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The main purpose of the present work was to evaluate the efforts taken by the Norwegian surgical community in order to promote and enhance the standards of rectal cancer treatment on a national level, in particular: - to examine the outcome of rectal cancer surgery following implementation of total mesorectal excision as the standard rectal resection technique - to explore the prognostic impact of the circumferential resection margin on local recurrence, distant metastases and overall survival following mesorectal excision - to evaluate the oncological outcomes following mesorectal excision of cancer of the lower rectum, particularly the rates of local recurrence and overall survival for patients with tumours in this areas - to illustrate the influence of a rectal cancer registry as a quality control instrument on outcome of rectal treatment, and furthermore, to investigate the rates of postoperative mortality, anastomic leakage, local recurrence (LR) and overall survival related to hospital caseload among Norwegian hospitals during implementation of mesorectal excision.

The aim of this thesis is to explore why parents bring their children to homeopaths and to investigate the effect of homeopathic treatment for prevention of upper respiratory tract infections (URTI) in children. The reason for doing studies on this is that there has been a nearly threefold increase in the proportion of children among patients visiting Norwegian homeopaths. This raised the question of why it is so. Furthermore, recurrent respiratory complaints are a main reason why child patients consult homeopaths. This raised the question of the effect of homeopathic treatment in this patient group, because there is very little research on this. The thesis builds on four different studies conducted between August 2002 and June 2004. Parents of nine children that recently had been to a homeopath for the first time were interviewed to explore why parents take their children to homeopaths. All parents had been to a medical doctor before consulting the homeopath. It was the experiences with conventional medical treatment that led the parents to look for alternatives. The reasons were that 1) the parents did not want to give the medication prescribed by the doctor, 2) they wanted treatment while waiting for a problem to be assessed, 3) they did not want to continue to use the prescribed medication, 4) they stopped taking conventional medication due to side effects or 5) they were not offered any treatment by the medical doctor. The parents would consult a medical doctor if they felt insecure about the health conditions of the child and would visit a homeopath when they felt that the situation was clarified. There are parents who take their child to homeopaths despite not understanding or having belief in whether ultramolecular homeopathic medicines can have effects. One hundred and sixty-one children who had been diagnosed with an URTI by a medical doctor were recruited to participate in a trial on the effect of treatment by homeopaths for prevention of URTI in children. The children were randomly allocated to two groups. One group received an appointment immediately with one of five homeopaths who treated the patients as they do in their everyday practice. The other group (control) got such treatment after three months. The occurrence of URTI judged by the parents were significantly lower among those treated immediately by homeopaths (median 8 days in three months) compared to the control group who used self-selected conventional health care (median 13 days) (p=0.006). Homeopathic medicines are frequently used for self-treatment (over the counter-OTC). It is not known if the choice of the patient is the same, as a homeopath would have prescribed. A study was therefore conducted to explore if there can be developed indications for homeopathic medicines that facilitate that parents can chose the same medicine as a homeopath would prescribe for children with URTI. Firstly, data from a survey was used to find three medicines Calcarea carb, Pulsatilla and Sulphur that accounted for 60% of all prescription made by Norwegian homeopaths for children with URTI. Simplified constitutional indications for these medicines were developed and tested by comparing the choices