly develop into lethal cancer, particularly in men 70 years or older and with a PSA level ≥ 4 μg/L. From the SPCG Trial No. 5, a subgroup of patients with M1b disease and favourable set of predictive factors survived more than 10 years under ADT with an acceptable QoL. Independent predictors of long-term survival were identified as performance status (PS) < 2, limited extent of bone metastases, and a PSA level < 231 μg/L at the time of enrolment in the trial. However, four independent clinical predictors of early ADT failure could be defined. Men exhibiting these features should be considered for an alternative treatment. Patient grouping based on three categories of extent of bone metastases related to PS, haemoglobin, and QoL at presentation, as independent predictors of mortality, may provide improved accuracy of prognosis.
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| 3. |
- Slind Olsen, Renate
(författare)
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Circulating and genetic factors in colorectal cancer : Potential factors for establishing prognosis?
- 2017
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Colorectal cancer (CRC) is defined as a cancer appearing in the colon or in the rectum. In Sweden, ~ 6300 individuals were diagnosed with the disease in 2014 and ~ 2550 individuals diagnosed with CRC die each year due to their cancer. Surgery is the main treatment option of CRC and a survival rate of ~ 10 % is estimated if distant metastases have developed. It is therefore of importance to find factors that may be useful together with tumour, node, metastasis (TNM) stage to establish early CRC diagnosis, prognosis and follow-up of CRC patients. The aim of this thesis was to study the possible association of CD93, PLA2G4C, PDGF-D and inflammatory cytokines with CRC disease progression.In a prospective study approach CD93 and PLA2G4C single nucleotide polymorphisms (SNPs) were of potential importance in CRC prognosis.The T/T genotype of CD93 was associated with an increased CD93 expression in CRC tissue. Further, CRC patients carrying this genotype were associated with disseminated CRC at diagnosis and a lower recurrence-free survival after surgery. The A allele of a SNP of PLA2G4C was a stronger predictor for CRC-specific mortality than the conventional risk factors used in the clinic for selection of TNM stage II patients for adjuvant treatment. This indicates that the T/T genotype of CD93 and the A allele of PLA2G4C may be potential genetic factors related to disease severity and spread. Furthermore, they distinguish CRC patients that may benefit from a more comprehensive follow-up and adjuvant treatment.To study the putative involvement of PDGF-D in CRC the effects of PDGF-D signalling was studied in vitro. PDGF-D signalling altered the expression of genes of importance in CRC carcinogenesis and proliferation which was blocked by imatinib, a tyrosine kinase inhibitor. This indicates that PDGF-D signalling may be an important pathway in CRC progression and a potential target in CRC treatment.The analysis of various inflammatory cytokines in plasma at diagnosis showed an association between high levels and increased total- or CRC-specific mortality two years after surgery. High levels of CCL1 and CCL24 was the only cytokines strongly correlated with a worse CRC prognosis after statistical adjustments and may be of interest for further evaluation.In conclusion, this thesis presents circulating and genetic factors such as CD93, PLA2G4C, PDGF-D, CCL1 and CCL24 that may be of importance in CRC progression and may be of clinical value together with TNM stage in establishing prognosis.
