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Fellström, Bengt
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Publications (10 of 84) Show all publications
Storey, B. C., Staplin, N., Haynes, R., Reith, C., Emberson, J., Herrington, W. G., . . . Baigent, C. (2018). Lowering LDL cholesterol reduces cardiovascular risk independently of presence of inflammation.. Kidney International, 93(4), 1000-1007
Open this publication in new window or tab >>Lowering LDL cholesterol reduces cardiovascular risk independently of presence of inflammation.
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2018 (English)In: Kidney International, ISSN 0085-2538, E-ISSN 1523-1755, Vol. 93, no 4, p. 1000-1007Article in journal (Refereed) Published
Abstract [en]

Markers of inflammation, including plasma C-reactive protein (CRP), are associated with an increased risk of cardiovascular disease, and it has been suggested that this association is causal. However, the relationship between inflammation and cardiovascular disease has not been extensively studied in patients with chronic kidney disease. To evaluate this, we used data from the Study of Heart and Renal Protection (SHARP) to assess associations between circulating CRP and LDL cholesterol levels and the risk of vascular and non-vascular outcomes. Major vascular events were defined as nonfatal myocardial infarction, cardiac death, stroke or arterial revascularization, with an expanded outcome of vascular events of any type. Higher baseline CRP was associated with an increased risk of major vascular events (hazard ratio per 3x increase 1.28; 95% confidence interval 1.19-1.38). Higher baseline LDL cholesterol was also associated with an increased risk of major vascular events (hazard ratio per 0.6 mmol/L higher LDL cholesterol; 1.14, 1.06-1.22). Higher baseline CRP was associated with an increased risk of a range of non-vascular events (1.16, 1.12-1.21), but there was a weak inverse association between baseline LDL cholesterol and non-vascular events (0.96, 0.92-0.99). The efficacy of lowering LDL cholesterol with simvastatin/ezetimibe on major vascular events, in the randomized comparison, was similar irrespective of CRP concentration at baseline. Thus, decisions to offer statin-based therapy to patients with chronic kidney disease should continue to be guided by their absolute risk of atherosclerotic events. Estimation of such risk may include plasma biomarkers of inflammation, but there is no evidence that the relative beneficial effects of reducing LDL cholesterol depends on plasma CRP concentration.

Keywords
C-reactive protein, LDL cholesterol, inflammation, randomized trials, vascular disease
National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:uu:diva-342346 (URN)10.1016/j.kint.2017.09.011 (DOI)000428169200028 ()29146277 (PubMedID)
Available from: 2018-02-20 Created: 2018-02-20 Last updated: 2018-06-20Bibliographically approved
Solbu, M. D., Mjøen, G., Mark, P. B., Holdaas, H., Fellström, B., Schmieder, R. E., . . . Jardine, A. G. (2018). Predictors of atherosclerotic events in patients on haemodialysis: post hoc analyses from the AURORA study.. Nephrology, Dialysis and Transplantation, 33(1), 102-112
Open this publication in new window or tab >>Predictors of atherosclerotic events in patients on haemodialysis: post hoc analyses from the AURORA study.
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2018 (English)In: Nephrology, Dialysis and Transplantation, ISSN 0931-0509, E-ISSN 1460-2385, Vol. 33, no 1, p. 102-112Article in journal (Refereed) Published
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.

Keywords
atherosclerosis, coronary artery disease, haemodialysis, statins, vascular calcification
National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:uu:diva-342349 (URN)10.1093/ndt/gfw360 (DOI)000422837000013 ()27798199 (PubMedID)
Funder
AstraZeneca
Available from: 2018-02-20 Created: 2018-02-20 Last updated: 2018-02-26Bibliographically approved
Schlackow, I., Kent, S., Herrington, W., Emberson, J., Haynes, R., Reith, C., . . . Mihaylova, B. (2017). A policy model of cardiovascular disease in moderate-to-advanced chronic kidney disease. Heart, 103(23), 1880-1890
Open this publication in new window or tab >>A policy model of cardiovascular disease in moderate-to-advanced chronic kidney disease
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2017 (English)In: Heart, ISSN 1355-6037, E-ISSN 1468-201X, Vol. 103, no 23, p. 1880-1890Article in journal (Refereed) Published
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.

National Category
Cardiac and Cardiovascular Systems
Identifiers
urn:nbn:se:uu:diva-342202 (URN)10.1136/heartjnl-2016-310970 (DOI)000415570400011 ()28780579 (PubMedID)
Available from: 2018-02-20 Created: 2018-02-20 Last updated: 2018-02-20Bibliographically approved
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, p. 285-296Article, 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, p. 14-23Article 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
Keywords
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, p. 528-533Article 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., Barratt, J., Flöge, J. & Jardine, A. (2017). Targeted-release budesonide therapy for IgA nephropathy - Authors' reply.. The Lancet, 390(10113), 2625-2626
Open this publication in new window or tab >>Targeted-release budesonide therapy for IgA nephropathy - Authors' reply.
2017 (English)In: The Lancet, ISSN 0140-6736, E-ISSN 1474-547X, Vol. 390, no 10113, p. 2625-2626Article in journal (Refereed) Published
National Category
Public Health, Global Health, Social Medicine and Epidemiology
Identifiers
urn:nbn:se:uu:diva-342374 (URN)10.1016/S0140-6736(17)32138-4 (DOI)000418101000021 ()29256402 (PubMedID)
Available from: 2018-02-20 Created: 2018-02-20 Last updated: 2018-04-11Bibliographically 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, p. 2117-2127Article 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, p. 371-380Article 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.

Keywords
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
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