of 70 parents with the prescription of eleven homeopaths. The parents were able to choose the same homeopathic medicine as homeopaths prescribed for 55% of the children. Two hundred and fifty-nine children who had been diagnosed with an URTI by a medical doctor were recruited to participate in a trial on the effect of one of three self-selected ultramolecular homeopathic medicines for prevention of URTI in children. The indications developed were used. The children was randomly allocated to receive either ultramolecular homeopathic medicine (C-30) or placebo. There was no difference in the occurrence of URTI judged by the parents among getting ultramolecular homeopathic medicine compared to those getting placebo (median 9 days in three months for both groups) (p=0.531). / Hensikten med denne avhandlingen er å undersøke hvorfor foreldre tar sine barn med til homøopat og å undersøke effekten av homøopatisk behandling i forebygging av øvre luftveisinfeksjoner (ØLI) hos barn. Bakgrunnen for de undersøkelsene som er gjort, er at det nesten er en tredobling i andelen barn blant pasienter hos homøopat. Dette utløste spørsmål om hvorfor det er slik. Videre er gjentatte luftveisplager en hovedårsak til at barn oppsøker homøopat. Fordi det er lite forskning på dette temaet ble spørsmålet om effekten av homøopatisk behandling i denne pasientgruppen også utløst. Avhandlingen bygger på fire ulike undersøkelser som er gjennomført mellom august 2002 og juni 2004. Foreldre til ni barn som nylig hadde vært hos homøopat for første gang ble intervjuet for å undersøke hvorfor foreldre tar sine barn med til homøopat. Alle foreldrene hadde vært hos lege før de kontaktet homøopaten, og det var erfaringer med legebehandlingen som fikk foreldrene til å søke alternativer. Årsakene var at foreldrene 1) ikke ønsket å gi den behandlingen lege foreskrev til barnet, 2) ønsket behandling mens barnet ventet på å bli ferdig utredet, 3) ønsket å avslutte bruken av de medisinene legen hadde foreskrevet for barnet, 4) opplevde at barnet fikk bivirkninger av behandlingen legen hadde gitt og 5) ikke ble tilbudt noen behandling hos legen. Foreldre oppsøker først lege når de er usikre eller bekymret for barnets helsetilstand. De oppsøker homøopat for behandling når dette er avklart. Det er foreldre som oppsøker homøopat med sine barn selv om de ikke forstår eller tror på effekten av homøopatiske medisiner (som kan være svært fortynnet). Ett hundre og sekstini barn som hadde vært til lege på grunn av en øvre luftveisinfeksjon ble rekruttert til å være med på en undersøkelse av effekten av behandling hos homøopat i forebyggingen av ØLI hos barn. Barna ble tilfeldig fordelt i to grupper. Barna i den ene gruppen fikk time med en gang hos en av fem homøopater som foreskrev homøopatisk behandling på vanlig måte. Den andre gruppen fikk slik behandling etter 3 måneder. Forekomsten av ØLI Hensikten med denne avhandlingen er å undersøke hvorfor foreldre tar sine barn med til homøopat og å undersøke effekten av homøopatisk behandling i forebygging av øvre luftveisinfeksjoner (ØLI) hos barn. Bakgrunnen for de undersøkelsene som er gjort, er at det nesten er en tredobling i andelen barn blant pasienter hos homøopat. Dette utløste spørsmål om hvorfor det er slik. Videre er gjentatte luftveisplager en hovedårsak til at barn oppsøker homøopat. Fordi det er lite forskning på dette temaet ble spørsmålet om effekten av homøopatisk behandling i denne pasientgruppen også utløst. Avhandlingen bygger på fire ulike undersøkelser som er gjennomført mellom august 2002 og juni 2004. Foreldre til ni barn som nylig hadde vært hos homøopat for første gang ble intervjuet for å undersøke hvorfor foreldre tar sine barn med til homøopat. Alle foreldrene hadde vært hos lege før de kontaktet homøopaten, og det var erfaringer med legebehandlingen som fikk foreldrene til å søke alternativer. Årsakene var at foreldrene 1) ikke ønsket å gi den behandlingen lege foreskrev til barnet, 2) ønsket behandling mens barnet ventet på å bli ferdig utredet, 3) ønsket å avslutte bruken av de medisinene legen hadde foreskrevet for barnet, 4) opplevde at barnet fikk bivirkninger av behandlingen legen hadde gitt og 5) ikke ble tilbudt noen behandling hos legen. Foreldre oppsøker først lege når de er usikre eller bekymret for barnets helsetilstand. De oppsøker homøopat