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Fellstrom, Bengt
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Publications (10 of 80) Show all publications
Wadström, J., Ericzon, B.-G., Halloran, P. F., Bechstein, W. O., Opelz, G., Seron, D., . . . Gray, M. (2017). Advancing Transplantation: New Questions, New Possibilities in Kidney and Liver Transplantation. Transplantation, 101.
Open this publication in new window or tab >>Advancing Transplantation: New Questions, New Possibilities in Kidney and Liver Transplantation
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2017 (English)In: Transplantation, ISSN 0041-1337, E-ISSN 1534-6080, Vol. 101Article in journal (Refereed) Published
Place, publisher, year, edition, pages
LIPPINCOTT WILLIAMS & WILKINS, 2017
National Category
Surgery Immunology in the medical area
Identifiers
urn:nbn:se:uu:diva-320812 (URN)10.1097/TP.0000000000001563 (DOI)000395632300001 ()28125449 (PubMedID)
Available from: 2017-04-26 Created: 2017-04-26 Last updated: 2018-01-13Bibliographically approved
Ekdahl, K. N., Soveri, I., Hilborn, J., Fellström, B. & Nilsson, B. (2017). Cardiovascular disease in haemodialysis: role of the intravascular innate immune system.. Nature Reviews Nephrology, 13(5), 285-296.
Open this publication in new window or tab >>Cardiovascular disease in haemodialysis: role of the intravascular innate immune system.
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2017 (English)In: Nature Reviews Nephrology, ISSN 1759-5061, E-ISSN 1759-507X, Vol. 13, no 5, 285-296 p.Article, review/survey (Refereed) Published
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.

National Category
Urology and Nephrology
Research subject
Medical Science
Identifiers
urn:nbn:se:uu:diva-319742 (URN)10.1038/nrneph.2017.17 (DOI)000399003200005 ()28239169 (PubMedID)
Funder
Swedish Research Council, 2013-65X-05647-34-4EU, FP7, Seventh Framework Programme, 602699
Available from: 2017-04-07 Created: 2017-04-07 Last updated: 2017-05-11Bibliographically approved
Wagner, S., Apetrii, M., Massy, Z. A., Kleber, M. E., Delgado, G. E., Scharnagel, H., . . . Zannad, F. (2017). Oxidized LDL, statin use, morbidity, and mortality in patients receiving maintenance hemodialysis. Free radical research, 51(1), 14-23.
Open this publication in new window or tab >>Oxidized LDL, statin use, morbidity, and mortality in patients receiving maintenance hemodialysis
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2017 (English)In: Free radical research, ISSN 1071-5762, E-ISSN 1029-2470, Vol. 51, no 1, 14-23 p.Article in journal (Refereed) Published
Abstract [en]

Statin treatment reduces the risk of cardiovascular mortality in the general population, but it has little or no benefit in hemodialyzed (HD) patients. This may reflect different underlying pathophysiology of cardiovascular disease (CVD) in patients treated with HD, maybe involving the oxidative stress. Our aim was to assess the association of oxidized low-density lipoprotein (oxLDL), determined by Mercodia oxLDL enzyme-linked immunosorbent assay (ELISA) kit, with major adverse cardiac events (MACE) and all-cause mortality in HD patients based on the AURORA trial (rosuvastatin vs placebo), and patients not on HD from the Ludwigshafen Risk and Cardiovascular Health (LURIC) study. We also assessed whether its decrease due to statin use improves these outcomes using Cox proportional hazard models. Baseline oxLDL level was 34.2 +/- 13.8 U/L in AURORA and did not differ between treatment groups, and 74.6 +/- 28.1 U/L in LURIC. Lower baseline oxLDL levels were associated with higher hazard ratios (HRs) for outcomes, but not anymore after adjusting for apolipoprotein B level in AURORA and was not related to mortality in LURIC. OxLDL levels decreased by 30.9% between baseline and 3 months in the statin-treated group and increased by 10.5% between 3 and 12 months. Nevertheless, oxLDL reduction was not significantly associated with adjusted HRs for MACE and for all-cause mortality. These results showed no association between oxLDL and MACE after adjustment on apolipoprotein B, which may relate to the properties of the method used for oxLDL. Our results also showed no benefit for oxLDL reduction by rosuvastatin on outcomes. Future clinical trials are needed to define the relative CVD risks and benefits of other modalities of oxidative stress modification in this population.

