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  • 1.
    Annuk, Margus
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Fellström, Bengt
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Lind, Lars
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Cyclooxygenase inhibition improves endothelium-dependent vasodilatation in patients with chronic renal failure2002In: Nephrology, Dialysis and Transplantation, ISSN 0931-0509, E-ISSN 1460-2385, Vol. 17, no 12, p. 2159-2163Article in journal (Refereed)
    Abstract [en]

    BACKGROUND: Some studies have demonstrated beneficial effects of L-arginine as a substrate for nitric oxide synthesis, and diclofenac as an inhibitor of cyclooxygenase (COX)-derived vasoconstrictive agents on vascular responses in humans during several pathological conditions. The aim of the present study was to investigate the acute effects of L-arginine and diclofenac on endothelium-dependent vasodilatation (EDV) and endothelium-independent vasodilatation (EIDV) in patients with chronic renal failure (CRF).

    METHODS: Effects of L-arginine and diclofenac on EDV and EIDV were measured in 15 patients with CRF and in 15 healthy controls by means of forearm blood flow measurements with venous occlusion plethysmography during local intra-arterial infusions of methacholine (2 and 4 micro g/min evaluating EDV) and sodium nitroprusside (5 and 10 micro g/min evaluating EIDV).

    RESULTS: L-Arginine infusion increased methacholine-induced vasodilatation both in patients with CRF and healthy controls. Diclofenac infusion increased methacholine-induced vasodilatation only in patients with CRF. There was no significant change in nitroprusside-induced vasodilatation after L-arginine and diclofenac infusions both in patients with CRF and healthy controls.

    CONCLUSIONS: These results suggest that COX inhibition reduces the levels of a prostanoid-derived vasoconstrictive agent contributing to the impaired EDV in patients with CRF, while in this age group L-arginine improves EDV regardless of renal function.

  • 2. Annuk, Margus
    et al.
    Fellström, Bengt
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Åkerblom, O.
    Zilmer, K.
    Vihalemm, T.
    Zilmer, M.
    Oxidative stress markers in pre-uremic patients2001In: Clinical Nephrology, ISSN 0301-0430, Vol. 56, no 4, p. 308-314Article in journal (Other (popular science, discussion, etc.))
    Abstract [en]

    AIM: The present study was designed to investigate a complex of oxidative stress (OS) markers in patients with chronic renal failure (CRF) and to study the relationship between different OS markers and degree of renal failure. The following indices of OS were measured in plasma: oxidized glutathione (GSSG), reduced glutathione (GSH), total glutathione (TGSH), glutathione redox ratio (GSSG/GSH) and resistance of lipoprotein fraction to oxidation (lag phase of LPF). Baseline diene conjugation level of lipoprotein fraction (BDC-LPF), total antioxidative activity (TAA), diene conjugates (DC), lipid hydroperoxides (LOOH) and thiobarbituric acid-reactive substances (TBARS) were measured in serum. All markers in plasma and serum were measured both in patients with CRF and in healthy controls.

    SUBJECTS AND METHODS: Blood samples were obtained from 38 patients with CRF and from 61 healthy controls. Routine biochemical analyses were performed by using commercially available kits.

    RESULTS: Levels of DC, BDC-LPF, LOOH, GSSG and GSSG/GSH ratio were significantly increased and lag phase of LPF was significantly shortened in patients with CRF compared with healthy controls. Serum creatinine and urea levels correlated significantly with GSSG level and GSSG/GSH in patients with CRF. A significant inverse correlation was found between glutathione redox ratio and lag phase of LPF and between GSSG level and BDC-LPF.

    CONCLUSIONS: The findings suggest that renal patients are in a state of oxidative stress compared with healthy controls. The most informative indices to evaluate the degree of OS in CRF were: GSSG level, GSSG/GSH status, lag phase of LPF and BDC-LPF.

  • 3.
    Annuk, Margus
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Lind, Lars
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Linde, Torbjörn
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Fellström, Bengt
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Impaired endothelium-dependent vasodilatation in renal failure in humans2001In: Nephrology, Dialysis and Transplantation, ISSN 0931-0509, E-ISSN 1460-2385, Vol. 16, no 2, p. 302-306Article in journal (Refereed)
    Abstract [en]

    BACKGROUND: The main causes of death in patients with chronic renal failure (CRF) are cardiovascular complications. The aim of the present study was to compare endothelium-dependent vasodilatation (EDV) in patients with chronic renal failure with a control population controlling for hypertension, diabetes mellitus and hypercholesterolaemia.

    METHODS: Fifty-six patients with moderate CRF (mean creatinine clearance 29.4 ml/min/1.73 m(2)) underwent evaluation of EDV and endothelium-independent vasodilatation (EIDV) by means of forearm blood flow (FBF) measurements with venous occlusion plethysmography during local intra-arterial infusions of methacholine (Mch, 2 and 4 microg/min evaluating EDV) and sodium nitroprusside (SNP, 5 and 10 microg/min evaluating EIDV). Fifty-six control subjects without renal impairment underwent the same investigation.