for behandling når dette er avklart. Det er foreldre som oppsøker homøopat med sine barn selv om de ikke forstår eller tror på effekten av homøopatiske medisiner (som kan være svært fortynnet). Ett hundre og sekstini barn som hadde vært til lege på grunn av en øvre luftveisinfeksjon ble rekruttert til å være med på en undersøkelse av effekten av behandling hos homøopat i forebyggingen av ØLI hos barn. Barna ble tilfeldig fordelt i to grupper. Barna i den ene gruppen fikk time med en gang hos en av fem homøopater som foreskrev homøopatisk behandling på vanlig måte. Den andre gruppen fikk slik behandling etter 3 måneder. Forekomsten av ØLI var signifikant lavere hos de som fikk behandling hos homøopat med én gang (median 8 dager på tre måneder) sammenlignet med den andre gruppen som brukte standard behandling ved behov mens de ventet (median 13 dager) (p=0,006). Homøopatisk medisin brukes internasjonalt i stor grad til selvbehandling. Man vet ikke om pasientens eget valg av homøopatisk medisin er lik det en homøopat ville foreskrevet. Det ble derfor gjennomført en undersøkelse av om det kan utvikles beskrivelser for indikasjoner for homøopatiske medisiner som gjør at foreldre kan velge samme medisin som en homøopat foreskriver for barn med ØLI. Først ble det funnet fram til tre medisiner, Calcarea carb, Pulsatilla og Sulphur som homøopater i Norge foreskriver til 60% av barn med ØLI. Så ble det utviklet indikasjoner for disse tre medisinene som ble testet ut ved at valgene til 70 foreldre ble sammenlignet med foreskrivingen til 11 homøopater. Foreldrene valgte samme medisin som homøopaten for 55% av barna. To hundre og femtien barn som hadde vært til lege på grunn av en øvre luftveisinfeksjon ble rekruttert til å være med på en undersøkelse av effekten av en av tre selvvalgte homøopatiske medisiner i forebyggingen av ØLI hos barn. Indikasjonene som ble utviklet ble brukt. Barna ble tilfeldig fordelt til enten å få homøopatisk medisin eller placebo. Det var ingen signifikant forskjell i forekomsten av ØLI mellom de som fikk homøopatisk medisin sammenlignet med de som fikk placebo (median 9 dager på tre måneder i begge grupper) (p=0,531).

IFN-α has been applied in medical treatment of various neuroendocrine (NE) tumors, either alone or combination with somatostatin analogues. They can improve clinical symptoms in 50-70% of patients but a significant tumor reduction is only observed in 5-15% patients. Vasostatin (vaso) is believed to be an angiogenic inhibitor. The aim of this study is to evaluate the feasibility to use IFN-α and vasostatin gene therapy in NE tumors. We constructed plasmid vectors carrying human IFN-α2 (hIFN-α2) gene and human vasostatin gene, which were transfected into BON I cell to obtain stable gene-expressing cell lines. We found that in animal tumor model and cell experiments gene transfer of vasostatin caused a faster cell growth and tumor development via down-regulation of the tumor suppressor gene and p27. Cell adhesion, spreading, migration and invasion ability were increased in vaso-expressing BON I cells. Transfecting chicken vinculin could reverse the malignant behavior and restored expression of tumor suppressor genes. Moreover, vinculin knockdown could result in a faster cell growth and an increased colony formation. Condition medium taken from hIFN-α2-expressing BON I cells showed significant antiproliferative effects both on the NE tumor cells, BON I and LCC18, and the endothelial cells, PAE. It also suppressed cell adhesion and cell invasion and inhibited angiogenesis on CAM assay. Mice implanted with a mixture of WT BON cells and hIFN-α2-expressing BON cells (1:1) demonstrated significantly lower tumor incidence and longer tumor doubling time. Furthermore, long-acting IFN-α2b (PEGIntron®) demonstrated a better anti-tumor effect in contrast with IFN-α2b (IntronA®). Intratumoral injection of hIFN-α2 plasmids significantly inhibited NE tumor growth and caused tumor regression. We concluded that gene transfer of vasostatin into BON I cells might cause an enhanced malignant tumor behavior. Therefore, vasostatin therapy can not be recommended for patients with NE tumors. Vinculin might play an important role in NE tumor development and growth regulation. Gene therapy by using plasmid DNA carrying hIFN-α2 gene is feasible and promising in NE tumors.

