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  • 1.
    Bergström, Marcus
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Clinical Immunology.
    Joly, A. -L
    Seiron, P.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Clinical Immunology.
    Isringhausen, S.
    Modig, E.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Clinical Immunology.
    Fellström, Bengt
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Renal Medicine.
    Andersson, J.
    Berglund, David
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Transplantation Surgery.
    Immunological Profiling of Haemodialysis Patients and Young Healthy Individuals with Implications for Clinical Regulatory T Cell Sorting2015In: Scandinavian Journal of Immunology, ISSN 0300-9475, E-ISSN 1365-3083, Vol. 81, no 5, p. 318-324Article in journal (Refereed)
    Abstract [en]

    With the increasing interest in clinical trials with regulatory T cells (Tregs), immunological profiling of prospective target groups and standardized procedures for Treg isolation are needed. In this study, flow cytometry was used to assess peripheral blood lymphocyte profiles of young healthy individuals and patients undergoing haemodialysis treatment. Tregs obtained from the former may be used in haematopoietic stem cell transplantation and Tregs from the latter in the prevention of kidney transplant rejection. FOXP3 mRNA expression with accompanying isoform distribution was also assessed by the quantitative reverse transcriptase polymerase chain reaction. Flow-cytometric gating strategies were systematically analysed to optimize the isolation of Tregs. Our findings showed an overall similar immunological profile of both cohorts in spite of great differences in both age and health. Analysis of flow-cytometric gating techniques highlighted the importance of gating for both CD25high and CD127low expression in the isolation of FOXP3-positive cells. This study provides additional insight into the immunological profile of young healthy individuals and uraemic patients as well as in-depth analysis of flow-cytometric gating strategies for Treg isolation, supporting the development of Treg therapy using cells from healthy donors and uraemic patients.

  • 2.
    Carlsson, Daniel O
    et al.
    Uppsala University, Disciplinary Domain of Science and Technology, Technology, Department of Engineering Sciences, Nanotechnology and Functional Materials.
    Ferraz, Natalia
    Uppsala University, Disciplinary Domain of Science and Technology, Technology, Department of Engineering Sciences, Nanotechnology and Functional Materials.
    Fellström, Bengt
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Renal Medicine.
    Nyholm, Leif
    Uppsala University, Disciplinary Domain of Science and Technology, Chemistry, Department of Chemistry - Ångström, Inorganic Chemistry.
    Mihranyan, Albert
    Uppsala University, Disciplinary Domain of Science and Technology, Technology, Department of Engineering Sciences, Nanotechnology and Functional Materials.
    Strømme, Maria
    Uppsala University, Disciplinary Domain of Science and Technology, Technology, Department of Engineering Sciences, Nanotechnology and Functional Materials.
    Towards blood purification applications of polypyrrole and cellulose nanocomposites2013Conference paper (Refereed)
  • 3.
    Carlsson, Daniel O
    et al.
    Uppsala University, Disciplinary Domain of Science and Technology, Technology, Department of Engineering Sciences, Nanotechnology and Functional Materials.
    Ferraz, Natalie
    Uppsala University, Disciplinary Domain of Science and Technology, Technology, Department of Engineering Sciences, Nanotechnology and Functional Materials.
    Hong, J
    Larsson, R
    Fellström, Bengt
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Renal Medicine.
    Nyholm, Leif
    Uppsala University, Disciplinary Domain of Science and Technology, Chemistry, Department of Chemistry - Ångström, Inorganic Chemistry.
    Strömme, Maria
    Uppsala University, Disciplinary Domain of Science and Technology, Technology, Department of Engineering Sciences, Nanotechnology and Functional Materials.
    Mihranyan, Albert
    Uppsala University, Disciplinary Domain of Science and Technology, Technology, Department of Engineering Sciences, Nanotechnology and Functional Materials.
    Conduting nanocellulose polypyrrole membranes intended for hemodialysis2012Conference paper (Refereed)
  • 4. Dahle, Dag Olav
    et al.
    Jenssen, Trond
    Holdaas, Hallvard
    Åsberg, Anders
    Soveri, Inga
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Renal Medicine.
    Holme, Ingar
    Mjøen, Geir
    Eide, Ivar A
    Pihlstrøm, Hege
    Dörje, Christina
    Halden, Thea A S
    Hartmann, Anders
    Uric acid and clinical correlates of endothelial function in kidney transplant recipients2014In: Clinical Transplantation, ISSN 0902-0063, E-ISSN 1399-0012, Vol. 28, no 10, p. 1167-1176Article in journal (Refereed)
    Abstract [en]

    Uric acid is associated with increased mortality in kidney transplant recipients (KTRs), but it is uncertain if this involves endothelial dysfunction. We hypothesized, first, that there was an association between uric acid and endothelial function, and second, that there were associations between endothelial function and cardiac and mortality risk scores.

    METHODS: One hundred and fifty-two patients were examined 10 wk after kidney transplantation by two measures of endothelial function, the brachial artery flow-mediated dilatation (FMD) expressed as percent dilatation (FMD%), and fingertip peripheral arterial tone (PAT) expressed as log-reactive hyperemia index (LnRHI). Risk scores were calculated from a recently validated formula. Other clinical correlates of endothelial function were described in stepwise linear regression models.

    RESULTS: Uric acid was associated negatively with FMD% in an age- and gender-adjusted model, while not in the multivariable model. No association was shown between uric acid and LnRHI. FMD% was associated negatively with risk scores in both crude and age- and gender-adjusted models (p < 0.01). LnRHI was associated negatively with risk scores in the latter model only (p < 0.05).

    CONCLUSIONS: Uric acid was neither associated with FMD% nor LnRHI in KTRs. There were significant associations between endothelial function indices and cardiac and mortality risk scores.

  • 5. Delanaye, Pierre
    et al.
    Ebert, Natalie
    Melsom, Toralf
    Gaspari, Flavio
    Mariat, Christophe
    Cavalier, Etienne
    Björk, Jonas
    Christensson, Anders
    Nyman, Ulf
    Porrini, Esteban
    Remuzzi, Giuseppe
    Ruggenenti, Piero
    Schaeffner, Elke
    Soveri, Inga
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Renal Medicine.
    Sterner, Gunnar
    Eriksen, Bjørn Odvar
    Bäck, Sten-Erik
    Iohexol plasma clearance for measuring glomerular filtration rate in clinical practice and research: a review. Part 1 How to measure glomerular filtration rate with iohexol?2016In: Clinical Kidney Journal, ISSN 2048-8505, E-ISSN 2048-8513, Vol. 9, no 5, p. 682-699Article in journal (Refereed)
    Abstract [en]

    While there is general agreement on the necessity to measure glomerular filtration rate (GFR) in many clinical situations, there is less agreement on the best method to achieve this purpose. As the gold standard method for GFR determination, urinary (or renal) clearance of inulin, fades into the background due to inconvenience and high cost, a diversity of filtration markers and protocols compete to replace it. In this review, we suggest that iohexol, a non-ionic contrast agent, is most suited to replace inulin as the marker of choice for GFR determination. Iohexol comes very close to fulfilling all requirements for an ideal GFR marker in terms of low extra-renal excretion, low protein binding and in being neither secreted nor reabsorbed by the kidney. In addition, iohexol is virtually non-toxic and carries a low cost. As iohexol is stable in plasma, administration and sample analysis can be separated in both space and time, allowing access to GFR determination across different settings. An external proficiency programme operated by Equalis AB, Sweden, exists for iohexol, facilitating interlaboratory comparison of results. Plasma clearance measurement is the protocol of choice as it combines a reliable GFR determination with convenience for the patient. Single-sample protocols dominate, but multiple-sample protocols may be more accurate in specific situations. In low GFRs one or more late samples should be included to improve accuracy. In patients with large oedema or ascites, urinary clearance protocols should be employed. In conclusion, plasma clearance of iohexol may well be the best candidate for a common GFR determination method.

  • 6. Delanaye, Pierre
    et al.
    Melsom, Toralf
    Ebert, Natalie
    Bäck, Sten-Erik
    Mariat, Christophe
    Cavalier, Etienne
    Björk, Jonas
    Christensson, Anders
    Nyman, Ulf
    Porrini, Esteban
    Remuzzi, Giuseppe
    Ruggenenti, Piero
    Schaeffner, Elke
    Soveri, Inga
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Renal Medicine.
    Sterner, Gunnar
    Eriksen, Bjørn Odvar
    Gaspari, Flavio
    Iohexol plasma clearance for measuring glomerular filtration rate in clinical practice and research: a review. Part 2 Why to measure glomerular filtration rate with iohexol?2016In: Clinical Kidney Journal, ISSN 2048-8505, E-ISSN 2048-8513, Vol. 9, no 5, p. 700-704Article in journal (Refereed)
    Abstract [en]

    A reliable assessment of glomerular filtration rate (GFR) is of paramount importance in clinical practice as well as epidemiological and clinical research settings. It is recommended by Kidney Disease: Improving Global Outcomes guidelines in specific populations (anorectic, cirrhotic, obese, renal and non-renal transplant patients) where estimation equations are unreliable. Measured GFR is the only valuable test to confirm or confute the status of chronic kidney disease (CKD), to evaluate the slope of renal function decay over time, to assess the suitability of living kidney donors and for dosing of potentially toxic medication with a narrow therapeutic index. Abnormally elevated GFR or hyperfiltration in patients with diabetes or obesity can be correctly diagnosed only by measuring GFR. GFR measurement contributes to assessing the true CKD prevalence rate, avoiding discrepancies due to GFR estimation with different equations. Using measured GFR, successfully accomplished in large epidemiological studies, is the only way to study the potential link between decreased renal function and cardiovascular or total mortality, being sure that this association is not due to confounders, i.e. non-GFR determinants of biomarkers. In clinical research, it has been shown that measured GFR (or measured GFR slope) as a secondary endpoint as compared with estimated GFR detected subtle treatment effects and obtained these results with a comparatively smaller sample size than trials choosing estimated GFR. Measuring GFR by iohexol has several advantages: simplicity, low cost, stability and low interlaboratory variation. Iohexol plasma clearance represents the best chance for implementing a standardized GFR measurement protocol applicable worldwide both in clinical practice and in research.

  • 7. Drechsler, Christiane
    et al.
    Philstrom, Hege
    Meinitzer, Andreas
    Pilz, Stefan
    Tomaschitz, Andreas
    Abedini, Sadollah
    Fellström, Bengt
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Renal Medicine.
    Jardine, Alan
    Wanner, Christoph
    Maerz, Winfried
    Holdaas, Hallvard
    Homoarginine and Clinical Outcomes in Renal Transplant Recipients: Results from the Alert Study2014In: Nephrology, Dialysis and Transplantation, ISSN 0931-0509, E-ISSN 1460-2385, Vol. 29, p. 539-539Article in journal (Other academic)
  • 8. Drechsler, Christiane
    et al.
    Pihlström, Hege
    Meinitzer, Andreas
    Pilz, Stefan
    Tomaschitz, Andreas
    Abedini, Sadollah
    Fellström, Bengt
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Renal Medicine.
    Jardine, Alan G
    Wanner, Christoph
    März, Winifred
    Holdaas, Hallvard
    Homoarginine and Clinical Outcomes in Renal Transplant Recipients: Results From the Assessment of Lescol in Renal Transplantation Study2015In: Transplantation, ISSN 0041-1337, E-ISSN 1534-6080, Vol. 99, no 7, p. 1470-1476Article in journal (Refereed)
    Abstract [en]

    Background: Despite improvements in kidney transplantation, complications, including cardiovascular morbidity and graft loss, contribute to reduced graft and patient survival. The amino acid homoarginine exerts a variety of beneficial effects that may be relevant for cardiovascular and graft outcomes, which is investigated in the present study.