    RESULTS: Infusion of Mch increased FBF significantly less in patients with renal failure than in controls (198 vs 374%, P<0.001), whereas no significant difference was seen regarding the vasodilatation induced by SNP (278 vs 269%). The differences in EDV between the groups were still significant after controlling for hypertension, blood glucose, and serum cholesterol in multiple regression analysis (P<0.001). EDV was related to serum creatinine (r=-0.37, P<0.01), creatinine clearance (r=0.45, P<0.005) and to serum triglyceride levels (r=-0.29, P<0.005) in the CRF group.

    CONCLUSIONS: Patients with moderate CRF have an impaired EDV even after correction for traditional cardiovascular risk factors and this impairment is related to the degree of renal failure.

  • 4.
    Annuk, Margus
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Linde, Torbjörn
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Lind, Lars
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Fellström, Bengt
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Erythropoietin impairs endothelial vasodilatory function in patients with renal anemia and in healthy subjects2006In: Nephron. Clinical practice, ISSN 1660-8151, E-ISSN 2235-3186, Vol. 102, no 1, p. c30-c34Article in journal (Refereed)
    Abstract [en]

    Background/Aim: The mechanisms underlying the aggravation or development of hypertension frequently seen during treatment of renal anemia with epoetins are not fully elucidated. The aim of the present study was to investigate the effects of epoetin alfa on endothelial vasodilatory function in patients with renal anemia and in healthy subjects. Methods: Eighteen preuremic patients with anemia (GFR 23.4 ± 11 SD ml/min, Hb 101 ± 8 g/l) and 10 healthy subjects underwent evaluation of endothelium-dependent vasodilation (EDV) and endothelium-independent vasodilation (EIDV) by means of forearm blood flow (FBF) measurements with venous occlusion plethysmography during local intra-arterial infusions of methacholine (MCh, evaluating EDV) and sodium nitroprusside (SNP, evaluating EIDV). These investigations were performed before and 30 min after an intravenous injection of epoetin alfa (10,000 IU). Ten healthy subjects underwent the same procedure with the exception that saline were given instead of epoetin. The patients were treated with epoetin alfa subcutaneously for 12-19 weeks and revaluated when Hb exceeded 120 g/l. Results: EDV was attenuated after the epoetin injection in both renal patients and healthy subjects. This impairment persisted after anemia had been treated. EDIV and blood pressure remained constant. Saline had no effect on the variables measured. Conclusion: Our results indicate that epoetin alfa impairs endothelial function in renal patients and healthy subjects which may have an impact on vascular complications.

  • 5.
    Annuk, Margus
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Soveri, Inga
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Zilmer, Mihkel
    Lind, Lars
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Hulthe, Johannes
    Fellström, Bengt
    Endothelial function, CRP and oxidative stress in chronic kidney disease2005In: JN. Journal of Nephrology (Milano. 1992), ISSN 1121-8428, E-ISSN 1724-6059, Vol. 18, no 6, p. 721-726Article in journal (Refereed)
    Abstract [en]

    BACKGROUND: Chronic kidney disease (CKD) is associated with increased morbidity and mortality in cardiovascular disease (CVD). Apart from traditional risk factors, chronic inflammation, oxidative stress, malnutrition and endothelial dysfunction are important in CVD development in renal patients. Our aim was to investigate the relationship between high sensitivity C-reactive protein (CRP), endothelium dependent vasodilation (EDV) and oxidative stress markers in patients with CKD K/DOQI stage 3-5.

    METHODS: Measurements of CRP, conjugated dienes (CD), lipid hydroperoxide (LOOH), oxidized low density lipoprotein,glutathione and albumin were performed in 44 consecutive patients with CKD stage 3-5. EDV was measured by methacholine infusion in the brachial artery and venous occlusion plethysmography.

    RESULTS: Patients with high CRP had significantly lower glomerular filtration rates and albumin, but increased LOOH and CD. In multiple regression analysis, only LOOH and CD remained significant. Patients with poor EDV had increased urea and lower glutathione (GSH). In multiple regression analysis, GSH and urea were independently related to EDV. No correlation was found between CRP and endothelial function.

    CONCLUSION: CRP was related to lipid peroxidation, while endothelial function was related to intracellular oxidative stress in patients with CKD. CRP and EDV were unrelated to each other. Therefore, CRP and endothelial function could provide complementary prognostic information regarding future cardiovascular disorders in renal patients.

  • 6. Annuk, Margus
    et al.
    Zilmer, Mihkel
    Fellström, Bengt
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Endothelium-dependent vasodilation and oxidative stress in chronic renal failure: impact on cardiovascular disease2003In: Kidney International, Supplement, ISSN 0098-6577, no 84, p. S50-S53Article in journal (Other academic)
    Abstract [en]