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| 4. |
- Aljabery, Firas
(författare)
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Staging and tumor biological mechanisms of lymph node metastasis in invasive urinary bladder cancer
- 2017
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Aim: To study the possibility of detecting lymph node metastasis in locally advanced urinary bladder cancer (UBC) treated with radical cystectomy (RC) by using preoperative positron emission tomography/computed tomography (PET/CT) and peroperative sentinel node biopsy (SNB) technique. We also investigate the clinical significance of macrophage traits expression by cancer cells, M2-macrophage infiltration (MI) in tumor stroma and the immunohistochemical expression of biomarkers in cancer cells in relation to clinicopathologic data.Patients and Methods: We studied prospectively 122 patients with UBC, pathological stage pT1–pT4 treated with RC and pelvic lymph node dissection (PLND) during 2005–2011 at the Department of Urology, Linköping University Hospital. In the first study, we compared the results of preoperative PET/CT and conventional CT with the findings of postoperative histopathological evaluation of lymph nodes (LNs). In the second study we investigated the value of SNB technique for detecting pathological LNs during RC in patients with UBC. W also examined the significance of the primary tumor location in the bladder in predicting the site of LN metastases, and the prognostic significance of lympho-vascular invasion (LVI) and lymph node metastasis density (LNMD) on survival. In the third study, we investigate the clinical significance of macrophage infiltration (MI) in tumor stroma and macrophage-traits expression by tumor cells. In the fourth study, we investigate the cell cycle suppression proteins p53, p21, pRb, p16, p14 ARF as well as tumors proliferative protein Ki67 and DNA repair protein ERCC1 expression in cancer cells. The results were compared with clinical and pathological characteristics and outcome.Results: Prior to RC, PET/CT was used to detect LN metastasis in 54 patients. PET/CT had 41% sensitivity, 86% specificity, 58% PPV, and 76% NPV, whereas the corresponding figures for conventional CT were 41%, 89%, 64%, and 77%. SNB was performed during RC in 103 patients. A median number of 29 (range 7–68) nodes per patient were examined. SNs were detected in 83 out of 103 patients (81%). The sensitivity and specificity for detecting metastatic disease by SNB varied among LN stations, with average values of 67% -90%. LNMD or ≥8% and LVI were significantly related to shorter survival. In 103 patients, MI was high in 33% of cases, while moderate and low infiltration occurred in 42% and 25% of tumors respectively. Patients with tumors containing high and moderate compared to low MI had low rate of LN metastases (P=0.06) and improved survival (P=0.06), although not at significant level. The expression of different tumor suppression proteins was altered in 47-91% of the patients. There were no significant association between cancer specific survival (CSS) and any of the studied biomarkers. In case of altered p14ARF, ERCC1 or p21, CSS was low in case of low p53 immunostaining but increased in case of p53 accumulation, although not at a significant level, indicating a possible protective effect of p53 accumulation in these cases.Conclusion: PET/ CT provided no improvement over conventional CT in detection and localization of regional LN metastases in bladder cancer. It is possible to detect the SN but the technique is not a reliable for perioperative localization of LN metastases; however, LVI and LNMD at a cut-off level of 8% had significant prognostic values. MI in the tumor microenvironment but not CD163 expression in tumor cells seems to be synergistic with the immune response against urinary bladder cancer. Our results further indicate that altered p53 might have protective effect on survival in case of altered p14ARF, p21, or ERCC1 indicating an interaction between these biomarkers.
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| 5. |
- Loftås, Per, 1964-
(författare)
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Response to neoadjuvant treatment in rectal cancer surgery
- 2016
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Rectal cancer is one of the three most common malignancies in Sweden with an annual incidence of about 2000 cases. Current treatment consists of surgical resection of the rectum including the loco-regional lymph nodes in the mesorectum. In advanced cases, neoadjuvant chemo-radiotherapy (CRT) prior to the operative treatment reduces local recurrences and enables surgery. The neoadjuvant treatment can also eradicate the tumour completely, i.e. complete response. This research project was designed to investigate the effects of preoperative radiotherapy/ CRT and analyze methods to predict response to CRT.Study I investigated the expression of the FXYD-3 protein with immunohistochemistry in rectal cancer, with or without preoperative radiotherapy. The results from the total cohort showed that, strong FXYD-3 expression was correlated to infiltrative tumour growth (p = 0.02). In the radiotherapy group, strong FXYD-3 expression was related to an unfavourable prognosis (p = 0.02). Tumours with strong FXYD-3 expression had less tumour necrosis (p = 0.02) after radiotherapy. FXYD-3 expression in the primary tumour was increased compared to normal mucosa (p=0.008). We concluded that FXYD-3 expression was a prognostic factor in patients receiving preoperative radiotherapy for rectal cancer.Study II investigated FXYD-3 expression in tumours that developed local recurrences following surgery and compared this with expression in tumours that did not develop local recurrences. There was no difference in the expression of FXYD-3 between the group that developed local recurrences and the group that did not develop local recurrences. There was no difference in survival between those with strong or weak FXYD-3 expression. We concluded that this study could not confirm the findings from study 1 i.e. that FXYD-3 expression has prognostic significance in rectal cancer.Study III was a register-based study on the incidence and effects of complete response to neoadjuvant treatment. Eight per cent of the patients with adequate CRT to achieve complete response also had a complete histological response of the luminal tumor in the resected bowel. Sixteen per cent of that group had remaining lymph node metastases in the operative specimen. Chemotherapy together with radiotherapy doubled the chance of complete response in the luminal tumour. Patients with remaining lymph node metastases had a lower survival rate compared to those without. We concluded that residual nodal involvement after neoadjuvant treatment was an important factor for reduced survival after complete response in the luminal tumour.Study IV followed up the results from the previous study by re-evaluating magnetic resonance imaging (MRI)- images in patients with complete tumour response. Two experienced MRI radiologists performed blinded re-staging of post CRT MR- images from patients with complete response in the luminal tumour. One group with lymph node metastases and another one without were studied and the results compared with the pathology reports. The sensitivity, specificity, and positive and negative predicted values for correct staging of positive lymph nodes was 37%, 84%, 70% and 57%. The size of the largest lymph node (4.5 mm, p=0.04) seemed to indicate presence of a tumour positive lymph node. We concluded that MRI couldn’t correctly stage patients for lymph node metastases in patients with complete response to CRT in the luminal tumour.