    Methods: Homoarginine was measured in 829 renal transplant recipients participating in the placebo group of the Assessment of Lescol in Renal Transplantation study. Mean follow-up was 6.7 years. By Cox regression analyses, we determined hazard ratios (HRs) to reach prespecified, adjudicated endpoints according to baseline homoarginine levels: major adverse cardiovascular events (n = 103), cerebrovascular events (n = 53), graft failure or doubling of serum creatinine (n = 140), noncardiovascular mortality (n = 51), and all-cause mortality (n = 107).

    Results: Patients mean age was 50 ± 11 years, homoarginine concentration was 1.96 ± 0.76 µmol/L, and 65% were men. Patients in the lowest homoarginine quartile (<1.40 µmol/L) had an adjusted 2.6-fold higher risk of cerebrovascular events compared to those in the highest quartile (>2.34 µmol/L) (HR, 2.56; 95% confidence interval [95% CI], 1.13–5.82). Similarly, the renal endpoint occurred at a significantly increased rate in the lowest homoarginine quartile (HR, 2.34; 95% CI, 1.36–4.02). For noncardiovascular and all-cause mortality, there was also increased risk associated with the lowest levels of homoarginine, with HRs of 4.34 (95% CI, 1.63–10.69) and 2.50 (95% CI, 1.38–4.55), respectively.

    Conclusions: Low homoarginine is strongly associated with cerebrovascular events, graft loss and progression of kidney failure and mortality in renal transplant recipients. Whether interventions with homoarginine supplementation improve clinical outcomes requires further evaluation.

  • 9.
    Ekdahl, Kristina N
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Clinical Immunology. Linnaeus Univ, Linnaeus Ctr Biomat Chem, SE-39182 Kalmar, Sweden.
    Soveri, Inga
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Renal Medicine.
    Hilborn, Jöns
    Uppsala University, Disciplinary Domain of Science and Technology, Chemistry, Department of Chemistry - Ångström, Polymer Chemistry.
    Fellström, Bengt
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Renal Medicine.
    Nilsson, Bo
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Clinical Immunology.
    Cardiovascular disease in haemodialysis: role of the intravascular innate immune system.2017In: Nature Reviews Nephrology, ISSN 1759-5061, E-ISSN 1759-507X, Vol. 13, no 5, p. 285-296Article, review/survey (Refereed)
    Abstract [en]

    Haemodialysis is a life-saving renal replacement modality for end-stage renal disease, but this therapy also represents a major challenge to the intravascular innate immune system, which is comprised of the complement, contact and coagulation systems. Chronic inflammation is strongly associated with cardiovascular disease (CVD) in patients on haemodialysis. Biomaterial-induced contact activation of proteins within the plasma cascade systems occurs during haemodialysis and initially leads to local generation of inflammatory mediators on the biomaterial surface. The inflammation is spread by soluble activation products and mediators that are generated during haemodialysis and transported in the extracorporeal circuit back into the patient together with activated leukocytes and platelets. The combined effect is activation of the endothelium of the cardiovascular system, which loses its anti-thrombotic and anti-inflammatory properties, leading to atherogenesis and arteriosclerosis. This concept suggests that maximum suppression of the intravascular innate immune system is needed to minimize the risk of CVD in patients on haemodialysis. A potential approach to achieve this goal is to treat patients with broad-specificity systemic drugs that target more than one of the intravascular cascade systems. Alternatively, 'stealth' biomaterials that cause minimal cascade system activation could be used in haemodialysis circuits.

  • 10.
    Eriksson, Daniel
    et al.
    Quantify Research, Stockholm, Sweden.
    Karlsson, Linda
    Quantify Research, Stockholm, Sweden.
    Eklund, Oskar
    Quantify Research, Stockholm, Sweden.
    Dieperink, Hans
    Department of Nephrology, Odense University Hospital, Odense C, Denmark.
    Honkanen, Eero
    Division of Nephrology, Department of Medicine , Helsinki University Central Hospital, Helsinki, Finland.
    Melin, Jan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Renal Medicine.
    Selvig, Kristian
    Department of Nephrology, Vestre Viken Hospital Trust, Drammen, Norway.
    Lundberg, Johan
    Otsuka Pharma Scandinavia, Stockholm, Sweden.
    Health-related quality of life across all stages of autosomal dominant polycystic kidney disease2016In: Nephrology, Dialysis and Transplantation, ISSN 0931-0509, E-ISSN 1460-2385Article in journal (Refereed)
    Abstract [en]

    BACKGROUND: A limited number of studies have assessed health-related quality of life (HRQoL) in autosomal dominant polycystic kidney disease (ADPKD). Results to date have been conflicting and studies have generally focused on patients with later stages of the disease. This study aimed to assess HRQoL in ADPKD across all stages of the disease, from patients with early chronic kidney disease (CKD) to patients with end-stage renal disease.

    METHODS: A study involving cross-sectional patient-reported outcomes and retrospective clinical data was undertaken April-December 2014 in Denmark, Finland, Norway and Sweden. Patients were enrolled into four mutually exclusive stages of the disease: CKD stages 1-3; CKD stages 4-5; transplant recipients; and dialysis patients.

    RESULTS: Overall HRQoL was generally highest in patients with CKD stages 1-3, followed by transplant recipients, patients with CKD stages 4-5 and patients on dialysis. Progressive disease predominately had an impact on physical health, whereas mental health showed less variation between stages of the disease. A substantial loss in quality of life was observed as patients progressed to CKD stages 4-5.

    CONCLUSIONS: Later stages of ADPKD are associated with reduced physical health. The value of early treatment interventions that can delay progression of the disease should be considered.

  • 11.
    Eriksson, Daniel
    et al.
    Quantify Res, Hantverkargatan 8, S-11221 Stockholm, Sweden..
    Karlsson, Linda
    Quantify Res, Hantverkargatan 8, S-11221 Stockholm, Sweden..
    Eklund, Oskar
    Quantify Res, Hantverkargatan 8, S-11221 Stockholm, Sweden..
    Dieperink, Hans
    Odense Univ Hosp, Dept Nephrol, Sdr Blvd 29, DK-5000 Odense C, Denmark..
    Honkanen, Eero
    Univ Helsinki, Cent Hosp, Dept Med, Div Nephrol, Haartmaninkatu 4,POB 372, FIN-00029 Hus Helsinki, Finland..
    Melin, Jan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Renal Medicine.
    Selvig, Kristian
    Vestre Viken Hosp Trust, Dept Nephrol, Postboks 800 3004, Drammen, Norway..
    Lundberg, Johan
    Otsuka Pharma Scandinavia, Birger Jarlsgatan 27, S-11145 Stockholm, Sweden..
    Real-world costs of autosomal dominant polycystic kidney disease in the Nordics2017In: BMC Health Services Research, ISSN 1472-6963, E-ISSN 1472-6963, Vol. 17, article id 560Article in journal (Refereed)
    Abstract [en]

    Background: There is limited real-world data on the economic burden of patients with autosomal dominant polycystic kidney disease (ADPKD). The objective of this study was to estimate the annual direct and indirect costs of patients with ADPKD by severity of the disease: chronic kidney disease (CKD) stages 1-3; CKD stages 4-5; transplant recipients; and maintenance dialysis patients. Methods: A retrospective study of ADPKD patients was undertaken April-December 2014 in Denmark, Finland, Norway and Sweden. Data on medical resource utilisation were extracted from medical charts and patients were asked to complete a self-administered questionnaire. Results: A total of 266 patients were contacted, 243 (91%) of whom provided consent to participate in the study. Results showed that the economic burden of ADPKD was substantial at all levels of the disease. Lost wages due to reduced productivity were large in absolute terms across all disease strata. Mean total annual costs were highest in dialysis patients, driven by maintenance dialysis care, while the use of immunosuppressants was the main cost component for transplant care. Costs were twice as high in patients with CKD stages 4-5 compared to CKD stages 1-3. Conclusions: Costs associated with ADPKD are significant and the progression of the disease is associated with an increased frequency and intensity of medical resource utilisation. Interventions that can slow the progression of the disease have the potential to lead to substantial reductions in costs for the treatment of ADPKD.

  • 12.
    Fellström, Bengt
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Renal Medicine.
    Risk Factors and Management Options for Cardiovascular Disease (CVD) in Kidney Transplantation2013In: Annals of Saudi Medicine, ISSN 0256-4947, E-ISSN 0975-4466, Vol. 33, no 2, p. S15-S16Article in journal (Refereed)
  • 13.
    Fellström, Bengt
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Renal Medicine.
    Barratt, Jonathan
    Univ Leicester, Dept Infect Immun & Inflammat, Leicester, Leics, England; Leicester Gen Hosp, John Walls Renal Unit, Leicester, Leics, England; Hlth Educ East Midlands, Postgrad Specialty Sch Clin Acad Training, Leicester, Leics, England.
    Flöge, Jürgen
    Rhein Westfal TH Aachen, Med Klin 2, Aachen, Germany.
    Jardine, Alan
    Univ Glasgow, Inst Cardiovasc & Med Sci, Glasgow, Lanark, Scotland; Queen Elizabeth Hosp, Glasgow Renal Transplant Unit, Glasgow, Lanark, Scotland.
    Targeted-release budesonide therapy for IgA nephropathy - Authors' reply.2017In: The Lancet, ISSN 0140-6736, E-ISSN 1474-547X, Vol. 390, no 10113, p. 2625-2626Article in journal (Refereed)
  • 14.
    Fellström, Bengt C.
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Renal Medicine.
    Barratt, Jonathan
    Univ Leicester, Leicester, Leics, England..
    Cook, Heather
    PharmaL Consulting AB, Stockholm, Sweden..
    Coppo, Rosanna
    Regina Margherita Hosp, Fdn Ric Molinette, Turin, Italy..
    Feehally, John
    Univ Leicester, Leicester, Leics, England..
    de Fijter, Johan W.
    Leiden Univ, Med Ctr, Leiden, Netherlands..
    Floege, Jürgen
    Rhein Westfal TH Aachen, Aachen, Germany..
    Hetzel, Gerd
    HeinrichHeine Univ, DaVita Renal Ctr, Dusseldorf, Germany..
    Jardine, Alan G.
    Univ Glasgow, Glasgow, Lanark, Scotland..
    Locatelli, Francesco
    Osped A Manzoni, Lecce, Italy..
    Maes, Bart D.
    AZ Delta, Roeselare, Belgium..
    Mercer, Alex
    Pharmalink AB, Stockholm, Sweden..
    Ortiz, Fernanda
    Helsinki Univ Hosp, Helsinki, Finland..
    Praga, Manuel
    Univ Complutense Madrid, Investigat Inst Hosp Octubre 12, Madrid, Spain..
    Sorensen, Soren S.
    Copenhagen Univ Hosp, Rigshosp, Copenhagen, Denmark..
    Tesar, Vladimir
    Charles Univ Prague, Prague, Czech Republic..
    Del Vecchio, Lucia
    Osped A Manzoni, Lecce, Italy..
    Targeted-release budesonide versus placebo in patients with IgA nephropathy (NEFIGAN): a double-blind, randomised, placebo-controlled phase 2b trial2017In: The Lancet, ISSN 0140-6736, E-ISSN 1474-547X, Vol. 389, no 10084, p. 2117-2127Article in journal (Refereed)
    Abstract [en]

    Background: IgA nephropathy is thought to be associated with mucosal immune system dysfunction, which manifests as renal IgA deposition that leads to impairment and end-stage renal disease in 20-40% of patients within 10-20 years. In this trial (NEFIGAN) we aimed to assess safety and efficacy of a novel targeted-release formulation of budesonide (TRF-budesonide), designed to deliver the drug to the distal ileum in patients with IgA nephropathy.