    Despite significant progress in renal replacement therapy, the mortality from cardiovascular disease (CVD) in patients with chronic renal failure (CRF) is many times higher than in the general population. The traditional risk factors are frequently present in CRF patients. However, based upon conventional risk factor analysis, these factors do not fully explain the extraordinary increase in morbidity and mortality in CVD among patients with CRF. Accumulating evidence suggests that CRF is associated with impaired endothelial cell function. In recent years, the role of endothelial dysfunction (ED) and excessive oxidative stress (OS) in the development of CVD has been highlighted. ED is an early feature of vascular disease in different diseases such diabetes, hypertension, hypercholesterolemia, and coronary heart disease. The precise mechanism which induces ED is not clear. Several factors however, including OS-related accumulation of uremic toxins, hypertension and shear stress, dyslipidemia with cytotoxic lipoprotein species such as small, dense low-density lipoprotein (LDL) particles, competitive inhibition of endothelial nitric oxide (NO) by increased production by asymmetrical dimethylarginine (ADMA) are pathogenic. In addition, it is known that excessive OS causes ED. An overproduction of reactive oxygen species (ROS) may injure the endothelial cell membrane, inactivate NO, and cause oxidation of an essential cofactor of nitric oxide synthase (NOS). Recent studies have demonstrated that an impaired endothelium-dependent vasodilation and OS are closely related to each other in patients with CRF.

  • 7.
    Annuk, Margus
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Zilmer, Mikhel
    Lind, Lars
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Linde, Torbjörn
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Fellström, Bengt
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Oxidative stress and endothelial function in chronic renal failure2001In: Journal of the American Society of Nephrology, ISSN 1046-6673, E-ISSN 1533-3450, Vol. 12, no 12, p. 2747-2752Article in journal (Other academic)
    Abstract [en]

    This study aimed to investigate the relationship between oxidative stress and endothelium-dependent vasodilation in patients with chronic renal failure (CRF). Thirty-seven patients with CRF underwent evaluation of endothelium-dependent vasodilation and endothelium-independent vasodilation by means of forearm blood flow measurements with venous occlusion plethysmography during local intra-arterial infusions of methacholine (evaluating endothelium-dependent vasodilation) and sodium nitroprusside (evaluating endothelium-independent vasodilation). Lag phase of lipoprotein fraction to oxidation, total antioxidative activity, diene conjugates, thiobarbituric acid reactive substances, lipid hydroperoxide, reduced glutathione (GSH), oxidized GSH (GSSG), and the GSH redox ratio (GSSG/GSH) were all measured as markers of oxidative stress. Two groups of healthy subjects (61 and 37 subjects, respectively) were used as controls. In one group, oxidative stress markers were measured, whereas endothelium-dependent vasodilation and endothelium-independent vasodilation were assessed in the other group. Compared with controls, the patients with renal insufficiency had an impaired endothelium-dependent vasodilation, a shorter lag phase of lipoprotein fraction, and higher levels of diene conjugates, lipid hydroperoxide, and GSSG levels. The GSSG/GSH ratio was lower in patients with CRF. Endothelium-dependent vasodilation was positively correlated with total antioxidative activity (r = 0.41, P = 0.016), GSH (r = 0.44, P < 0.0098), and lag phase of LDL (r = 0.35, P = 0.036) and negatively correlated with GSSG (r = -0.40, P < 0.018), GSSG/GSH (r = -0.47, P = 0.0057), and diene conjugates (r = -0.53 P < 0.0015) in patients with CRF. These results show that an impaired endothelium vasodilation function and oxidative stress are related to each other in patients with CRF.

  • 8. Baigent, C
    et al.
    Blackwell, L
    Emberson, J
    Holland, LE
    Reith, C
    Bhala, N
    Peto, R
    Barnes , EH
    Keech, A
    Simes, J
    Collins, R
    Efficacy and safety of more intensive lowering of LDL cholesterol: a meta-analysis of data from 170,000 participants in 26 randomized trials2010In: The Lancet, ISSN 0140-6736, E-ISSN 1474-547X, Vol. 376, no 9753, p. 1670-1681Article in journal (Refereed)
    Abstract [en]

    Background

    Lowering of LDL cholesterol with standard statin regimens reduces the risk of occlusive vascular events in a wide range of individuals. We aimed to assess the safety and efficacy of more intensive lowering of LDL cholesterol with statin therapy.

    Methods

    We undertook meta-analyses of individual participant data from randomised trials involving at least 1000 participants and at least 2 years' treatment duration of more versus less intensive statin regimens (five trials; 39 612 individuals; median follow-up 5·1 years) and of statin versus control (21 trials; 129 526 individuals; median follow-up 4·8 years). For each type of trial, we calculated not only the average risk reduction, but also the average risk reduction per 1·0 mmol/L LDL cholesterol reduction at 1 year after randomisation.