Place, publisher, year, edition, pages
Taylor & Francis, 2017
Keyword
Oxidized LDL, hemodialyzed patients, statin, mortality, cardiovascular risks
National Category
Biochemistry and Molecular Biology
Identifiers
urn:nbn:se:uu:diva-319319 (URN)10.1080/10715762.2016.1241878 (DOI)000393893200002 ()27667446 (PubMedID)
Available from: 2017-04-10 Created: 2017-04-10 Last updated: 2017-11-29Bibliographically approved
Pihlstrøm, H. K., Mjøen, G., Mucha, S., Haraldsen, G., Franke, A., Jardine, A., . . . Melum, E. (2017). Single Nucleotide Polymorphisms and Long-Term Clinical Outcome in Renal Transplant Patients: A Validation Study. American Journal of Transplantation, 17(2), 528-533.
Open this publication in new window or tab >>Single Nucleotide Polymorphisms and Long-Term Clinical Outcome in Renal Transplant Patients: A Validation Study
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2017 (English)In: American Journal of Transplantation, ISSN 1600-6135, E-ISSN 1600-6143, Vol. 17, no 2, 528-533 p.Article in journal (Refereed) Published
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.

Place, publisher, year, edition, pages
WILEY, 2017
National Category
Surgery
Identifiers
urn:nbn:se:uu:diva-320695 (URN)10.1111/ajt.13995 (DOI)000397418300027 ()27483393 (PubMedID)
Available from: 2017-04-24 Created: 2017-04-24 Last updated: 2017-04-24Bibliographically approved
Fellström, B. C., Barratt, J., Cook, H., Coppo, R., Feehally, J., de Fijter, J. W., . . . Del Vecchio, L. (2017). Targeted-release budesonide versus placebo in patients with IgA nephropathy (NEFIGAN): a double-blind, randomised, placebo-controlled phase 2b trial. The Lancet, 389(10084), 2117-2127.
Open this publication in new window or tab >>Targeted-release budesonide versus placebo in patients with IgA nephropathy (NEFIGAN): a double-blind, randomised, placebo-controlled phase 2b trial
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2017 (English)In: The Lancet, ISSN 0140-6736, E-ISSN 1474-547X, Vol. 389, no 10084, 2117-2127 p.Article in journal (Refereed) Published
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.

National Category
Urology and Nephrology
Identifiers
urn:nbn:se:uu:diva-325692 (URN)10.1016/S0140-6736(17)30550-0 (DOI)000401973300030 ()28363480 (PubMedID)
Available from: 2017-06-27 Created: 2017-06-27 Last updated: 2017-06-27Bibliographically approved
Staplin, N., Haynes, R., Herrington, W. G., Reith, C., Cass, A., Fellström, B., . . . Emberson, J. (2016). Smoking and Adverse Outcomes in Patients With CKD: The Study of Heart and Renal Protection (SHARP). American Journal of Kidney Diseases, 68(3), 371-380.
Open this publication in new window or tab >>Smoking and Adverse Outcomes in Patients With CKD: The Study of Heart and Renal Protection (SHARP)
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2016 (English)In: American Journal of Kidney Diseases, ISSN 0272-6386, E-ISSN 1523-6838, Vol. 68, no 3, 371-380 p.Article in journal (Refereed) Published
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.

Keyword
Cigarette smoking, tobacco, chronic kidney disease (CKD), vascular morbidity, end-stage renal disease (ESRD), risk factor, cause-specific mortality, vascular events, cancer, estimated glomerular filtration rate (eGFR), disease progression, Study of Heart and Renal Protection (SHARP)
National Category
Urology and Nephrology
Identifiers
urn:nbn:se:uu:diva-317064 (URN)10.1053/j.ajkd.2016.02.052 (DOI)000383891000008 ()27118687 (PubMedID)
Available from: 2017-04-04 Created: 2017-04-04 Last updated: 2017-11-29Bibliographically approved
Drechsler, C., Pihlström, H., Meinitzer, A., Pilz, S., Tomaschitz, A., Abedini, S., . . . Holdaas, H. (2015). Homoarginine and Clinical Outcomes in Renal Transplant Recipients: Results From the Assessment of Lescol in Renal Transplantation Study. Transplantation, 99(7), 1470-1476.
Open this publication in new window or tab >>Homoarginine and Clinical Outcomes in Renal Transplant Recipients: Results From the Assessment of Lescol in Renal Transplantation Study
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2015 (English)In: Transplantation, ISSN 0041-1337, E-ISSN 1534-6080, Vol. 99, no 7, 1470-1476 p.Article in journal (Refereed) Published
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.