    Methods: We did a randomised, double-blind, placebo-controlled phase 2b trial, comprised of 6-month run-in, 9-month treatment, and 3-month follow-up phases at 62 nephrology clinics across ten European countries. We recruited patients aged at least 18 years with biopsy-confirmed primary IgA nephropathy and persistent proteinuria despite optimised renin-angiotensin system (RAS) blockade. We randomly allocated patients with a computer algorithm, with a fixed block size of three, in a 1:1:1 ratio to 16 mg/day TRF-budesonide, 8 mg/day TRF-budesonide, or placebo, stratified by baseline urine protein creatinine ratio (UPCR). Patients self-administered masked capsules, once daily, 1 h before breakfast during the treatment phase. All patients continued optimised RAS blockade treatment throughout the trial. Our primary outcome was mean change from baseline in UPCR for the 9-month treatment phase, which was assessed in the full analysis set, defined as all randomised patients who took at least one dose of trial medication and had at least one post-dose efficacy measurement. Safety was assessed in all patients who received the intervention. This trial is registered with ClinicalTrials.gov, number NCT01738035.

    Findings: Between Dec 11, 2012, and June 25, 2015, 150 randomised patients were treated (safety set) and 149 patients were eligible for the full analysis set. Overall, at 9 months TRF-budesonide (16 mg/day plus 8 mg/day) was associated with a 24.4% (SEM 7.7%) decrease from baseline in mean UPCR (change in UPCR vs placebo 0.74; 95% CI 0.59-0.94; p=0.0066). At 9 months, mean UPCR had decreased by 27.3% in 48 patients who received 16 mg/day (0.71; 0.53-0.94; p=0.0092) and 21.5% in the 51 patients who received 8 mg/day (0.76; 0.58-1.01; p=0.0290); 50 patients who received placebo had an increase in mean UPCR of 2.7%. The effect was sustained throughout followup. Incidence of adverse events was similar in all groups (43 [88%] of 49 in the TRF-budesonide 16 mg/day group, 48 [94%] of 51 in the TRF-budesonide 8 mg/day, and 42 [84%] of 50 controls). Two of 13 serious adverse events were possibly associated with TRF-budesonide-deep vein thrombosis (16 mg/day) and unexplained deterioration in renal function in follow-up (patients were tapered from 16 mg/day to 8 mg/day over 2 weeks and follow-up was assessed 4 weeks later).

    Interpretation: TRF-budesonide 16 mg/day, added to optimised RAS blockade, reduced proteinuria in patients with IgA nephropathy. This effect is indicative of a reduced risk of future progression to end-stage renal disease. TRF-budesonide could become the first specific treatment for IgA nephropathy targeting intestinal mucosal immunity upstream of disease manifestation.

  • 15.
    Fellström, Bengt
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Renal Medicine.
    Holdaas, Hallvard
    Jardine, Alan
    Functional Cardiopulmonary Exercise Testing in Potential Renal Transplant Recipients2014In: Journal of the American Society of Nephrology, ISSN 1046-6673, E-ISSN 1533-3450, Vol. 25, no 1, p. 8-9Article in journal (Other academic)
  • 16.
    Ferraz, Natalia
    et al.
    Uppsala University, Disciplinary Domain of Science and Technology, Technology, Department of Engineering Sciences, Nanotechnology and Functional Materials.
    Carlsson, Daniel O.
    Uppsala University, Disciplinary Domain of Science and Technology, Technology, Department of Engineering Sciences, Nanotechnology and Functional Materials.
    Hong, Jaan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Clinical Immunology.
    Larsson, Rolf
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Clinical Immunology.
    Fellström, Bengt
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Renal Medicine.
    Nyholm, Leif
    Uppsala University, Disciplinary Domain of Science and Technology, Chemistry, Department of Chemistry - Ångström, Inorganic Chemistry.
    Strømme, Maria
    Uppsala University, Disciplinary Domain of Science and Technology, Technology, Department of Engineering Sciences, Nanotechnology and Functional Materials.
    Mihranyan, Albert
    Uppsala University, Disciplinary Domain of Science and Technology, Technology, Department of Engineering Sciences, Nanotechnology and Functional Materials.
    Haemocompatibility and ion exchange capability of nanocellulose polypyrrole membranes intended for blood purification2012In: Journal of the Royal Society Interface, ISSN 1742-5689, E-ISSN 1742-5662, Vol. 9, no 73, p. 1943-1955Article in journal (Refereed)
    Abstract [en]

    Composites of nanocellulose and the conductive polymer polypyrrole (PPy) are presented as candidates for a new generation of haemodialysis membranes. The composites may combine active ion exchange with passive ultrafiltration, and the large surface area (about 80 m2 g−1) could potentially provide compact dialysers. Herein, the haemocompatibility of the novel membranes and the feasibility of effectively removing small uraemic toxins by potential-controlled ion exchange were studied. The thrombogenic properties of the composites were improved by applying a stable heparin coating. In terms of platelet adhesion and thrombin generation, the composites were comparable with haemocompatible polymer polysulphone, and regarding complement activation, the composites were more biocompatible than commercially available membranes. It was possible to extract phosphate and oxalate ions from solutions with physiological pH and the same tonicity as that of the blood. The exchange capacity of the materials was found to be 600 ± 26 and 706 ± 31 μmol g−1 in a 0.1 M solution (pH 7.4) and in an isotonic solution of phosphate, respectively. The corresponding values with oxalate were 523 ± 5 in a 0.1 M solution (pH 7.4) and 610 ± 1 μmol g−1 in an isotonic solution. The heparinized PPy–cellulose composite is consequently a promising haemodialysis material, with respect to both potential-controlled extraction of small uraemic toxins and haemocompatibility.

  • 17.
    Furuland, Hans
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Renal Medicine.
    McEwan, Phil
    HEOR Ltd, Hlth Econ & Outcomes Res, Cardiff, S Glam, Wales; Swansea Univ, Sch Human & Hlth Sci, Swansea, W Glam, Wales.
    Evans, Marc
    Llandough Hosp, Diabet Resource Ctr, Cardiff, S Glam, Wales.
    Linde, Cecilia
    Karolinska Univ Hosp, Heart & Vasc Theme, Stockholm, Sweden.;Karolinska Inst, Stockholm, Sweden.
    Ayoubkhani, Daniel
    HEOR Ltd, Hlth Econ & Outcomes Res, Cardiff, S Glam, Wales.
    Bakhai, Ameet
    Royal Free Hosp, Dept Cardiol, London, England.
    Grandy, Susan
    AstraZeneca, Global Hlth Econ, Gaithersburg, MD USA.
    Palaka, Eirini
    AstraZeneca, Global Hlth Econ, Cambridge, England.
    Qin, Lei
    AstraZeneca, Global Hlth Econ, Gaithersburg, MD USA.
    RECURRENT HYPERKALAEMIA AND ASSOCIATION WITH LENGTH-OF-STAY AND MORTALITY FOLLOWING HOSPITALISATION: REAL-WORLD EVIDENCE FROM UK PATIENTS WITH CKD2018In: Nephrology, Dialysis and Transplantation, ISSN 0931-0509, E-ISSN 1460-2385, Vol. 33, no Supplement: 1, p. 157-157Article in journal (Other academic)
  • 18. Haynes, Richard
    et al.
    Lewis, David
    Emberson, Jonathan
    Reith, Christina
    Agodoa, Lawrence
    Cass, Alan
    Craig, Jonathan C.
    de Zeeuw, Dick
    Feldt-Rasmussen, Bo
    Fellström, Bengt
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Renal Medicine.
    Levin, Adeera
    Wheeler, David C.
    Walker, Rob
    Herrington, William G.
    Baigent, Colin
    Landray, Martin J.
    Effects of Lowering LDL Cholesterol on Progression of Kidney Disease2014In: Journal of the American Society of Nephrology, ISSN 1046-6673, E-ISSN 1533-3450, Vol. 25, no 8, p. 1825-1833Article in journal (Refereed)
    Abstract [en]

    Lowering LDL cholesterol reduces the risk of developing atherosclerotic events in CKD, but the effects of such treatment on progression of kidney disease remain uncertain. Here, 6245 participants with CKD (not on dialysis) were randomly assigned to simvastatin (20 mg) plus ezetimibe (10 mg) daily or matching placebo. The main prespecified renal outcome was ESRD (defined as the initiation of maintenance dialysis or kidney transplantation). During 4.8 years of follow-up, allocation to simvastatin plus ezetimibe resulted in an average LDL cholesterol difference (SEM) of 0.96 (0.02) mmol/L compared with placebo. There was a nonsignificant 3% reduction in the incidence of ESRD (1057 [33.9%] cases with simvastatin plus ezetimibe versus 1084 [34.6%] cases with placebo; rate ratio, 0.97; 95% confidence interval [95% CI], 0.89 to 1.05; P=0.41). Similarly, allocation to simvastatin plus ezetimibe had no significant effect on the prespecified tertiary outcomes of ESRD or death (1477 [47.4%] events with treatment versus 1513 [48.3%] events with placebo; rate ratio, 0.97; 95% CI, 0.90 to 1.04; P=0.34) or ESRD or doubling of baseline creatinine (1189 [38.2%] events with treatment versus 1257 [40.2%] events with placebo; rate ratio, 0.93; 95% CI, 0.86 to 1.01; P=0.09). Exploratory analyses also showed no significant effect on the rate of change in eGFR. Lowering LDL cholesterol by 1 mmol/L did not slow kidney disease progression within 5 years in a wide range of patients with CKD.