    Findings

    In the trials of more versus less intensive statin therapy, the weighted mean further reduction in LDL cholesterol at 1 year was 0·51 mmol/L. Compared with less intensive regimens, more intensive regimens produced a highly significant 15% (95% CI 11–18; p<0·0001) further reduction in major vascular events, consisting of separately significant reductions in coronary death or non-fatal myocardial infarction of 13% (95% CI 7–19; p<0·0001), in coronary revascularisation of 19% (95% CI 15–24; p<0·0001), and in ischaemic stroke of 16% (95% CI 5–26; p=0·005). Per 1·0 mmol/L reduction in LDL cholesterol, these further reductions in risk were similar to the proportional reductions in the trials of statin versus control. When both types of trial were combined, similar proportional reductions in major vascular events per 1·0 mmol/L LDL cholesterol reduction were found in all types of patient studied (rate ratio [RR] 0·78, 95% CI 0·76–0·80; p<0·0001), including those with LDL cholesterol lower than 2 mmol/L on the less intensive or control regimen. Across all 26 trials, all-cause mortality was reduced by 10% per 1·0 mmol/L LDL reduction (RR 0·90, 95% CI 0·87–0·93; p<0·0001), largely reflecting significant reductions in deaths due to coronary heart disease (RR 0·80, 99% CI 0·74–0·87; p<0·0001) and other cardiac causes (RR 0·89, 99% CI 0·81–0·98; p=0·002), with no significant effect on deaths due to stroke (RR 0·96, 95% CI 0·84–1·09; p=0·5) or other vascular causes (RR 0·98, 99% CI 0·81–1·18; p=0·8). No significant effects were observed on deaths due to cancer or other non-vascular causes (RR 0·97, 95% CI 0·92–1·03; p=0·3) or on cancer incidence (RR 1·00, 95% CI 0·96–1·04; p=0·9), even at low LDL cholesterol concentrations.

    Interpretation

    Further reductions in LDL cholesterol safely produce definite further reductions in the incidence of heart attack, of revascularisation, and of ischaemic stroke, with each 1·0 mmol/L reduction reducing the annual rate of these major vascular events by just over a fifth. There was no evidence of any threshold within the cholesterol range studied, suggesting that reduction of LDL cholesterol by 2–3 mmol/L would reduce risk by about 40–50%.

    Funding

    UK Medical Research Council, British Heart Foundation, European Community Biomed Programme, Australian National Health and Medical Research Council, and National Heart Foundation.