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| 6. |
- Malmgren, Linnea
(författare)
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Kidney Function During Ageing and its Association with Bone Mass, Fracture and Mortality
- 2020
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Osteoporosis and osteoporosis related fractures are a major health care challenge both in Sweden and globally. The cost and suffering from osteoporosis are expected to increase since the population of elderly is increasing. Bone health can be affected by altered mineral homeostasis, which in its turn can be affected by reduced kidney function. However, the course of age-related decline in kidney function and its association to osteoporosis andfracture in the very elderly need further investigation since longitudinal data are scarce. Therefore, this thesis has two main aims; 1) to investigate kidney function during ageing and 2) its association to bone health in a cohort ofelderly women.Data was collected through the Malmö Osteoporosis Prospective Risk Assessment (OPRA) cohort, a prospective cohort of 1044 community dwelling women, all aged 75 and followed for ten years with reinvestigations at age 80and 85. Data on BMD, fracture and blood biochemistry was available at all three time points.Estimated kidney function greatly depends on which marker and study equation is used. The discrepancies are to such an extent that could affect whether a person is diagnosed with chronic kidney disease (CKD) or not, of particular importance in the elderly. Only women with the worst kidney function, corresponding to CKD stage 3b-5, had continuously increased mortality risk. This indicates that an age-dependent CKD definition would be of valuein elderly women.Kidney function in elderly women was associated with markers of mineral homeostasis, bone loss and BMD, but the effect size was relatively small compared to other risk factors. Also, fracture risk was increased only in womenwith mild-moderate reduction of kidney function (CKD stage 3a) and not in women with the worst kidney function (CKD stage 3b-5). Low BMD was associated with increased fracture risk independent of kidney function. Havingboth reduced kidney function and osteoporosis could present an additional risk increase.In conclusion, estimated kidney function in elderly women greatly depends on method of estimation and the results advocate for an age-adapted CKD definition. Maintaining adequate kidney function is important formaintaining bone health, although in old age it is probable that the effect size of any single specific risk factor is smaller compared with younger individuals.
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| 7. |
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| 8. |
- Omling, Erik
(författare)
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Paediatric surgical care in Sweden. Studies on incidence, outcome and access
- 2019
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Abstract Background: Advanced paediatric surgery is increasingly centralised in Sweden in order to improve treatment outcomes and reduce surgical risks. However, the overall need for surgery in the paediatric population has not been estimated, and the association between geographic access to surgical facilities and timely treatment for common surgical conditions in children is largely unknown. Aims: To estimate the overall incidence of surgery for Swedish children (I); to describe disease-specific incidences, treatment characteristics and surgical risks for one paediatric non-emergent surgical condition (cryptorchidism) (II) and one acute surgical condition (appendicitis) (III); and to assess for associations between distance to surgical facility and timely treatment with adjustment for medical and socioeconomic risk (IV-V). Methods: National healthcare and population registers of the total Swedish paediatric population, or subsets of it, for the years 2001-2014, were analysed in five observational cohort studies. The overall incidence of surgery was estimated in the Swedish paediatric population, and the disease-specific incidences were analysed for cryptorchidism and appendicitis. Treatment characteristics and surgical risks were presented, and the associations between travel time to hospital and treatment delay were analysed for these two conditions. Regression methods and survival analysis have been applied to estimate associations and calculate cumulative incidences. Results: On average, every year of childhood, 1 in 20 children had some kind of surgical procedures (6784 operations per 100,000 person-years), and 27% of all paediatric hospital admissions involved surgical procedures. >67% of all operations were performed as day surgery. 