  • 19. Herrington, William
    et al.
    Emberson, Jonathan
    Staplin, Natalie
    Blackwell, Lisa
    Fellström, Bengt
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Renal Medicine.
    Walker, Robert
    Levin, Adeera
    Hooi, Lai Seong
    Massy, Ziad A
    Tesar, Vladimir
    Reith, Christina
    Haynes, Richard
    Baigent, Colin
    Landray, Martin J
    The effect of lowering LDL cholesterol on vascular access patency: post hoc analysis of the Study of Heart and Renal Protection2014In: Clinical journal of the American Society of Nephrology : CJASN, ISSN 1555-905X, Vol. 9, no 5, p. 914-919Article in journal (Refereed)
    Abstract [en]

    BACKGROUND AND OBJECTIVES:

    Reducing LDL cholesterol (LDL-C) with statin-based therapy reduces the risk of major atherosclerotic events among patients with CKD, including dialysis patients, but the effect of lowering LDL-C on vascular access patency is unclear.

    DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS:

    The Study of Heart and Renal Protection (SHARP) randomized patients with CKD to 20 mg simvastatin plus 10 mg ezetimibe daily versus matching placebo. This study aimed to explore the effects of treatment on vascular access occlusive events, defined as any access revision procedure, access thrombosis, removal of an old dialysis access, or formation of new permanent dialysis access.

    RESULTS:

    Among 2353 SHARP participants who had functioning vascular access at randomization, allocation to simvastatin plus ezetimibe resulted in a 13% proportional reduction in vascular access occlusive events (355 [29.7%] for simvastatin/ezetimibe versus 388 [33.5%] for placebo; risk ratio [RR], 0.87; 95% confidence interval [95% CI], 0.75 to 1.00; P=0.05). There was no evidence that the effects of treatment differed for any of the separate components of this outcome. To test the hypothesis raised by SHARP, comparable analyses were performed using the AURORA (A Study to Evaluate the Use of Rosuvastatin in Subjects on Regular Hemodialysis: An Assessment of Survival and Cardiovascular Events) trial cohort. AURORA did not provide independent confirmation (vascular access occlusive events: 352 [28.9%] for rosuvastatin versus 337 [27.6%] for placebo; RR, 1.06, 95% CI, 0.91 to 1.23; P=0.44). After combining the two trials, the overall effect of reducing LDL-C with a statin-based regimen on vascular access occlusive events was not statistically significant (707 [29.3%] with any LDL-C-lowering therapy versus 725 [30.5%] with placebo; RR, 0.95, 95% CI, 0.85 to 1.05; P=0.29).

    CONCLUSIONS:

    Exploratory analyses from SHARP suggest that lowering LDL-C with statin-based therapy may improve vascular access patency, but there was no evidence of benefit in AURORA. Taken together, the available evidence suggests that any benefits of lowering LDL-C on vascular access patency are likely to be modest.

  • 20. Holme, Ingar
    et al.
    Fellström, Bengt C.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Renal Medicine.
    Jardine, Alan G.
    Hartmann, Anders
    Holdaas, Hallvard
    Model Comparisons of Competing Risk and Recurrent Events for Graft Failure in Renal Transplant Recipients2013In: American Society of Nephrology. Clinical Journal, ISSN 1555-9041, E-ISSN 1555-905X, Vol. 8, no 2, p. 241-247Article in journal (Refereed)
    Abstract [en]

    Background and objectives Risk factor analysis of long-term graft survival in kidney transplant recipients is usually based on Cox regression models of time to first occurrence of doubling of serum creatinine or graft loss (DSCGL). However, death is a competing cause of failure, and censoring patients who die could bias estimates. We therefore compared estimates of time to first event versus estimates that included death as a competing risk and recurrent events. Design, setting, participants, & measurements A Cox regression analysis of 1997-2002 data from the Assessment of Lescol in Renal Transplant (ALERT) trial population identified an eight-factor risk model, by analyzing time to first occurrence of DSCGL. The same factors were re-analyzed, allowing for death as competing. The probability of survival free of DSCGL was estimated; and two recurrent models (marginal and conditional) were used for time to events. Results Creatinine, systolic BP, and HLA-DR mismatches lost 33%-46% of their strength of association with DSCGL when death was included as a competing risk. Small changes were observed if recurrent events were analyzed in the marginal model. Conclusion The relationship between serum creatinine and DSCGL was attenuated when death was considered as a competing risk; inclusion of recurrent events had little effect. These findings have important implications for analysis and trial design in populations at high mortality risk.

  • 21.
    Linde, Cecilia
    et al.
    Karolinska Univ Hosp, Heart & Vasc Theme, Stockholm, Sweden; Karolinska Inst, Heart & Vasc Theme, Stockholm, Sweden.
    McEwan, Phil
    HEOR Ltd, Hlth Econ & Outcomes Res, Cardiff, S Glam, Wales; Swansea Univ, Sch Human & Hlth Sci, Swansea, W Glam, Wales.
    Bakhai, Ameet
    Royal Free Hosp, Dept Cardiol, London, England.
    Furuland, Hans
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Renal Medicine.
    Evans, Marc
    Llandough Hosp, Diabet Resource Ctr, Cardiff, S Glam, Wales.
    Ayoubkhani, Daniel
    HEOR Ltd, Hlth Econ & Outcomes Res, Cardiff, S Glam, Wales.
    Grandy, Susan
    AstraZeneca, Global Hlth Econ, Gaithersburg, MD USA.
    Palaka, Eirini
    AstraZeneca, Global Hlth Econ, Cambridge, England.
    Qin, Lei
    AstraZeneca, Global Hlth Econ, Gaithersburg, MD USA.
    RELATIONSHIP BETWEEN HYPERKALAEMIA AND DOWN-TITRATION OR DISCONTINUATION OF RENIN-ANGIOTENSIN-ALDOSTERONE SYSTEM INHIBITORS IN UK PATIENTS WITH CKD2018In: Nephrology, Dialysis and Transplantation, ISSN 0931-0509, E-ISSN 1460-2385, Vol. 33, no Supplement: 1, p. 145-145Article in journal (Other academic)
  • 22. McQuarrie, EP
    et al.
    Fellström, Bengt
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Renal Medicine.
    Holdaas, H
    Jardine, AG
    Cardiovascular disease in renal transplant recipients2010In: Journal of Renal Care, ISSN 1755-6678, E-ISSN 1755-6686, Vol. 36, no Suppl 1, p. 136-145Article, review/survey (Refereed)
    Abstract [en]

    Renal transplant recipients have a markedly increased risk of premature cardiovascular disease (CVD) compared with the general population, although considerably lower than that of patients receiving maintenance haemodialysis. CVD in transplant recipients is poorly characterised and differs from the nonrenal population, with a much higher proportion of fatal to nonfatal cardiac events. In addition to traditional ischaemic heart disease risk factors such as age, gender, diabetes and smoking, there are additional factors to consider in this population such as the importance of hypertension, left ventricular hypertrophy and uraemic cardiomyopathy. There are factors specific to transplantation such immunosuppressive therapies and graft dysfunction which contribute to this altered risk profile. However, understanding and treatment is limited by the absence of large randomised intervention trials addressing risk factor modification, with the exception of the ALERT study. The approach to managing these patients should begin early and be multifactorial in nature.

  • 23. Mjoen, Geir
    et al.
    Zannad, Faiez
    Jardine, Alan
    Schmieder, Roland
    Fellström, Bengt
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Renal Medicine.
    Holdaas, Hallvard
    Pulse Pressure Superior to Systolic or Diastolic Blood Pressure in Predicting Mortality in Hemodialysis Patients2014In: Nephrology, Dialysis and Transplantation, ISSN 0931-0509, E-ISSN 1460-2385, Vol. 29, p. 79-79Article in journal (Other academic)
  • 24. Naess, Hege
    et al.
    Fellström, Bengt
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Renal Medicine.
    Jardine, Alan G.
    Schmieder, Roland E.
    Zannad, Faiez
    Holdaas, Hallvard
    Mjoen, Geir
    Risk Factors for Cardiovascular Events and All-Cause Mortality in Diabetic Hemodialysis Patients2014In: Nephrology, Dialysis and Transplantation, ISSN 0931-0509, E-ISSN 1460-2385, Vol. 29, p. 487-487Article in journal (Other academic)
  • 25.
    Naess, Hege
    et al.
    Ringerike Hosp, Med, Honefoss, Norway..
    Zannad, Faiez
    Nancy Univ, Dept Cardiol, Nancy, France..
    Jardine, Alan G.
    Univ Glasgow, Renal Res Grou, Glasgow, Lanark, Scotland..
    Schmieder, Roland E.
    Univ Hosp Erlangen, Dept Hypertens & Nephrol, Erlangen, Germany..
    Fellström, Bengt
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Renal Medicine.
    Holdaas, Hallvard
    Oslo Univ Hosp, Dept Transplant Med, Oslo, Norway..
    Mjoen, Geir
    Oslo Univ Hosp, Dept Nephrol, Oslo, Norway..
    NON-TRADITIONAL CARDIOVASCULAR RISK FACTORS PREDOMINATE IN HEMODIALYSIS PATIENTS WITH PRE-EXISTIN CARDIOVASCULAR DISEASE2015In: Nephrology, Dialysis and Transplantation, ISSN 0931-0509, E-ISSN 1460-2385, Vol. 30Article in journal (Other academic)
  • 26. Nilssen, Camilla
    et al.
    Zannad, Faiez
    Jardine, Alan
    Schmieder, Roland
    Fellström, Bengt
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Renal Medicine.
    Holdaas, Hallvard
    Mjoen, Geir
    Risk Factors for Stroke in Hemodialysis Patients2014In: Nephrology, Dialysis and Transplantation, ISSN 0931-0509, E-ISSN 1460-2385, Vol. 29, p. 484-484Article in journal (Other academic)
  • 27. Perl, Jeffrey
    et al.
    Zhang, Jinyao
    Gillespie, Brenda
    Wikström, Björn
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Renal Medicine.
    Fort, Joan
    Hasegawa, Takeshi
    Fuller, Douglas S.
    Pisoni, Ronald L.
    Robinson, Bruce M.
    Tentori, Francesca
    Reduced survival and quality of life following return to dialysis after transplant failure: the Dialysis Outcomes and Practice Patterns Study2012In: Nephrology, Dialysis and Transplantation, ISSN 0931-0509, E-ISSN 1460-2385, Vol. 27, no 12, p. 4464-4472Article in journal (Refereed)
    Abstract [en]

    Although dialysis after kidney transplant failure (TF) is common, the outcomes of these patients remain unclear. We compared outcomes of TF patients with transplant-nave (TN) patients wait-listed for kidney transplantation. We used data from the Dialysis Outcomes and Practice Patterns Study (DOPPS), including laboratory markers and health-related quality of life (HR-QOL). Mortality and hospitalization of participants with one prior TF versus TN patients were compared using the Cox regression analysis. HR-QOL physical and mental component summary scores (PCS and MCS) were examined using linear mixed models, and clinical practices were compared using logistic regression. Compared with TN patients (n 2806), TF patients (n 1856) were younger (48 versus 51 years, P 0.003), less likely to be diabetic (18 versus 27, P 0.0001) and to use a permanent surgical vascular access {adjusted odds ratio (AOR): 0.85 [95 confidence interval (CI): 0.701.03], P 0.10}, particularly within the first 3 months after TF [AOR 0.45 (0.320.62), P 0.0001]. TF patients also had lower PCS [mean difference 2.56 (3.36, 1.75), P 0.0001] but not MCS [0.42 (1.34, 0.50), P 0.37]. All-cause mortality [adjusted hazard ratio (AHR): 1.32 (95 CI: 1.051.66), P 0.02], especially infection-related [AHR 2.45 (95 CI: 1.364.41), P 0.01], was higher among TF patients. TF patients have reduced QOL and higher mortality, particularly due to infections, than TN patients. Interventions to optimize care before and after starting dialysis remain to be identified and applied in clinical practice.