  • 9.
    Barbour, Sean J.
    et al.
    Univ British Columbia, Div Nephrol, 2775 Laurel St,Fifth Floor, Vancouver, BC V5Z 1M9, Canada;BC Renal, Vancouver, BC, Canada.
    Coppo, Rosanna
    Regina Margherita Childrens Univ Hosp, Turin, Italy.
    Zhang, Hong
    Peking Univ, Inst Nephrol, Beijing, Peoples R China.
    Liu, Zhi-Hong
    Nanjing Univ, Sch Med, Nanjing, Jiangsu, Peoples R China.
    Suzuki, Yusuke
    Juntendo Univ, Fac Med, Tokyo, Japan.
    Matsuzaki, Keiichi
    Juntendo Univ, Fac Med, Tokyo, Japan.
    Katafuchi, Ritsuko
    Natl Fukuoka Higashi Med Ctr, Fukuoka, Fukuoka, Japan.
    Er, Lee
    BC Renal, Vancouver, BC, Canada.
    Espino-Hernandez, Gabriela
    BC Renal, Vancouver, BC, Canada.
    Kim, S. Joseph
    Univ Toronto, Div Nephrol, Toronto, ON, Canada.
    Reich, Heather N.
    Univ Toronto, Div Nephrol, Toronto, ON, Canada.
    Feehally, John
    Leicester Gen Hosp, John Walls Renal Unit, Leicester, Leics, England.
    Cattran, Daniel C.
    Univ Toronto, Div Nephrol, Toronto, ON, Canada.
    Russo, M. L.
    Fdn Ric Molinette, Turin, Italy.
    Troyanov, S.
    Hop Sacre Coeur Montreal, Dept Med, Div Nephrol, Montreal, PQ, Canada;Hop Sacre Coeur Montreal, Dept Med, Div Nephrol, Montreal, PQ, Canada.
    Cook, H. T.
    Imperial Coll, Dept Med, Ctr Complement & Inflammat Res, London, England.
    Roberts, I.
    Oxford Univ Hosp NHS Fdn Trust, John Radcliffe Hosp, Dept Cellular Pathol, Oxford, England.
    Tesar, V.
    Charles Univ Prague, Fac Med 1, Dept Nephrol, Prague, Czech Republic;Charles Univ Prague, Gen Univ Hosp, Prague, Czech Republic.
    Maixnerova, D.
    Charles Univ Prague, Fac Med 1, Dept Nephrol, Prague, Czech Republic;Charles Univ Prague, Gen Univ Hosp, Prague, Czech Republic.
    Lundberg, S.
    Karolinska Inst, Dept Clin Sci, Nephrol Unit, Stockholm, Sweden.
    Gesualdo, L.
    Univ Bah Aldo Moro, Dept Nephrol Emergency & Organ Transplantat, Foggia, Italy.
    Emma, F.
    Bambino Gesu Pediat Hosp, IRCCS, Dept Pediat Subspecialties, Div Nephrol, Rome, Italy.
    Fuiano, L.
    Bambino Gesu Pediat Hosp, IRCCS, Dept Pediat Subspecialties, Div Nephrol, Rome, Italy.
    Beltrame, G.
    San Giovanni Bosco Hosp, Nephrol & Dialysis Unit, Turin, Italy;Univ Turin, Turin, Italy.
    Rollino, C.
    San Giovanni Bosco Hosp, Nephrol & Dialysis Unit, Turin, Italy;Univ Turin, Turin, Italy.
    Amore, A.
    Regina Margherita Childrens Hosp, Nephrol Unit, Turin, Italy;Univ Turin, Regina Margherita Childrens Hosp, Nephrol Dialysis & Transplantat Unit, Turin, Italy.
    Camilla, R.
    Regina Margherita Childrens Hosp, Nephrol Unit, Turin, Italy.
    Peruzzi, L.
    Regina Margherita Childrens Hosp, Nephrol Unit, Turin, Italy.
    Praga, M.
    Hosp 12 Octubre, Nephrol Unit, Madrid, Spain.
    Feriozzi, S.
    Belcolle Hosp, Nephrol Unit, Viterbo, Italy.
    Polci, R.
    Belcolle Hosp, Nephrol Unit, Viterbo, Italy.
    Segoloni, G.
    Univ Turin, Turin, Italy;Citta Salute & Sci Hosp, Dept Med Sci, Div Nephrol Dialysis & Transplantat, Turin, Italy.
    Colla, L.
    Univ Turin, Turin, Italy;Citta Salute & Sci Hosp, Dept Med Sci, Div Nephrol Dialysis & Transplantat, Turin, Italy.
    Pani, A.
    G Brotzu Hosp, Nephrol Unit, Cagliari, Italy.
    Piras, D.
    G Brotzu Hosp, Nephrol Unit, Cagliari, Italy.
    Angioi, A.
    G Brotzu Hosp, Nephrol Unit, Cagliari, Italy.
    Cancarini, G.
    Spedali Civili Univ Hosp, Nephrol Unit, Brescia, Italy.
    Ravera, S.
    Spedali Civili Univ Hosp, Nephrol Unit, Brescia, Italy.
    Durlik, M.
    Med Univ Warsaw, Dept Transplantat Med Nephrol & Internal Med, Warsaw, Poland.
    Moggia, E.
    Santa Croce Hosp, Nephrol Unit, Cuneo, Italy.
    Ballarin, J.
    Fdn Puigvert, Dept Nephrol, Barcelona, Spain.
    Di Giulio, S.
    San Camillo Forlanini Hosp, Nephrol Unit, Rome, Italy.
    Pugliese, F.
    Policlin Umberto Univ Hosp, Dept Nephrol, Rome, Italy.
    Serriello, I.
    Policlin Umberto Univ Hosp, Dept Nephrol, Rome, Italy.
    Caliskan, Y.
    Istanbul Univ, Istanbul Fac Med, Dept Internal Med, Div Nephrol, Istanbul, Turkey.