1.4% of Swedish boys were treated for cryptorchidism by age 14, and 1.8% were treated by 18 years of age, with prematurity and low birth weight being strongly associated with this risk. Only a minority (<6%) were treated during their first year of life according to the recommendations, with considerable regional variations. There was no postoperative mortality detected, and the risk of postoperative infection was low (1.4%), with no geographic variations. There was an association between travel time to hospital and timely treatment at 3 years of age, adjusted for birth-related risk factors and socioeconomic determinants (per 30-minute increase in travel time: aHR 0.91 [95% CI 0.88-0.95], p<0.001). 1 in 40 Swedish children (2.5%) had appendicitis during childhood. One in 6 (17%) had a more severe type of appendicitis, with increased postoperative infection rate (5.9% versus 2.3%, aOR 2.6 [2.2-3.2]) and readmission rate (5.5% versus 1.2%, aOR 4.8 [95% CI 4.1-5.5]), and higher risk for small bowel obstruction later on (0.2% versus 0.7%, aHR 3.9 [95% CI 2.6-5.8]). These risks were also associated with treatment modality; postoperative infection rates (aOR 0.6 [95% CI 0.5-0.8]) and small bowel obstruction rates (aHR 0.3 [95% CI 0.1-0.6], p=0.002) were lower after laparoscopic surgery, as compared to open appendectomy. There was no observed association between travel time to treatment and the risk for more severe type of paediatric appendicitis in Sweden. Significance: In this thesis, the overall incidence of surgery in Swedish children has been estimated. One elective condition and one emergency surgical condition have been anlysed for outcomes in terms of timing of treatment and surgery-related risks. Access to timely surgical treatment have been estimated in the elective and the emergancy care settings. Findings from these studies may be relevant to consider on a regional and national level in future planning of paediatric surgery.
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| 9. |
- Nerpin, Elisabet, 1962-
(författare)
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The Kidney in Different Stages of the Cardiovascular Continuum
- 2013
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Patients with chronic kidney disease are at higher risk of developing cardiovascular disease. The complex, interaction between the kidney and the cardiovascular system is incompletely understood, particularly at the early stages of the cardiovascular continuum.The overall aim of this thesis was to clarify novel aspects of the interplay between the kidney and the cardiovascular system at different stages of the cardiovascular continuum; from risk factors such as insulin resistance, inflammation and oxidative stress, via sub-clinical cardiovascular damage such as endothelial dysfunction and left ventricular dysfunction, to overt cardiovascular death.This thesis is based on two community-based cohorts of elderly, Uppsala Longitudinal Study of Adult Men (ULSAM) and Prospective Investigation of the Vasculature in Uppsala Seniors (PIVUS).The first study, show that higher insulin sensitivity, measured with euglycemic-hyperinsulinemic clamp technique was associated to improve estimated glomerular filtration rate (eGFR) in participants with normal fasting plasma glucose, normal glucose tolerance and normal eGFR. In longitudinal analyses, higher insulin sensitivity at baseline was associated with lower risk of impaired renal function during follow-up. In the second study, eGFR was inversely associated with different inflammatory markers (C-reactive protein, interleukin-6, serum amyloid A) and positively associated with a marker of oxidative stress (urinary F2-isoprostanes). In line with this, the urinary albumin/creatinine ratio was positively associated with these inflammatory markers, and negatively associated with oxidative stress.In study three, higher eGFR was associated with better endothelial function as assessed by the invasive forearm model. Further, in study four, higher eGFR was significantly associated with higher left ventricular systolic function (ejection fraction). The 5th study of the thesis shows that higher urinary albumin excretion rate (UAER) and lower eGFR was independently associated with an increased risk for cardiovascular mortality. Analyses of global model fit, discrimination, calibration, and reclassification suggest that UAER and eGFR add relevant prognostic information beyond established cardiovascular risk factors in participants without prevalent cardiovascular disease.Conclusion: this thesis show that the interaction between the kidney and the cardiovascular system plays an important role in the development of cardiovascular disease and that this interplay begins at an early asymptomatic stage of the disease process.