  • 28. Pihlstrom, H.
    et al.
    Dahle, D.
    Mjoen, G.
    Pilz, S.
    Maerz, W.
    Holme, I.
    Fellström, Bengt
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Renal Medicine.
    Jardine, A.
    Holdaas, H.
    Hyperparathyroidism in Stable Renal Transplant Recipients Is Associated With All-Cause Mortality and Renal Graft Loss2014In: American Journal of Transplantation, ISSN 1600-6135, E-ISSN 1600-6143, Vol. 14, p. 126-126Article in journal (Other academic)
  • 29. Pihlstrom, H.
    et al.
    Dahle, D.
    Mjoen, G.
    Pilz, S.
    Maerz, W.
    Holme, I.
    Fellström, Bengt
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Renal Medicine.
    Jardine, A.
    Holdaas, H.
    Hyperparathyroidism in Stable Renal Transplant Recipients Is Associated With All-Cause Mortality and Renal Graft Loss2014In: Transplantation, ISSN 0041-1337, E-ISSN 1534-6080, Vol. 98, p. 126-126Article in journal (Other academic)
  • 30. Pihlstrom, H.
    et al.
    Mjoen, G.
    Dahle, D.
    Pilz, S.
    Midtvedt, K.
    Maerz, W.
    Abedini, S.
    Holme, I.
    Fellström, Bengt
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Renal Medicine.
    Holdaas, H.
    Symmetric Dimethylarginine as Predictor of Graft Loss and All-Cause Mortality in Renal Transplant Recipients2014In: Transplantation, ISSN 0041-1337, E-ISSN 1534-6080, Vol. 98, p. 102-102Article in journal (Other academic)
  • 31. Pihlstrom, H.
    et al.
    Mjoen, G.
    Dahle, D.
    Pilz, S.
    Midtvedt, K.
    Maerz, W.
    Abedini, S.
    Holme, I.
    Fellström, Bengt
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Renal Medicine.
    Holdaas, H.
    Symmetric Dimethylarginine as Predictor of Graft Loss and All-Cause Mortality in Renal Transplant Recipients2014In: American Journal of Transplantation, ISSN 1600-6135, E-ISSN 1600-6143, Vol. 14, p. 102-102Article in journal (Other academic)
  • 32. Pihlstrom, Hege
    et al.
    Dahle, Dag Olav
    Mjoen, Geir
    Pilz, Stefan
    Maerz, Winfried
    Abedini, Sadollah
    Holme, Ingar
    Fellström, Bengt
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Renal Medicine.
    Jardine, Alan G.
    Holdaas, Hallvard
    Increased Risk of All-Cause Mortality and Renal Graft Loss in Stable Renal Transplant Recipients With Hyperparathyroidism2015In: Transplantation, ISSN 0041-1337, E-ISSN 1534-6080, Vol. 99, no 2, p. 351-359Article in journal (Refereed)
    Abstract [en]

    Background. Hyperparathyroidism is reported in 10% to 66% of renal transplant recipients (RTR). The influence of persisting hyperparathyroidism on long-term clinical outcomes in RTR has not been examined in a large prospective study. Methods. We investigated the association between baseline parathyroid hormone (PTH) levels and major cardiovascular events, renal graft loss, and all-cause mortality by Cox Proportional Hazard survival analyses in 1840 stable RTR derived from the Assessment of LEscol in Renal Transplantation trial. Patients were recruited in a mean of 5.1 years after transplantation, and follow-up time was 6 to 7 years. Results. Significant associations between PTH and all 3 outcomes were found in univariate analyses. When adjusting for a range of plausible confounders, including measures of renal function and serum mineral levels, PTH remained significantly associated with all-cause mortality (4% increased risk per 10 units; P = 0.004), and with graft loss (6% increased risk per 10 units; P < 0.001), but not with major cardiovascular events. Parathyroid hormone above the upper limit of normal (65 pg/mL) indicated a 46% (P = 0.006) higher risk of death and an 85% higher risk of graft loss (P < 0.001) compared with low/normal values. Conclusions. Hyperparathyroidismis an independent, potentially remediable, risk factor for renal graft loss and all-cause mortality in RTR.

  • 33. Pihlstrom, Hege
    et al.
    Mjoen, Geir
    Dahle, Dag Olav
    Pilz, Stefan
    Midtvedt, Karsten
    Marz, Winfried
    Abedini, Sadollah
    Holme, Ingar
    Fellström, Bengt
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Renal Medicine.
    Jardine, Alan
    Holdaas, Hallvard
    Symmetric Dimethylarginine as Predictor of Graft loss and All-Cause Mortality in Renal Transplant Recipients2014In: Transplantation, ISSN 0041-1337, E-ISSN 1534-6080, Vol. 98, no 11, p. 1219-1225Article in journal (Refereed)
    Abstract [en]

    BACKGROUND: Elevated symmetric dimethylarginine (SDMA) has been shown to predict cardiovascular events and all cause mortality in diverse populations. The potential role of SDMA as a risk marker in renal transplant recipients (RTR) has not been investigated. METHODS: We analyzed SDMA in the placebo arm of the Assessment of Lescol in Renal Transplantation study, a randomized controlled trial of fluvastatin in RTR. Mean follow-up was 5.1 years. Patients were grouped into quartiles based on SDMA levels at study inclusion. Relationships between SDMA and traditional risk factors for graft function and all-cause mortality were analyzed in 925 RTR using univariate and multivariate survival analyses. RESULTS: In univariate analysis, SDMA was significantly associated with renal graft loss, all-cause death, and major cardiovascular events. After adjustment for established risk factors including estimated glomerular filtration rate, an elevated SDMA-level (4th quartile, >1.38 mumol/L) was associated with renal graft loss; hazard ratio (HR), 5.51; 95% confidence interval (CI), 1.95-15.57; P=0.001, compared to the 1st quartile. Similarly, SDMA in the 4th quartile was independently associated with all-cause mortality (HR, 4.56; 95% CI, 2.15-9.71; P<0.001), and there was a strong borderline significant trend for an association with cardiovascular mortality (HR, 2.86; 95% CI, 0.99-8.21; P=0.051). CONCLUSION: In stable RTR, an elevated SDMA level is independently associated with increased risk of all-cause mortality and renal graft loss.

  • 34. Pihlstrom, Hege
    et al.
    Mjoen, Geir
    Maerz, Winfried
    Dahle, Dag Olav
    Abedini, Sadollah
    Holme, Ingar
    Fellström, Bengt
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Renal Medicine.
    Jardine, Alan
    Pilz, Stefan
    Holdaaas, Hallvard
    Neopterin is associated with cardiovascular events and all-cause mortality in renal transplant patients2014In: Clinical Transplantation, ISSN 0902-0063, E-ISSN 1399-0012, Vol. 28, no 1, p. 111-119Article in journal (Refereed)
    Abstract [en]

    BackgroundInflammatory markers show significant associations with cardiovascular events and all-cause mortality after kidney transplantation. Neopterin, reflecting interferon--release, may better reflect the proinflammatory state of recipients than less specific markers. MethodsKidney transplant recipients in the Assessment of LEscol in Renal Transplant (ALERT) trial were examined and investigated for an association between serum neopterin and subsequent clinical events: graft loss, major cardiovascular events (MACE) and all-cause mortality. ResultsAfter adjustment for established and emerging risk factors neopterin expressed as neopterin-to-creatinine ratio was significantly associated with MACE (p=0.009) and all-cause mortality (p=0.002). Endpoints were more frequent with increasing quartiles of neopterin-to-creatinine ratio. The incidence rates of MACE and all-cause mortality were significantly increased in the upper quartiles compared with the first. ConclusionsThis long-term prospective analysis in stable kidney allograft recipients suggests that neopterin is associated with long-term risk of cardiovascular events and all-cause mortality, but not renal outcomes.

  • 35.
    Pihlstrøm, H. K.
    et al.
    Natl Hosp Norway, Oslo Univ Hosp, Nephrol Sect, Dept Transplantat Med,Div Surg Inflammatory Med &, Oslo, Norway..
    Mjøen, G.
    Natl Hosp Norway, Oslo Univ Hosp, Nephrol Sect, Dept Transplantat Med,Div Surg Inflammatory Med &, Oslo, Norway..
    Mucha, S.
    Christian Albrechts Univ Kiel, Univ Hosp Schleswig Holstein, Inst Clin Mol Biol, Kiel, Germany..
    Haraldsen, G.
    Univ Oslo, Inst Clin Med, KG Jebsen Inflammat Res Ctr, Oslo, Norway.;Oslo Univ Hosp, Dept Pathol, Oslo, Norway..
    Franke, A.
    Christian Albrechts Univ Kiel, Univ Hosp Schleswig Holstein, Inst Clin Mol Biol, Kiel, Germany..
    Jardine, A.
    Glasgow Cardiovasc Res Ctr, British Heart Fdn, Glasgow, Lanark, Scotland..
    Fellström, Bengt
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Renal Medicine.
    Holdaas, H.
    Natl Hosp Norway, Oslo Univ Hosp, Nephrol Sect, Dept Transplantat Med,Div Surg Inflammatory Med &, Oslo, Norway..
    Melum, E.
    Univ Oslo, Inst Clin Med, KG Jebsen Inflammat Res Ctr, Oslo, Norway.;Natl Hosp Norway, Oslo Univ Hosp, Div Surg Inflammatory Med & Transplantat, Norwegian PSC Res Ctr, Oslo, Norway.;Natl Hosp Norway, Oslo Univ Hosp, Div Surg Inflammatory Med & Transplantat, Internal Med Res Inst, Oslo, Norway.;Natl Hosp Norway, Oslo Univ Hosp, Div Surg Inflammatory Med & Transplantat, Sect Gastroenterol,Dept Transplantat Med, Oslo, Norway..
    Single Nucleotide Polymorphisms and Long-Term Clinical Outcome in Renal Transplant Patients: A Validation Study2017In: American Journal of Transplantation, ISSN 1600-6135, E-ISSN 1600-6143, Vol. 17, no 2, p. 528-533Article in journal (Refereed)
    Abstract [en]

    Genome-wide association studies (GWAS) are designed to investigate single nucleotide polymor-phisms (SNPs) and the association with a clinical phenotype. A previous GWAS performed in 300 renal transplant recipients identified two SNPs (rs3811321 and rs6565887) associated with serum creatinine and clinical outcome. We sought to validate these findings. Genotyping of the two SNPs was performed using Taqman assays in 1638 Caucasians participating in the Assessment of LEscol in Renal Transplant (ALERT) study. Primary endpoint was death-censored graft loss, and secondary endpoint was all-cause mortality. Applying Cox regression, no crude association to graft loss was found for rs3811321 on chromosome 14 (hazard ratio [HR] 0.87, 95% CI 0.59-1.29, p = 0.50) or rs6565887 on chromosome 18 (HR 0.88, CI 0.62-1.25, p = 0.48). Multivariable adjustments did not change results, nor did evaluation of the number of risk alleles formed by the two SNPs. No association with mortality was detected. In conclusion, an impact of two SNPs on chromosomes 14 and 18 on death-censored graft survival or all-cause mortality was not confirmed. Our results emphasize the importance of validating findings from high-throughput genetics studies and call for large collaborative research initiatives in the field of transplantation outcomes.