The polymorphonuclear neutrophil granulocytes (neutrophils) are gaining renewed interest regarding their involvement in chronic inflammatory disorders, including rheumatoid arthritis (RA). Besides phagocytic and destructive capabilities, neutrophils have regulatory roles, e.g. by influencing responses from dendritic cells and lymphocytes. Several animal models have revealed that neutrophils are crucial for the initiation and maintenance of chronic inflammatory diseases. Neutrophil function is highly dependent on their ability to produce superoxide, an oxygen radical which can be further metabolized to other free radicals. Whether or not neutrophils are capable of producing the oxygen radical nitric oxide (NO˙) has been a matter of debate. In this thesis it was shown that freshly isolated neutrophils from the joint cavity of patients with RA, but not from other arthritis patients, had ongoing intracellular production of superoxide, indicating the processing of ingested material. The finding that joint neutrophils, but seemingly not circulating cells, expressed the NO-inducing enzyme iNOS, led to a series of experiments aimed to elucidate where in the exudative process this enzyme could first be detected. We could finally, for the first time, present evidence that human neutrophils actually express iNOS constitutively. Our data also suggest that neutrophil iNOS may be membrane associated, thus differing from the cytosolic location in other cell types. Since NOS activity was not demonstrated in isolated cells, the notion that neutrophil iNOS is regulated primarily at the transcriptional level must be questioned. NO production from iNOS requires the presence of its substrate, L-arginine. To test the hypothesis that neutrophil arginase prevents neutrophil NO-production, we investigated whether arginase inhibition affects neutrophil NO-dependent oxidative function. Initial data revealed a difference in the effect of arginase inhibition comparing neutrophil stimulus with a soluble formylated tri-peptide (fMLF) and integrin-mediated stimulation with particle-bound collagen type-1. This led to the hypothesis that integrin-ligation on neutrophils induces extracellular liberation of arginase, which was confirmed both by measuring arginase and its enzyme activity. The findings in this thesis may be important not only regarding the role of neutrophils in chronic joint inflammation, but also as a link in the accelerated atherosclerosis observed in chronic inflammatory disorders, e.g. RA. / Vid reumatiska ledinflammationer ansamlas mycket stora mängder polymorfkärniga neutrofila granulocyter (neutrofiler) inne i den vätskefyllda ledhålan. Neutrofiler har kraftfull destruktiv potential och anses kunna bidra till uppkomst av skada i leden. Då flera djurmodeller av ledinflammation har visat sig omöjliga att initiera i frånvaro av neutrofiler, har intresset för denna celltyp åter ökat efter att de under lång tid har stått i skuggan av andra typer av vita blodkroppar. En viktig del i avdödning av mikroorganismer och cellsignalering är förmågan att bilda fria syreradikaler, t.ex. superoxid (˙O2-) och kväveoxid (NO˙). Denna avhandling belyser aspekter kring produktionen av dessa reaktiva syreprodukter och mekanismer av potentiell betydelse vid ledinflammation. I det första arbetet visas att neutrofiler isolerade ur ledvätska från patienter med ledgångsreumatism (RA) har ett unikt beteende avseende superoxidproduktion jämfört med motsvarande celler från patienter med andra reumatiska sjukdomar. RA-neutrofiler från ledvätska (men inte från blod) producerar superoxid intracellulärt redan i vila och stimulering via vidhäftningsmolekyler ger en snabb ytterligare ökning av denna aktivitet. Fyndet antyder att cellerna är engagerade med hantering av endocyterade partiklar och/eller immunkomplex/immunaggregat. I de båda nästkommande arbetena undersöktes förekomst av det NO˙-producerande enzymet iNOS i neutrofiler. En rad tidigare publikationer har rapporterat motsägelsefulla resultat i denna fråga. Efter en serie experiment kunde vi konstatera att humana neutrofiler uttrycker iNOS konstitutivt, men att både dess cellulära lokalisation och reglering skiljer sig från andra celler. Neutrofiler har nyligen även visats innehålla arginas, ett enzym som konkurrerar med iNOS om bindningen till L-arginin och som