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| 10. |
- Nilsson, Christopher
(författare)
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Aspects of ethnicity on blood pressure regulating mechanisms and kidney function in a defined population
- 2021
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Background: Middle Eastern immigrants represent a growing population in Sweden today. This group are at higher risk for type 2 diabetes than the native population, but are also shown to exhibit unique properties; despite an abundance in traditional cardiometabolic risk factors such as obesity, dearranged blood lipids and diminished physical acitivity, this group seem to exhibit lower blood pressure levels. Further, people with type 2 diabetes of Middle Eastern descent have lower all cause and cardiovascular mortality rates, as compared to the native Swedish population. This indicates that Middle Eastern immmigrants may exhibit protective mechanisms towards cardiovascular diseases (CVD) that remain to be unravelled. Renal function is closely related to blood pressure. Further, new evidence on mechanisms in relation to blood pressure regulation and renal function has emerged, including vascular ageing, i.e. gradual change in the vascular structure and the endogenous opioid marker Pro-Enkephalin (PENK), which is shown to exhibit a direct cardiodepressive effect on the kidneys.Aims: The general aim was to study potential differences across ethnicities on renal function, blood pressure and its regulating mechanisms as well as characteristics on diabetes and its complications - all of them, strongly associated with CVD. In specific, the aims were to study the contributing role of ethnicity (born in Iraq or Sweden) in each paper on: Renal function and its association with blood pressure (paper I), diabetes traits and incidence in diabetic complications (paper II), the biomarker PENK and its association with renal function (paper III) and arterial stiffness as an indicator of vascular ageing (paper IV). In this paper the aim was further to validate eGFR equations across a Middle Eastern ethnicity. Methods: The thesis is based on data from three different cohorts comparing Iraqi and Swedish born subjects: the MEDIM study (paper I and III), a population-based cross-sectional study, conducted in 2010-2012. The study included physical examinations, blood sampling and collection of information on lifestyle, comorbidity and medication. The ANDIS study (paper II), a longitudinal follow-up study, recruiting patients diagnosed with diabetes during 2008-2016 and followed for complications until 2017. The MEDIM 2019 population-based study (paper IV), a cross-sectional study conducted in 2019-2020 assessing iohexol clearance for determining measured GFR (mGFR), pulse wave velocity (PWV) as measurement of arterial stiffness, physical examinations, blood sampling and information on comorbidity, lifestyle and medication.Results: In paper I, Iraqi-born immigrants (n=1214) exhibited a better renal function as described by higher levels of estimated GFR (eGFR) in comparison to the Swedish-born control group (n=659) (96.5 vs 93.6 mL/min/1.73m2, p=0.009). Further, the association between blood pressure and renal function was significantly weaker in the Iraqi group as confirmed by a signification interaction (Pinteractino = Country of birth x eGFRCAPA=0.004). In paper II, a larger proportion of Iraqi-born immigrants (n=183) had insulin-deficient diabetes in comparison to the Swedish-born control group (n=7044) (27.9 vs. 16.2%, p<0.001) and a lower proportion had insulin-resistant diabetes (5.5 vs. 16.3%, p<0.001). The risk for chronic kidney disease (CKD) among diabetes patients was lower in the Iraqi-born group (HR 0.26, 95% CI 0.08-0.8). In paper III, levels of PENK did not differ between Iraqi-born immigrants (n=1263) and the Swedish-born control group (n=680), despite higher eGFR in the Iraqi group. The association between PENK and renal function was weaker in the Iraqi group as supported by a significant interaction (Pinteractino = Country of birth x PENK=0.031). In paper IV, PWV did not differ between Iraqi-born immigrants (n=31) and the Swedish-born control group (n=32). When comparing mGFR to eGFR based on various equations, the commonly used CAPA equation was less accurate in the Iraqi group. The results indicated that the CKD-EPI equations could be accurate equations in the Iraqi group.Conclusion: Iraqi born immigrants had a more favorable renal function, an insulin deficient diabetes trait and considerably lower risk for diabetic kidney disease, than for the native Swedish population. The impact on renal function of blood pressure as well as of the cardiodepressive opioid PENK was weaker among Iraqi-born immigrants, which may contribute to a preserved renal function in the Iraqi-born group. In the long run, a more favorable renal function and less susceptible kidneys could serve as an important advantageous mechanism in the protection against CVD among Iraqi-born immigrants.
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