  • 36. Robinson, Bm
    et al.
    Wang, Mia
    Bieber, Brian
    Fluck, Richard
    Kerr, Peter G.
    Wikström, Björn
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Renal Medicine.
    Krishnan, Mahesh
    Nissenson, Allen
    Pisoni, Ronald L.
    International variation in influenza vaccination practices and coverage rates among hemodialysis patients: an opportunity to improve care2012In: Nephrology, Dialysis and Transplantation, ISSN 0931-0509, E-ISSN 1460-2385, Vol. 27, p. 397-397Article in journal (Other academic)
  • 37. Sandqvist, A. M.
    et al.
    Henrohn, Dan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Schneede, J.
    Egerod, H. C.
    Hedeland, M.
    Bondesson, U. G.
    Wikstrom, Björn G.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Renal Medicine.
    Comparison of vardenafil and adenosine for vasoreactivity testing in patients with pulmonary hypertension2012In: European Heart Journal, ISSN 0195-668X, E-ISSN 1522-9645, Vol. 33, no Suppl 1, p. 1013-1013Article in journal (Other academic)
  • 38. Sandqvist, A. M.
    et al.
    Henrohn, Dan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Schneede, J.
    Hedeland, Mikael
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Analytical Pharmaceutical Chemistry.
    Egerod, H. C.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Bondesson, Ulf G.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Analytical Pharmaceutical Chemistry.
    Wikström, Björn G.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Renal Medicine.
    High inter-individual variability of vardenafil pharmacokinetics in patients with pulmonary hypertension2013In: European Journal of Clinical Pharmacology, ISSN 0031-6970, E-ISSN 1432-1041, Vol. 69, no 2, p. 197-207Article in journal (Refereed)
    Abstract [en]

    To evaluate the pharmacokinetic parameters of a single oral dose of vardenafil in patients with pulmonary hypertension (PH). Sixteen patients with PH received vardenafil in single oral doses (20, 10 or 5 mg), and repeated blood sampling for up to 9 h was performed. Vardenafil plasma concentration was determined using liquid chromatography tandem mass spectrometry. Pharmacokinetic parameters were calculated using model-independent analysis. The plasma vardenafil concentration increased rapidly and exhibited a median time to maximum plasma concentration (t(max)) of 1 h and a mean elimination half-life (t(1/2)) of 3.4 h. The geometric mean and standard deviation of (1) the peak plasma concentration (C-max) was 21.4 +/- 1.7 mu g/L, (2) the normalized C-max (C-max,C- norm) 79.1 +/- 1.6 g/L, (3) the area under the time-concentration curve (AUC) 71.5 +/- 1.6 mu g center dot h/L and (4) the normalized AUC (AUC(norm)) 261.6 A +/- 1.7 g center dot h/L. Patients co-medicated with bosentan reached t(max) later and had a 90% reduction of C-max, C-max,C- norm, AUC and AUC(norm). The pharmacokinetic profile of vardenafil overall revealed considerable inter-individual variability in patients with PH. Co-medication with bosentan resulted in a pharmacokinetic drug interaction, leading to significantly decreased plasma concentrations of vardenafil. Therapeutic drug monitoring for individual dose optimization may be warranted.

  • 39. Schjelderup, Patrick
    et al.
    Dahle, Dag Olav
    Holdaas, Hallvard
    Mjoen, Geir
    Nordby, Gudrun
    Abedini, Sadollah
    Jardine, Alan
    Fellström, Bengt
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Renal Medicine.
    Svensson, My
    Anemia is a predictor of graft loss but not cardiovascular events and all-cause mortality in renal transplant recipients: follow-up data from the ALERT study2013In: Clinical Transplantation, ISSN 0902-0063, E-ISSN 1399-0012, Vol. 27, no 6, p. E636-E643Article in journal (Refereed)
    Abstract [en]

    BackgroundIt is well established that post-transplantation anemia (PTA) in renal transplant recipients (RTRs) is associated with reduced graft survival. However, there is an uncertainty of the effect of PTA on cardiovascular events and all-cause mortality. We examined prospectively in a large cohort of erythropoietin-naive patients the effects of PTA on cardiovascular morbidity, patient survival, and graft survival. MethodsA prospective cohort study of RTRs (n=2102) included in the ALERT study. Cox regression models were used to evaluate the impact of PTA on study endpoints: first occurrence of a major adverse cardiac event, all-cause death, and the incidence of death-censored graft loss. Mean follow-up was 6.7yr. All endpoints were adjudicated by an independent endpoint committee. ResultsTwenty-nine percent of women and 30% of men were anemic. Hemoglobin levels were not associated with any effect on cardiovascular morbidity and mortality (HR 0.97 [0.90-1.05] per g/dL, p=0.48) or all-cause death (HR 0.96 [0.90-1.03] per g/dL, p=0.24) after extensive multivariate adjustments for clinical and demographic factors. Hemoglobin levels were negatively associated with graft loss (HR 0.86 [0.80-0.92] per g/dL, p<0.001). ConclusionsPTA was not associated with an increased incidence of cardiovascular morbidity and mortality or all-cause mortality.

  • 40.
    Schlackow, Iryna
    et al.
    Univ Oxford, Nuffield Dept Populat Hlth, Hlth Econ Res Ctr, Oxford, England..
    Kent, Seamus
    Univ Oxford, Nuffield Dept Populat Hlth, Hlth Econ Res Ctr, Oxford, England..
    Herrington, William
    Univ Oxford, Nuffield Dept Populat Hlth, Clin Trial Serv Unit, Oxford, England.;Univ Oxford, Nuffield Dept Populat Hlth, Epidemiol Studies Unit, Oxford, England..
    Emberson, Jonathan
    Univ Oxford, Nuffield Dept Populat Hlth, Clin Trial Serv Unit, Oxford, England.;Univ Oxford, Nuffield Dept Populat Hlth, Epidemiol Studies Unit, Oxford, England..
    Haynes, Richard
    Univ Oxford, Nuffield Dept Populat Hlth, Clin Trial Serv Unit, Oxford, England.;Univ Oxford, Nuffield Dept Populat Hlth, Epidemiol Studies Unit, Oxford, England..
    Reith, Christina
    Univ Oxford, Nuffield Dept Populat Hlth, Clin Trial Serv Unit, Oxford, England.;Univ Oxford, Nuffield Dept Populat Hlth, Epidemiol Studies Unit, Oxford, England..
    Wanner, Christoph
    Univ Hosp Wurzburg, Dept Med, Div Nephrol, Wurzburg, Germany..
    Fellström, Bengt
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Renal Medicine. Univ Hosp, Uppsala, Sweden..
    Gray, Alastair
    Univ Oxford, Nuffield Dept Populat Hlth, Hlth Econ Res Ctr, Oxford, England..
    Landray, Martin J.
    Univ Oxford, Nuffield Dept Populat Hlth, Clin Trial Serv Unit, Oxford, England.;Univ Oxford, Nuffield Dept Populat Hlth, Epidemiol Studies Unit, Oxford, England..
    Baigent, Colin
    Univ Oxford, Nuffield Dept Populat Hlth, Clin Trial Serv Unit, Oxford, England.;Univ Oxford, Nuffield Dept Populat Hlth, Epidemiol Studies Unit, Oxford, England.;Univ Oxford, Nuffield Dept Populat Hlth, MRC, Populat Hlth Res Unit, Oxford, England..
    Mihaylova, Borislava
    Univ Oxford, Nuffield Dept Populat Hlth, Hlth Econ Res Ctr, Oxford, England..
    A policy model of cardiovascular disease in moderate-to-advanced chronic kidney disease2017In: Heart, ISSN 1355-6037, E-ISSN 1468-201X, Vol. 103, no 23, p. 1880-1890Article in journal (Refereed)
    Abstract [en]

    Objective: To present a long-term policy model of cardiovascular disease (CVD) in moderate-to-advanced chronic kidney disease (CKD).

    Methods: A Markov model with transitions between CKD stages (3B, 4, 5, on dialysis, with kidney transplant) and cardiovascular events (major atherosclerotic events, haemorrhagic stroke, vascular death) was developed with individualised CKD and CVD risks estimated using the 5 years' follow-up data of the 9270 patients with moderate-to-severe CKD in the Study of Heart and Renal Protection (SHARP) and multivariate parametric survival analysis. The model was assessed in three further CKD cohorts and compared with currently used risk scores.

    Results: Higher age, previous cardiovascular events and advanced CKD were the main contributors to increased individual disease risks. CKD and CVD risks predicted by the state-transition model corresponded well to risks observed in SHARP and external cohorts. The model's predictions of vascular risk and progression to end-stage renal disease were better than, or comparable to, those produced by other risk scores. As an illustration, at age 60-69 years, projected survival for SHARP participants in CKD stage 3B was 13.5 years (10.6 quality-adjusted life years (QALYs)) in men and 14.8 years (10.7 QALYs) in women. Corresponding projections for participants on dialysis were 7.5 (5.6 QALYs) and 7.8 years (5.4 QALYs). A non-fatal major atherosclerotic event reduced life expectancy by about 2 years in stage 3B and by 1 year in dialysis.

    Conclusions: The SHARP CKD-CVD model is a novel resource for evaluating health outcomes and cost-effectiveness of interventions in CKD.

  • 41. Schneider, Andreas
    et al.
    Jardine, Alan G.
    Schneider, Markus P.
    Holdaas, Hallvard
    Holme, Ingar
    Fellström, Bengt C.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Renal Medicine.
    Zannad, Faiez
    Schmieder, Roland E.
    Determinants of Cardiovascular Risk in Haemodialysis Patients: Post hoc Analyses of the AURORA Study2013In: American Journal of Nephrology, ISSN 0250-8095, E-ISSN 1421-9670, Vol. 37, no 2, p. 144-151Article in journal (Refereed)
    Abstract [en]

    Background: Haemodialysis patients are at high risk for cardiovascular (CV) events. The aim of the current study was to characterise the role of traditional and uraemia-specific CV risk factors in this patient population. Methods: A post hoc analysis of the AURORA trial which enrolled 2,776 haemodialysis patients from 280 centres and had a mean follow-up period of 3.2 years. Determinants of CV endpoints (time to major cardiovascular event (MACE), cardiac event, CV death) were identified by univariate Cox regression analysis. Subsequently, independent determinants were identified by multivariate regression analysis. Results: For the primary endpoint MACE (myocardial infarction, stroke and cardiac death), multivariate analysis revealed that independent determinants were: age (hazard ratio (HR) 1.03 per year), serum phosphate level (HR 1.50 per mmol/l), albumin level (HR 0.94 per gip, years on haemodialysis (HR 1.03 per year), diabetes mellitus (HR 1.38), preexisting coronary heart disease (HR 1.54) and C-reactive protein (CRP) level (HR 1.14 per mg/l). However, conventional risk factors such as smoking, dyslipidaemia, systolic and diastolic blood pressure and pulse pressure had no significant effect. Conclusions: Although we identify CRP, low albumin, and high phosphorus as risk factors for MACE, lowering CRP did not influence MACE outcomes in our trial. Caution is therefore warranted in implying risk factors being causal in end-stage renal disease.