därmed kan hämma NO˙-produktion. I det fjärde arbetet undersökte vi därför om hämning av arginas påverkade neutrofilernas funktion och produktion av superoxid. Vi fann att effekterna av arginashämning var större hos celler som stimulerats genom vidhäftning av kollagenklädda partiklar jämfört med en löslig formylerad tri-peptid (fMLF). Vidare, kunde vi visa att vidhäftning av kollagenklädda partiklar medför större extracellulär frisättning av arginas. Med stöd av dessa fynd kunde vi i påföljande försök bekräfta hypotesen att extracellulär frisättning av arginas är större efter vidhäftning av kollagen-partiklar än med fMLF-stimulering. Fysiologiskt är fyndet logiskt då det skulle medföra ökade vidhäftningsmöjligheter för neutrofilen inne i blodbanan genom att begränsa blodkärlets egen NO˙ produktion. Fyndet är också förenligt med den ökade frekvensen hjärt- och kärlsjukdomar vid RA, då en intensiv kontinuerlig utvandring av neutrofiler skulle medföra ökad arginas frisättning, sänkta argininnivåer och endotelial dysfunktion.

Stroke is a common, multifactorial cardiovascular disease. A stroke event is the result of traditional risk factors (i.e. hypertension, diabetes, smoking), environmental exposures and genetic factors in a complex interplay. The genetic contribution is, as estimated by studies on the influence of family history on the risk of stroke, limited on the individual level, and overridden by, for example the excess risk associated with smoking. On the population level, and as a means to better understand the etiology of stroke, genetics can play a major role. Northern Sweden is well suited for studying the genetic aspects of stroke. The population shows signs of founder effects, and is relatively homogeneous. Large-scale cardiovascular health surveys, the MONICA Project and the Västerbotten Intervention Program, allow studies on risk factors in relation to stroke. Two prospective nested case-referent study samples, (113 cases and 226 controls; 275 cases and 549 controls), and a set of 56 families (117 affected) were collected for functional candidate gene association, and linkage, studies. The selected candidate genes included haemostatic factors and genes within the renin angiotensin system (RAS). Functional single nucleotide polymorphisms (SNPs) that influence the levels of PAI-1 (PAI-1 4G/5G), and tPA (tPA -7,351C>T), have been identified. The angiotensin converting enzyme insertion/deletion polymorphism (ACE I/D) has been shown to be associated with ischaemic stroke. The angiotensin II receptor type 1 A1166C polymorphism (AT1R A1166C), less extensively studied, has been suggested to be associated with stroke, and to interact with the ACE I/D. We found that the PAI-1 4G/4G genotype was associated with an increased risk of future ischaemic stroke (OR 1.79, 95%CI 1.01-3.19), and this was replicated in a second study sample. Furthermore, levels of serum triglycerides modulated the effect of the genotype. In the study on tPA, no association between the tPA -7,351C>T polymorphism and the risk of stroke was found in an analysis of the two study samples pooled. The two RAS polymorphisms were prospectively associated with ischaemic stroke independently of each other and other risk factors (OR 1.60, p=0.02 and OR 1.60, p=0.04, respectively). A candidate region linkage study, focusing on a previously reported stroke susceptibility locus on chromosome 5, was performed in a set of families. In addition, association between ischemic stroke and the positional candidate gene phosphodiesterase 4D (PDE4D) was tested. Linkage to 5q12 was replicated in this independent population, but not PDE4D association with stroke. This suggests that alternative genotypes in this stroke susceptibility locus contribute in different populations. In conclusion, the genetic component in the causation of stroke was investigated. The results of the functional candidate gene association studies showed (1) interaction between PAI-1 genotype and a putatively modifiable risk factor, triglycerides, (2) a prospective testing of the tPA SNP with no association detected, and (3) a novel, hypothesis-generating, finding in the case of AT1R polymorphism and the risk of ischaemic stroke. The replication of linkage to chromosome 5q12 in our northern Swedish population was interesting, and it will be further explored.