    Sever, M.
    Istanbul Univ, Istanbul Fac Med, Dept Internal Med, Div Nephrol, Istanbul, Turkey.
    Kilicaslan, I.
    Istanbul Univ, Istanbul Fac Med, Dept Pathol, Istanbul, Turkey.
    Locatelli, F.
    ASST Lecco, Alessandro Manzoni Hosp, Dept Nephrol & Dialysis, Lecce, Italy.
    Del Vecchio, L.
    ASST Lecco, Alessandro Manzoni Hosp, Dept Nephrol & Dialysis, Lecce, Italy.
    Wetzels, J. F. M.
    Radboud Univ Nijmegen, Med Ctr, Dept Nephrol, Nijmegen, Netherlands.
    Peters, H.
    Radboud Univ Nijmegen, Med Ctr, Dept Nephrol, Nijmegen, Netherlands.
    Berg, U.
    Dept Clin Sci Intervent & Technol, Div Pediat, Huddinge, Sweden.
    Carvalho, F.
    Hosp Curry Cabral, Nephrol Unit, Lisbon, Portugal.
    da Costa Ferreira, A. C.
    Hosp Curry Cabral, Nephrol Unit, Lisbon, Portugal.
    Maggio, M.
    Hosp Maggiore Lodi, Nephrol Unit, Lodi, Italy.
    Wiecek, A.
    Silesian Univ Med, Dept Nephrol Endocrinol & Metab Dis, Katowice, Poland.
    Ots-Rosenberg, M.
    Tartu Univ Clin, Nephrol Unit, Tartu, Estonia.
    Magistroni, R.
    Policlin Modena & Reggio Emilia, Dept Nephrol, Modena, Italy.
    Topaloglu, R.
    Hacettepe Univ, Dept Pediat Nephrol & Rheumatol, Ankara, Turkey.
    Bilginer, Y.
    Hacettepe Univ, Dept Pediat Nephrol & Rheumatol, Ankara, Turkey.
    D'Amico, M.
    St Anna Hosp, Nephrol Unit, Como, Italy.
    Stangou, M.
    Aristotle Univ Thessaloniki, Hippokrat Gen Hosp, Dept Nephrol, Thessaloniki, Greece.
    Giacchino, F.
    Ivrea Hosp, Nephrol Unit, Ivrea, Italy.
    Goumenos, D.
    Univ Hosp Patras, Dept Nephrol, Patras, Greece.
    Kalliakmani, P.
    Univ Hosp Patras, Dept Nephrol, Patras, Greece.
    Gerolymos, M.
    Univ Hosp Patras, Dept Nephrol, Patras, Greece.
    Galesic, K.
    Univ Hosp Dubrava, Dept Nephrol, Zagreb, Croatia.
    Geddes, C.
    Western Infirm Glasgow, Renal Unit, Glasgow, Lanark, Scotland;Western Infirm & Associated Hosp, Renal Unit, Glasgow, Lanark, Scotland.
    Siamopoulos, K.
    Univ Ioannina, Med Sch, Nephrol Unit, Ioannina, Greece.
    Balafa, O.
    Univ Ioannina, Med Sch, Nephrol Unit, Ioannina, Greece.
    Galliani, M.
    S Pertini Hosp, Nephrol Unit, Rome, Italy.
    Stratta, P.
    Piemonte Orientale Univ, Maggiore Carita Hosp, Dept Nephrol, Novara, Italy.
    Quaglia, M.
    Piemonte Orientale Univ, Maggiore Carita Hosp, Dept Nephrol, Novara, Italy.
    Bergia, R.
    Infermi Hosp, Nephrol Unit, Biella, Italy.
    Cravero, R.
    Infermi Hosp, Nephrol Unit, Biella, Italy.
    Salvadori, M.
    Careggi Hosp, Dept Nephrol, Florence, Italy.
    Cirami, L.
    Careggi Hosp, Dept Nephrol, Florence, Italy.
    Fellström, Bengt
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Renal Medicine.
    Smerud, Hilde Kloster
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Renal Medicine.
    Ferrario, F.
    San Gerardo Hosp, Nephropathol Unit, Monza, Italy;San Gerardo Hosp, Nephropathol Unit, Monza, Italy;San Carlo Borromeo Hosp, Renal Immunopathol Ctr, Milan, Italy.
    Stellato, T.
    San Gerardo Hosp, Nephropathol Unit, Monza, Italy.
    Egido, J.
    Fdn Jimenez Diaz, Dept Nephrol, Madrid, Spain.
    Martin, C.
    Fdn Jimenez Diaz, Dept Nephrol, Madrid, Spain.
    Floege, J.
    Univ Aachen, Med Klin 2, Nephrol & Immunol, Aachen, Germany.
    Eitner, F.
    Univ Aachen, Med Klin 2, Nephrol & Immunol, Aachen, Germany.
    Lupo, A.
    Univ Verona, Dept Nephrol, Verona, Italy.
    Bernich, P.
    Univ Verona, Dept Nephrol, Verona, Italy.
    Mene, R.
    S Andrea Hosp, Dept Nephrol, Rome, Italy.
    Morosetti, M.
    Grassi Hosp, Nephrol Unit, Ostia, Italy.
    van Kooten, C.
    Leiden Univ, Med Ctr, Dept Nephrol, Leiden, Netherlands.
    Rabelink, T.
    Leiden Univ, Med Ctr, Dept Nephrol, Leiden, Netherlands.
    Reinders, M. E. J.
    Leiden Univ, Med Ctr, Dept Nephrol, Leiden, Netherlands.
    Boria Grinyo, J. M.
    Bellvitge Hosp, Dept Nephrol, Barcelona, Spain.
    Cusinato, S.
    Borgomanero Hosp, Nephrol Unit, Borgomanero, Italy.
    Benozzi, L.
    Borgomanero Hosp, Nephrol Unit, Borgomanero, Italy.
    Savoldi, S.