  • 42. Solbu, Marit D
    et al.
    Mjøen, Geir
    Mark, Patrick B
    Holdaas, Hallvard
    Fellström, Bengt
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Renal Medicine.
    Schmieder, Roland E
    Zannad, Faiez
    Herrington, William G
    Jardine, Alan G
    Predictors of atherosclerotic events in patients on haemodialysis: post hoc analyses from the AURORA study.2018In: Nephrology, Dialysis and Transplantation, ISSN 0931-0509, E-ISSN 1460-2385, Vol. 33, no 1, p. 102-112Article in journal (Refereed)
    Abstract [en]

    Background: Patients on haemodialysis (HD) are at high risk for cardiovascular events, but heart failure and sudden death are more common than atherosclerotic events. The A Study to Evaluate the Use of Rosuvastatinin in Subjects on Regular Hemodialysis: An Assessment of Survival and Cardiovascular Events (AURORA) trial was designed to assess the effect of rosuvastatin on myocardial infarction and death from any cardiac cause in 2773 HD patients. We studied predictors of the atherosclerotic cardiovascular events in AURORA.

    Methods: We readjudicated all deaths and presumed myocardial infarctions according to the criteria used in the Study of Heart and Renal Protection (SHARP); these were specifically developed to separate atherosclerotic from non-atherosclerotic cardiovascular events. The readjudicated atherosclerotic end point included the first event of the following: non-fatal myocardial infarction, fatal coronary heart disease, non-fatal and fatal non-haemorrhagic stroke, coronary revascularization procedures and death from ischaemic limb disease. Stepwise Cox regression analysis was used to identify the predictors of such events.

    Results: During a mean follow-up of 3.2 years, 506 patients experienced the new composite atherosclerotic outcome. Age, male sex, prevalent diabetes, prior cardiovascular disease, weekly dialysis duration, baseline albumin [hazard ratio (HR) 0.96; 95% confidence interval (CI) 0.94-0.99 per g/L increase], high-sensitivity C-reactive protein (HR 1.13; 95% CI 1.04-1.22 per mg/L increase) and oxidized low-density lipoprotein (LDL) cholesterol (HR 1.09; 95% CI 1.03-1.17 per 10 U/L increase) were selected as significant predictors in the model. Neither LDL cholesterol nor allocation to placebo/rosuvastatin therapy predicted the outcome.

    Conclusions: Even with the use of strict criteria for end point definition, non-traditional risk factors, but not lipid disturbances, predicted atherosclerotic events in HD patients.

  • 43.
    Soveri, Inga
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Renal Medicine.
    Back, Sten-Erik
    In Reply to 'Measuring GFR Using the Plasma Clearance of Tc-99m-DTPA'2015In: American Journal of Kidney Diseases, ISSN 0272-6386, E-ISSN 1523-6838, Vol. 65, no 5, p. 806-807Article in journal (Refereed)
  • 44.
    Soveri, Inga
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Renal Medicine.
    Berg, Ulla B
    Björk, Jonas
    Elinder, Carl-Gustaf
    Grubb, Anders
    Mejare, Ingegerd
    Sterner, Gunnar
    Bäck, Sten-Erik
    Measuring GFR: A Systematic Review2014In: American Journal of Kidney Diseases, ISSN 0272-6386, E-ISSN 1523-6838, Vol. 64, no 3, p. 411-424Article, review/survey (Refereed)
    Abstract [en]

    Background

    No comprehensive systematic review of the accuracy of glomerular filtration rate (GFR) measurement methods using renal inulin clearance as reference has been published.

    Study Design

    Systematic review with meta-analysis of cross-sectional diagnostic studies.

    Setting & Population

    Published original studies and systematic reviews in any population.

    Selection Criteria for Studies

    Index and reference measurements conducted within 48 hours; at least 15 participants studied; GFR markers measured in plasma or urine; plasma clearance calculation algorithm verified in another study; tubular secretion of creatinine had not been blocked by medicines.

    Index Tests

    Endogenous creatinine clearance; renal or plasma clearance of chromium 51−labeled ethylenediaminetetraacetic acid (51Cr-EDTA), diethylenetriaminepentaacetic acid (DTPA), iohexol, and iothalamate; and plasma clearance of inulin.

    Reference Test

    Renal inulin clearance measured under continuous inulin infusion and urine collection.

    Results

    Mean bias < 10%, median bias < 5%, the proportion of errors in the index measurements that did not exceed 30% (P30) ≥ 80%, and P10 ≥ 50% were set as requirements for sufficient accuracy. Based on the GRADE (Grading of Recommendations Assessment, Development and Evaluation) approach, the quality of evidence across studies was rated for each index method. Renal clearance of iothalamate measured GFR with sufficient accuracy (strong evidence). Renal and plasma clearance of 51Cr-EDTA and plasma clearance of iohexol were sufficiently accurate to measure GFR (moderately strong evidence). Renal clearance of DTPA, renal clearance of iohexol, and plasma clearance of inulin had sufficient accuracy (limited evidence). Endogenous creatinine clearance was an inaccurate method (strong evidence), as was plasma clearance of DTPA (limited evidence). The evidence to determine the accuracy of plasma iothalamate clearance was insufficient. With the exception of plasma clearance of inulin, only renal clearance methods had P30 > 90%.

    Limitations

    The included studies were few and most were old and small, which may limit generalizability. Requirements for sufficient accuracy may depend on clinical setting.

    Conclusions

    At least moderately strong evidence suggests that renal clearance of 51Cr-EDTA or iothalamate and plasma clearance of 51Cr-EDTA or iohexol are sufficiently accurate methods to measure GFR.

  • 45.
    Soveri, Inga
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Renal Medicine.
    Holme, Ingar
    Holdaas, Hallvard
    Budde, Klemens
    Jardine, Alan G
    Fellström, Bengt
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Renal Medicine.
    A Cardiovascular Risk Calculator for Renal Transplant Recipients2012In: Transplantation, ISSN 0041-1337, E-ISSN 1534-6080, Vol. 94, no 1, p. 57-62Article in journal (Refereed)
    Abstract [en]

    BACKGROUND:

    Renal transplant recipients (RTRs) have increased cardiovascular disease (CVD) risk. Standard CVD risk calculators are poorly predictive in RTRs; we therefore aimed to develop and validate an equation for CVD risk prediction in this population.

    METHODS:

    We used data from the Assessment of Lescol in Renal Transplantation trial, which are randomly divided into an assessment sample and a test sample (67% and 33%, respectively, of the total population). For variable selection in the assessment sample, backward stepwise Cox regression was used. Using the regression coefficients and centralized prognostic index, risk was calculated for individual patients. The equation was then validated for calibration and discrimination using the test sample.

    RESULTS:

    Major adverse cardiac events could be predicted using a seven-variable model including age, previous coronary heart disease, diabetes, low-density lipoprotein, creatinine, number of transplants, and smoking. The calibration of the model was good in the test sample with a Hosmer-Lemeshow chi-square value of 11.47 and a P value of 0.245. The areas under the receiver operating characteristic curve were 0.738 in the assessment sample and 0.740 in the test sample. Total mortality could be predicted using a six-variable model including age, coronary heart disease, diabetes, creatinine, total time on renal replacement therapy, and smoking. The calibration of the model was acceptable in the test sample with a Hosmer-Lemeshow chi-square value of 13.08 and a P value of 0.109. The areas under the receiver operating characteristic curve were 0.734 in the assessment sample and 0.720 in the test sample.

    CONCLUSIONS:

    Using the Assessment of Lescol in Renal Transplantation trial population, a formula for 7-year CVD and mortality risk calculation for prevalent RTRs has been developed.

  • 46.
    Soveri, Inga
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Renal Medicine.
    Kals, Jaak
    Low dialysate potassium and central arterial pressure waveform2015In: Upsala Journal of Medical Sciences, ISSN 0300-9734, E-ISSN 2000-1967, Vol. 120, no 3, p. 207-212Article in journal (Refereed)
    Abstract [en]

    Background. Cardiovascular mortality is high in hemodialysis (HD) patients. Early arterial pressure wave reflections predict mortality in HD patients, and HD acutely improves the central pressure waveform. Potassium (K) plays a crucial role in cardiac electrophysiology, and patients with end-stage kidney disease depend on HD for neutral K balance. We aimed to study the impact of dialysate K concentrations on central arterial pressure waveform. Methods. Thirty-three chronic HD patients were studied before and after a HD session, and the prescribed dialysate K concentration was recorded. In a subset of 23 patients without arrhythmias, pulse wave analysis was performed on radial arteries. Nine patients had dialysate K set to 1 mmol/L (group 1), and 14 patients had K set to 2 or 3 mmol/L (group 2). Augmentation index (AIx), defined as difference between the second and first systolic peak divided by central pulse pressure, was used as a measure of arterial stiffness. Results. HD reduced the AIx in group 1 only (p = 0.0005). Likewise, central systolic pressure was reduced in group 1 only (p = 0.006). The relative reduction of AIx post-HD was significantly higher in group 1 compared with group 2 (p < 0.0001). The association between low dialysate K and AIx reduction remained statistically significant after adjustment for variables including the change in central and peripheral systolic pressure and mean arterial pressure. Conclusion. Low dialysate K is strongly and independently associated with the acute improvement of AIx.