<p>Anemia is common in patients with chronic kidney disease (CDK), contributes to reduced Quality of Life (QoL) and is associated with cardiovascular disease, morbidity and mortality. Epoetin raises hemoglobin (Hb) and increases QoL and physical exercise capacity. Because of concerns about safety and economics, current anemia treatment with epoetin aims to achieve subnormal Hb (110-120 g/l). Normalization of Hb may be of additional benefit regarding QoL and cardiovascular effects. The present study examines the effects of Hb normalization with epoetin on safety variables, QoL, graft function after kidney transplantation, dialysis adequacy, hemorheology, hemodynamics and cardiac autonomic function in CKD patients. </p><p>In a randomized, multicenter study comprising 416 pre-dialysis and dialysis patients no difference was observed between patients treated to a normal or a subnormal Hb level on mortality, thrombovascular events, serious adverse events, vascular access thrombosis and residual renal function. QoL was enhanced in a subgroup of hemodialysis patients. Pretransplant epoetin treatment directed toward normal Hb levels did not result in worse graft function during 6 postoperative months. Dialysis adequacy was reduced in a subgroup of hemodialysis patients after normalization of Hb. The blood flow properties of pre-dialysis patients were altered. The hemorheological investigation demonstrated that Hb normalization caused a parallel increase in hematocrit and blood viscosity without other hemorheological changes. While the total peripheral resistance index increased, the cardiac index (CI) decreased. In a separate study cardiac autonomic function, measured by heart rate variability, was decreased in pre-dialysis patients. It was improved, but not fully normalized, by Hb normalization. </p><p>On the basis of this study, Hb normalization with epoetin appears to be safe and increases QoL in hemodialysis patients though may result in lower dialysis adequacy and increased blood pressure. A reduction in CI and improved cardiac autonomic function indicate a positive effect on cardiovascular function.</p>

<p>Diabetes is a major risk factor for ischemic stroke and is associated with increased mortality. Additionally, hyperglycemia, a common complication in acute stroke, is associated with poor outcome.</p><p>In order to identify the correlation between blood glucose and early mortality, multiple logistic regression analyses were used and odds ratios calculated in a retrospective study of 447 stroke patients. Eighty-one patients (18%) had diabetes. The odds ratios for 30-day case-fatality and blood glucose were 1.9 and 1.6 in diabetic and non-diabetic patients respectively. Optimal blood glucose concentrations in respective group were 10.3 and 6.3 mmol/L, as determined by receiver operator characteristic (ROC) curves.</p><p>Cerebral ischemia triggers different signaling pathways including mitogen-activated protein kinases (MAPK) which regulate fundamental cell functions. In an experimental rat model of combined hyperglycemia and transient middle cerebral artery occlusion (MCAO), the activation pattern of one such MAPK, extracellular signal-regulated kinase (ERK) was studied along with infarct volumes and neurological function. Hyperglycemia resulted in markedly increased ERK activation and approximately three-fold increase of infarcts compared with controls. </p><p>Based on the increased ERK activation, further experiments were conducted to limit the hyperglycemic-ischemic damage by interfering with ERK and supposedly related mechanisms. Consequently, rats were given U0126 (inhibiting ERK activation), PBN (anti-oxidative), PP2 (inhibiting src-family kinases), or vehicle. PBN reduced infarcts and improved neurological function compared with controls while no statistically significant effects were observed for U0126 or PP2. However, when the dose was doubled, U0126 significantly reduced infarcts and improved neurological function after 1 day in hyperglycemic rats. Post-ischemic ERK activation was completely inhibited by U0126 as demonstrated with Western immunoblotting. The findings suggest that ERK is an important mediator of hyperglycemic-ischemic brain injury and possible target for future interventions.</p>