National Category
Urology and Nephrology
Identifiers
urn:nbn:se:uu:diva-264184 (URN)10.1097/TP.0000000000000568 (DOI)000369083200032 ()25675199 (PubMedID)
Available from: 2015-10-07 Created: 2015-10-07 Last updated: 2017-12-01Bibliographically approved
Bergström, M., Joly, A.-L. -., Seiron, P., Isringhausen, S., Modig, E., Fellström, B., . . . Berglund, D. (2015). Immunological Profiling of Haemodialysis Patients and Young Healthy Individuals with Implications for Clinical Regulatory T Cell Sorting. Scandinavian Journal of Immunology, 81(5), 318-324.
Open this publication in new window or tab >>Immunological Profiling of Haemodialysis Patients and Young Healthy Individuals with Implications for Clinical Regulatory T Cell Sorting
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2015 (English)In: Scandinavian Journal of Immunology, ISSN 0300-9475, E-ISSN 1365-3083, Vol. 81, no 5, 318-324 p.Article in journal (Refereed) Published
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.

National Category
Immunology in the medical area
Identifiers
urn:nbn:se:uu:diva-253244 (URN)10.1111/sji.12287 (DOI)000353401300007 ()25737071 (PubMedID)
Note

A.-L. Joly and P. Seiron contributed equally to this work.

Available from: 2015-06-17 Created: 2015-05-25 Last updated: 2018-01-11Bibliographically approved
Pihlstrom, H., Dahle, D. O., Mjoen, G., Pilz, S., Maerz, W., Abedini, S., . . . Holdaas, H. (2015). Increased Risk of All-Cause Mortality and Renal Graft Loss in Stable Renal Transplant Recipients With Hyperparathyroidism. Transplantation, 99(2), 351-359.
Open this publication in new window or tab >>Increased Risk of All-Cause Mortality and Renal Graft Loss in Stable Renal Transplant Recipients With Hyperparathyroidism
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2015 (English)In: Transplantation, ISSN 0041-1337, E-ISSN 1534-6080, Vol. 99, no 2, 351-359 p.Article in journal (Refereed) Published
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.

National Category
Immunology in the medical area Urology and Nephrology
Identifiers
urn:nbn:se:uu:diva-248206 (URN)10.1097/TP.0000000000000583 (DOI)000349493900025 ()25594550 (PubMedID)
Available from: 2015-03-31 Created: 2015-03-30 Last updated: 2018-01-11Bibliographically approved
Naess, H., Zannad, F., Jardine, A. G., Schmieder, R. E., Fellström, B., Holdaas, H. & Mjoen, G. (2015). NON-TRADITIONAL CARDIOVASCULAR RISK FACTORS PREDOMINATE IN HEMODIALYSIS PATIENTS WITH PRE-EXISTIN CARDIOVASCULAR DISEASE. Paper presented at 52nd Congress of the European-Renal-Association-European-Dialysis-and-Transplant-Assocation, MAY 28-31, 2015, London, ENGLAND. Nephrology, Dialysis and Transplantation, 30.
Open this publication in new window or tab >>NON-TRADITIONAL CARDIOVASCULAR RISK FACTORS PREDOMINATE IN HEMODIALYSIS PATIENTS WITH PRE-EXISTIN CARDIOVASCULAR DISEASE
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2015 (English)In: Nephrology, Dialysis and Transplantation, ISSN 0931-0509, E-ISSN 1460-2385, Vol. 30Article in journal, Meeting abstract (Other academic) Published
National Category
Cardiac and Cardiovascular Systems
Identifiers
urn:nbn:se:uu:diva-266182 (URN)000361215101118 ()
Conference
52nd Congress of the European-Renal-Association-European-Dialysis-and-Transplant-Assocation, MAY 28-31, 2015, London, ENGLAND
Available from: 2015-11-06 Created: 2015-11-05 Last updated: 2017-12-01Bibliographically approved
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