  • 47.
    Soveri, Inga
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Renal Medicine.
    Snyder, Jon
    Holdaas, Hallvard
    Holme, Ingar
    Jardine, Alan G.
    L'Italien, Gilbert J.
    Fellström, Bengt
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Renal Medicine.
    The External Validation of the Cardiovascular Risk Equation for Renal Transplant Recipients: Applications to BENEFIT and BENEFIT-EXT Trials2013In: Transplantation, ISSN 0041-1337, E-ISSN 1534-6080, Vol. 95, no 1, p. 142-147Article in journal (Refereed)
    Abstract [en]

    Background. Renal transplant recipients (RTRs) have increased cardiovascular disease risk. Recently, major adverse cardiac event (MACE) and mortality risk calculators for prevalent RTRs were developed. We aimed to externally validate these risk equations in an international transplant database and subsequently demonstrate application to 2 clinical trials: Belatacept Evaluation of Nephroprotection and Efficacy as First-line Immunosuppression Trial (BENEFIT) and Belatacept Evaluation of Nephroprotection and Efficacy as First-line Immunosuppression Trial-EXTended criteria donors (BENEFIT-EXT). Methods. The 7-year risk calculators were developed using data from the ALERT trial and validated for discrimination and calibration in the Patient Outcomes in Renal Transplantation (PORT) study cohort. The outlier laboratory readings were trimmed to the 99th percentile observed in the PORT database. Diabetes mellitus, LDL-cholesterol, and serum creatinine values 3 years posttransplantation were used when applying the calculators to BENEFIT and BENEFIT-EXT trial treatment arms. Results. MACE could be predicted using a 7-variable model. The area under the ROC curve was 0.738 in ALERT and 0.740 in PORT, indicating preserved discrimination. In PORT, the calibration of the model indicated significant underestimation of risk in decile 5 and 9. Total mortality could be predicted using a 6-variable model. The area under the ROC curve was 0.734 in ALERT and 0.721 in PORT, indicating preserved discrimination. In PORT, the calibration of the model indicated significant underestimation of risk in decile 7 and significant overestimation in the highest risk decile. In BENEFIT and BENEFIT-EXT trial, the calculator estimated that belatacept use may result in reduction in MACE (>20%) and mortality (similar to 18%-30%). Conclusion. The MACE and mortality risk calculators for prevalent RTRs have been externally validated and found suitable for generic risk stratification.

  • 48.
    Soveri, Inga
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Renal Medicine.
    Ärnlöv, Johan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Public Health and Caring Sciences, Geriatrics.
    Berglund, Lars
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Public Health and Caring Sciences, Geriatrics. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm, UCR-Uppsala Clinical Research Center.
    Lind, Lars
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Cardiovascular epidemiology.
    Fellström, Bengt
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Renal Medicine.
    Sundström, Johan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Cardiology.
    Kidney function and discrimination of cardiovascular risk in middle-aged men2009In: Journal of Internal Medicine, ISSN 0954-6820, E-ISSN 1365-2796, Vol. 266, no 4, p. 406-413Article in journal (Refereed)
    Abstract [en]

    Objective

    To define the optimal glomerular filtration rate (GFR) cut off for discriminating the risk of myocardial infarction or cardiovascular death.

    Design

    Prospective longitudinal observational study.

    Setting

    A community-based cohort.

    Participants

    A total of 2176 nondiabetic 50-year-old men without cardiovascular disease.

    Methods

    The men were followed until age 70. GFR was estimated at baseline using the Cockcroft–Gault formula. The optimal GFR cut-off points for discriminating risk of a fatal or nonfatal myocardial infarction and cardiovascular death were defined as the GFR levels maximizing integrated discrimination improvement (IDI).

    Main outcome measures

    Fatal or nonfatal myocardial infarction, cardiovascular death.

    Results

    During follow-up, 264 men experienced a fatal or nonfatal myocardial infarction, and 218 died of cardiovascular disease. The IDI-defined optimal GFR cut offs in this study were 98 mL min−1 for discriminating myocardial infarction risk and 92 mL min−1 for discriminating risk of cardiovascular death. In Cox proportional hazard models adjusting for established risk factors, the myocardial infarction risk was substantially higher in men with GFR below versus above 98 mL min−1 [hazard ratio (HR) 1.7, 95% confidence interval (CI) 1.3–2.3, P < 0.001], and the risk of cardiovascular death was doubled in men with GFR below versus above 92 mL min−1 (HR 2.1, 95% CI 1.5–3.0, P < 0.001).

    Conclusion

    The GFR cut-off point for optimal discrimination of cardiovascular risk in the general population may be higher than previously suggested.

  • 49.
    Staplin, Natalie
    et al.
    Univ Oxford, Nuffield Dept Populat Hlth, Clin Trial Serv Unit, Oxford, England.;Univ Oxford, Nuffield Dept Populat Hlth, Epidemiol Studies Unit, Oxford, England..
    Haynes, Richard
    Univ Oxford, Nuffield Dept Populat Hlth, Clin Trial Serv Unit, Oxford, England.;Univ Oxford, Nuffield Dept Populat Hlth, Epidemiol Studies Unit, Oxford, England..
    Herrington, William G.
    Univ Oxford, Nuffield Dept Populat Hlth, Clin Trial Serv Unit, Oxford, England.;Univ Oxford, Nuffield Dept Populat Hlth, Epidemiol Studies Unit, Oxford, England..
    Reith, Christina
    Univ Oxford, Nuffield Dept Populat Hlth, Clin Trial Serv Unit, Oxford, England.;Univ Oxford, Nuffield Dept Populat Hlth, Epidemiol Studies Unit, Oxford, England..
    Cass, Alan
    Menzies Inst, Darwin, NT, Australia..
    Fellström, Bengt
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Renal Medicine.
    Jiang, Lixin
    Fuwai Hosp, China Oxford Ctr Int Hlth Res, Beijing, Peoples R China..
    Kasiske, Bertram L.
    Univ Minnesota, Minneapolis, MN USA..
    Krane, Vera
    Univ Wuerzberg, Div Nephrol, Wuerzberg, Germany..
    Levin, Adeera
    Univ British Columbia, Vancouver, BC, Canada..
    Walker, Robert
    Univ Otago, Dunedin, New Zealand..
    Wanner, Christoph
    Univ Wuerzberg, Div Nephrol, Wuerzberg, Germany..
    Wheeler, David C.
    UCL, London, England..
    Landray, Martin J.
    Univ Oxford, Nuffield Dept Populat Hlth, Clin Trial Serv Unit, Oxford, England.;Univ Oxford, Nuffield Dept Populat Hlth, Epidemiol Studies Unit, Oxford, England..
    Baigent, Colin
    Univ Oxford, Nuffield Dept Populat Hlth, Clin Trial Serv Unit, Oxford, England.;Univ Oxford, Nuffield Dept Populat Hlth, Epidemiol Studies Unit, Oxford, England..
    Emberson, Jonathan
    Univ Oxford, Nuffield Dept Populat Hlth, Clin Trial Serv Unit, Oxford, England.;Univ Oxford, Nuffield Dept Populat Hlth, Epidemiol Studies Unit, Oxford, England..
    Smoking and Adverse Outcomes in Patients With CKD: The Study of Heart and Renal Protection (SHARP)2016In: American Journal of Kidney Diseases, ISSN 0272-6386, E-ISSN 1523-6838, Vol. 68, no 3, p. 371-380Article in journal (Refereed)
    Abstract [en]

    Background: The absolute and relative importance of smoking to vascular and nonvascular outcomes in people with chronic kidney disease (CKD), as well its relevance to kidney disease progression, is uncertain. Study Design: Observational study. Setting & Participants: 9,270 participants with CKD enrolled in SHARP. Predictor: Baseline smoking status (current, former, and never). Outcomes: Vascular events, site-specific cancer, ESRD, rate of change in estimated glomerular filtration rate (eGFR), and cause-specific mortality. Results: At baseline, 1,243 (13%) participants were current smokers (median consumption, 10 cigarettes/day); 3,272 (35%), former smokers; and 4,755 (51%), never smokers. Median follow-up was 4.9 years. Vascular event rates were 36% higher for current than never smokers (2,317 events; relative risk [RR], 1.36; 95% CI, 1.19-1.55), reflecting increases in both atherosclerotic (RR, 1.49; 95% CI, 1.26-1.76) and nonatherosclerotic (RR, 1.25; 95% CI, 1.05-1.50) events. Cancer was 37% higher among current smokers (632 events; RR, 1.37; 95% CI, 1.07-1.76), with the biggest RRs for lung (RR, 9.31; 95% CI, 4.37-19.83) and upper aerodigestive tract (RR, 4.87; 95% CI, 2.10-11.32) cancers. For 6,245 patients not receiving dialysis at baseline, ESRD incidence did not differ significantly between current and never smokers (2,141 events; RR, 1.02; 95% CI, 0.89-1.17), nor did estimated rate of change in eGFR (current smokers, -1.77 +/- 0.14 [SE]; never smokers, -1.70 +/- 0.07 mL/min/1.73 m(2) per year). All-cause mortality was 48% higher among current smokers (2,257 events; RR, 1.48; 95% CI, 1.30-1.70), with significant increases in vascular (RR, 1.35; 95% CI, 1.07-1.69) and nonvascular (RR, 1.60; 95% CI, 1.34-1.91) causes of death, especially cancer (RR, 2.32; 95% CI, 1.58-3.40) and respiratory (RR, 2.25; 95% CI, 1.51-3.35) mortality. Limitations: Smoking status not assessed during follow-up. Conclusions: In this study of patients with CKD, smoking significantly increased the risks for vascular and nonvascular morbidity and mortality, but was not associated with kidney disease progression. The associations with vascular and neoplastic disease are in keeping with those observed in the general population and are likely modifiable by cessation.

  • 50.
    Stenberg, Jenny
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Renal Medicine.
    Henriksson, Catrin
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Cardiology. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm, UCR-Uppsala Clinical Research Center.
    Lindberg, Magnus
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm, Centre for Research and Development, Gävleborg. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Public Health and Caring Sciences, Caring Sciences.
    Furuland, Hans
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Renal Medicine.
    Perspectives on clinical use of bioimpedance in hemodialysis: focus group interviews with renal care professionals2018In: BMC Nephrology, ISSN 1471-2369, E-ISSN 1471-2369, Vol. 19, article id 121Article in journal (Refereed)
    Abstract [en]

    Background

    Inadequate volume control may be a main contributor to poor survival and high mortality in hemodialysis patients. Bioimpedance measurement has the potential to improve fluid management, but several dialysis centers lack an agreed fluid management policy, and the method has not yet been implemented. Our aim was to identify renal care professionals’ perceived barriers and facilitators for use of bioimpedance in clinical practice.

    Methods

    Qualitative data were collected through four focus group interviews with 24 renal care professionals: dieticians, nephrologists and nurses, recruited voluntarily from a nation-wide selection of hemodialysis centers, having access to a bioimpedance-device. The participants were connected to each other and a moderator via equipment for telemedicine and the sessions were recorded. The interviews were semi-structured, focusing on the participants’ perceptions of use of bioimpedance in clinical practice. Thematic content analysis was performed in consecutive steps, and data were extracted by employing an inductive, interactive, comparative process.

    Results

    Several barriers and facilitators to the use of bioimpedance in clinical practice were identified, and a multilevel approach to examining barriers and incentives for change was found to be applicable to the ideas and categories that arose from the data. The determinants were categorized on five levels, and the different themes of the levels illustrated with quotations from the focus groups participants.

    Conclusions

    Determinants for use of bioimpedance were identified on five levels: 1) the innovation itself, 2) the individual professional, 3) the patient, 4) the social context and 5) the organizational context. Barriers were identified in the areas of credibility, awareness, knowledge, self-efficacy, care processes, organizational structures and regulations. Facilitators were identified in the areas of the innovation’s attractiveness, advantages in practice, and collaboration. Motivation, team processes and organizational capacities appeared as both barriers and facilitators.

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