Diabetes is a major risk factor for ischemic stroke and is associated with increased mortality. Additionally, hyperglycemia, a common complication in acute stroke, is associated with poor outcome. In order to identify the correlation between blood glucose and early mortality, multiple logistic regression analyses were used and odds ratios calculated in a retrospective study of 447 stroke patients. Eighty-one patients (18%) had diabetes. The odds ratios for 30-day case-fatality and blood glucose were 1.9 and 1.6 in diabetic and non-diabetic patients respectively. Optimal blood glucose concentrations in respective group were 10.3 and 6.3 mmol/L, as determined by receiver operator characteristic (ROC) curves. Cerebral ischemia triggers different signaling pathways including mitogen-activated protein kinases (MAPK) which regulate fundamental cell functions. In an experimental rat model of combined hyperglycemia and transient middle cerebral artery occlusion (MCAO), the activation pattern of one such MAPK, extracellular signal-regulated kinase (ERK) was studied along with infarct volumes and neurological function. Hyperglycemia resulted in markedly increased ERK activation and approximately three-fold increase of infarcts compared with controls. Based on the increased ERK activation, further experiments were conducted to limit the hyperglycemic-ischemic damage by interfering with ERK and supposedly related mechanisms. Consequently, rats were given U0126 (inhibiting ERK activation), PBN (anti-oxidative), PP2 (inhibiting src-family kinases), or vehicle. PBN reduced infarcts and improved neurological function compared with controls while no statistically significant effects were observed for U0126 or PP2. However, when the dose was doubled, U0126 significantly reduced infarcts and improved neurological function after 1 day in hyperglycemic rats. Post-ischemic ERK activation was completely inhibited by U0126 as demonstrated with Western immunoblotting. The findings suggest that ERK is an important mediator of hyperglycemic-ischemic brain injury and possible target for future interventions.

Anemia is common in patients with chronic kidney disease (CDK), contributes to reduced Quality of Life (QoL) and is associated with cardiovascular disease, morbidity and mortality. Epoetin raises hemoglobin (Hb) and increases QoL and physical exercise capacity. Because of concerns about safety and economics, current anemia treatment with epoetin aims to achieve subnormal Hb (110-120 g/l). Normalization of Hb may be of additional benefit regarding QoL and cardiovascular effects. The present study examines the effects of Hb normalization with epoetin on safety variables, QoL, graft function after kidney transplantation, dialysis adequacy, hemorheology, hemodynamics and cardiac autonomic function in CKD patients. In a randomized, multicenter study comprising 416 pre-dialysis and dialysis patients no difference was observed between patients treated to a normal or a subnormal Hb level on mortality, thrombovascular events, serious adverse events, vascular access thrombosis and residual renal function. QoL was enhanced in a subgroup of hemodialysis patients. Pretransplant epoetin treatment directed toward normal Hb levels did not result in worse graft function during 6 postoperative months. Dialysis adequacy was reduced in a subgroup of hemodialysis patients after normalization of Hb. The blood flow properties of pre-dialysis patients were altered. The hemorheological investigation demonstrated that Hb normalization caused a parallel increase in hematocrit and blood viscosity without other hemorheological changes. While the total peripheral resistance index increased, the cardiac index (CI) decreased. In a separate study cardiac autonomic function, measured by heart rate variability, was decreased in pre-dialysis patients. It was improved, but not fully normalized, by Hb normalization. On the basis of this study, Hb normalization with epoetin appears to be safe and increases QoL in hemodialysis patients though may result in lower dialysis adequacy and increased blood pressure. A reduction in CI and improved cardiac autonomic function indicate a positive effect on cardiovascular function.