    Civile Hosp, Nephrol Unit, Cirie, Italy.
    Licata, C.
    Civile Hosp, Nephrol Unit, Cirie, Italy.
    Mizerska-Wasiak, M.
    Med Univ Warsaw, Dept Pediat, Warsaw, Poland.
    Martina, G.
    Chivasso Hosp, Nephrol Unit, Chivasso, Italy.
    Messuerotti, A.
    Chivasso Hosp, Nephrol Unit, Chivasso, Italy.
    Dal Canton, A.
    San Matteo Hosp, Nephrol Unit, Pavia, Italy.
    Esposito, C.
    Maugeri Fdn, Nephrol Unit, Pavia, Italy.
    Migotto, C.
    Maugeri Fdn, Nephrol Unit, Pavia, Italy.
    Triolo, G.
    Nephrol Unit CTO, Turin, Italy.
    Mariano, F.
    Nephrol Unit CTO, Turin, Italy.
    Pozzi, C.
    Bassini Hosp, Nephrol Unit, Cinisello Balsamo, Italy.
    Boero, R.
    Martini Hosp, Nephrol Unit, Turin, Italy.
    Bellur, S.
    Oxford Univ Hosp NHS Fdn Trust, John Radcliffe Hosp, Dept Cellular Pathol, Oxford, England.
    Mazzucco, G.
    Univ Turin, Pathol Dept, Turin, Italy.
    Giannakakis, C.
    Sapienza Univ, Pathol Dept, Rome, Italy.
    Honsova, E.
    Inst Clin & Expt Med, Dept Clin & Transplant Pathol, Prague, Czech Republic.
    Sundelin, B.
    Karolinska Univ Hosp, Karolinska Inst, Dept Pathol & Cytol, Stockholm, Sweden.
    Di Palma, A. M.
    Aldo Moro Univ, Nephrol Unit, Foggia, Italy.
    Gutierrez, E.
    Univ Autonoma Madrid, Fdn Jimenez Diaz, Fdn Inst Invest Sanitarias, Renal Vasc & Diabet Res Lab, Madrid, Spain.
    Asunis, A. M.
    Brotzu Hosp, Dept Pathol, Cagliari, Italy.
    Barratt, J.
    Leicester Gen Hosp, John Walls Renal Unit, Leicester, Leics, England;Leicester Gen Hosp, John Walls Renal Unit, Leicester, Leics, England.
    Tardanico, R.
    Univ Brescia, Spedali Civili Hosp, Dept Pathol, Brescia, Italy.
    Perkowska-Ptasinska, A.
    Med Univ Warsaw, Dept Transplantat Med Nephrol & Internal Med, Warsaw, Poland.
    Arce Terroba, J.
    Fundacio Puigvert, Pathol Dept, Barcelona, Spain.
    Fortunato, M.
    S Croce Hosp, Pathol Dept, Cuneo, Italy.
    Pantzaki, A.
    Hippokrateion Hosp, Dept Pathol, Thessaloniki, Greece.
    Ozluk, Y.
    Istanbul Univ, Istanbul Fac Med, Dept Pathol, Istanbul, Turkey.
    Steenbergen, E.
    Radboud Univ Nijmegen, Med Ctr, Dept Pathol, Nijmegen, Netherlands.
    Soderberg, M.
    Dept Pathol Drug Safety & Metab, Huddinge, Sweden.
    Riispere, Z.
    Univ Tartu, Dept Pathol, Tartu, Estonia.
    Furci, L.
    Univ Modena, Pathol Dept, Modena, Italy.
    Orhan, D.
    Hacettepe Univ, Fac Med, Div Rheumatol, Dept Pediat, Ankara, Turkey.
    Kipgen, D.
    Queen Elizabeth Univ Hosp, Pathol Dept, Glasgow, Lanark, Scotland.
    Casartelli, D.
    Manzoni Hosp, Pathol Dept, Lecce, Italy.
    Ljubanovic, D. Galesic
    Univ Hosp Zagreb, Nephrol Dept, Zagreb, Croatia.
    Gakiopoulou, H.
    Univ Athens, Dept Pathol, Athens, Greece.
    Bertoni, E.
    Careggi Hosp, Nephrol Dept, Florence, Italy.
    Cannata Ortiz, P.
    UAM, IIS Fdn Jimenez Diaz, Pathol Dept, Madrid, Spain.
    Karkoszka, H.
    Med Univ Silesia, Nephrol Endocrinol & Metab Dis, Katowice, Poland.
    Groene, H. J.
    German Canc Res Ctr, Cellular & Mol Pathol, Heidelberg, Germany.
    Stoppacciaro, A.
    Sapienza Univ Rome, Osped St Andrea, Dept Clin & Mol Med, Surg Pathol Unit, Rome, Italy.
    Bajema, I.
    Leiden Univ, Med Ctr, Dept Pathol, Leiden, Netherlands.
    Bruijn, J.
    Leiden Univ, Med Ctr, Dept Pathol, Leiden, Netherlands;Leiden Univ, Med Ctr, Dept Pathol, Leiden, Netherlands.
    Fulladosa Oliveras, X.
    Bellvitge Univ Hosp, Nephrol Unit, Barcelona, Spain.
    Maldyk, J.
    Med Univ Warsaw, Childrens Clin Hosp, Div Pathomorphol, Warsaw, Poland.
    Loachim, E.
    Univ Ioannina, Med Sch, Dept Pathol, Ioannina, Greece.
    Bavbek, N.
    Vanderbilt Univ, Dept Pathol, Nashville, TN USA.
    Cook, T.
    Imperial Coll, London, England.
    Alpers, C.
    Univ Washington, Med Ctr, Dept Pathol, Seattle, WA 98195 USA.
    Berthoux, F.
    CHU St Etienne, Hop Nord, Dept Nephrol Dialysis & Renal Transplantat, St Etienne, France.
    Bonsib, S.
    LSU Hlth Sci Ctr, Dept Pathol, Shreveport, LA USA.
    D'Agati, V
    Columbia Univ, Coll Phys & Surg, Dept Pathol, New York, NY USA.
    D'Amico, G.
    Fdn DAmico Ric Malattie Renali, Milan, Italy.
    Emancipator, S.
    Case Western Reserve Univ, Dept Pathol, Cleveland, OH 44106 USA.
    Emmal, F.
    Bambino Gesu Childrens Hosp & Res Inst, Dept Nephrol & Urol, Div Nephrol & Dialysis, Rome, Italy.
    Fervenza, F.
    Mayo Clin, Div Nephrol & Hypertens, Rochester, MN USA.
    Florquin, S.
    Univ Amsterdam, Acad Med Ctr, Dept Pathol, Amsterdam, Netherlands.
    Fogo, A.
    Vanderbilt Univ, Dept Pathol, Nashville, TN USA.
    Groene, H.
    German Canc Res Ctr, Dept Cellular & Mol Pathol, Heidelberg, Germany.
    Haas, M.
    Cedars Sinai Med Ctr, Dept Pathol & Lab Med, Los Angeles, CA 90048 USA.
    Hill, P.
    St Vincents Hosp, Melbourne, Vic, Australia.
    Hogg, R.
    Scott & White Med Ctr, Temple, TX USA.
    Hsu, S.
    Univ Florida, Coll Med, Div Nephrol Hypertens & Renal Transplantat, Gainesville, FL USA.
    Hunley, T.
    Vanderbilt Univ, Dept Pathol, Nashville, TN USA.
    Hladunewich, M.
    Jennette, C.
    Univ N Carolina, Dept Pathol & Lab Med, Chapel Hill, NC 27515 USA.
    Joh, K.
    East Natl Hosp, Clin Res Ctr Chiba, Div Immunopathol, Chiba, Japan.
    Julian, B.
    Univ Alabama Birmingham, Dept Med, Birmingham, AL 35294 USA.
    Kawamura, T.
    Jikei Univ, Sch Med, Div Nephrol & Hypertens, Tokyo, Japan;Jikei Univ, Sch Med, Dept Internal Med, Div Nephrol & Hypertens, Tokyo, Japan.
    Lai, F.
    Chinese Univ Hong Kong, Hong Kong, Peoples R China.
    Leung, C.
    Chinese Univ Hong Kong, Prince Wales Hosp, Dept Med, Hong Kong, Peoples R China.
    Li, L.
    Nanjing Univ, Sch Med, Jinling Hosp, Res Inst Nephrol, Nanjing, Jiangsu, Peoples R China.
    Li, P.
    Chinese Univ Hong Kong, Prince Wales Hosp, Dept Med, Hong Kong, Peoples R China.
    Liu, Z.
    Nanjing Univ, Sch Med, Nanjing, Jiangsu, Peoples R China;Nanjing Univ, Sch Med, Jinling Hosp, Res Inst Nephrol, Nanjing, Jiangsu, Peoples R China.
    Massat, A.
    Mayo Clin, Div Nephrol & Hypertens, Rochester, MN USA.
    Mackinnon, B.
    Western Infirm & Associated Hosp, Renal Unit, Glasgow, Lanark, Scotland.
    Mezzano, S.
    Univ Austral Chile, Escuela Med, Dept Nefrol, Valdivia, Chile.
    Schena, F.
    Policlinico, Renal Dialysis & Transplant Unit, Bari, Italy.
    Tomino, Y.
    Juntendo Univ, Sch Med, Dept Internal Med, Div Nephrol, Tokyo, Japan.
    Walker, P.
    Nephropathol Associates, Little Rock, AR USA.
    Wang, H.
    Peking Univ, Inst Nephrol, Hosp 1, Renal Div, Beijing, Peoples R China.
    Weening, J.
    Erasmus MC, Rotterdam, Netherlands.
    Yoshikawa, N.
    Wakayama Med Univ, Dept Pediat, Wakayama, Japan.
    Zeng, Cai-Hong
    Nanjing Univ, Sch Med, Nanjing, Jiangsu, Peoples R China.
    Shi, Sufang
    Peking Univ, Inst Nephrol, Beijing, Peoples R China.
    Nogi, C.
    Juntendo Univ, Fac Med, Tokyo, Japan.
    Suzuki, H.
    Juntendo Univ, Fac Med, Tokyo, Japan;Juntendo Univ, Fac Med, Tokyo, Japan.
    Koike, K.
    Jikei Univ, Sch Med, Dept Internal Med, Div Nephrol & Hypertens, Tokyo, Japan.
    Hirano, K.
    Jikei Univ, Sch Med, Dept Internal Med, Div Nephrol & Hypertens, Tokyo, Japan.
    Yokoo, T.
    Jikei Univ, Sch Med, Dept Internal Med, Div Nephrol & Hypertens, Tokyo, Japan.
    Hanai, M.
    Kurume Univ, Sch Med, Dept Med, Div Nephrol, Fukuoka, Fukuoka, Japan.
    Fukami, K.
    Kurume Univ, Sch Med, Dept Med, Div Nephrol, Fukuoka, Fukuoka, Japan.
    Takahashi, K.
    Fujita Hlth Univ, Sch Med, Dept Nephrol, Toyoake, Aichi, Japan.
    Yuzawa, Y.
    Fujita Hlth Univ, Sch Med, Dept Nephrol, Toyoake, Aichi, Japan.
    Niwa, M.
    Nagoya Univ, Grad Sch Med, Dept Nephrol, Nagoya, Aichi, Japan.
    Yasuda, Y.
    Nagoya Univ, Grad Sch Med, Dept Nephrol, Nagoya, Aichi, Japan.
    Maruyama, S.
    Nagoya Univ, Grad Sch Med, Dept Nephrol, Nagoya, Aichi, Japan.
    Ichikawa, D.
    St Marianna Univ, Sch Med, Dept Internal Med, Div Nephrol & Hypertens, Kawasaki, Kanagawa, Japan.
    Suzuki, T.
    Juntendo Univ, Fac Med, Tokyo, Japan;St Marianna Univ, Sch Med, Dept Internal Med, Div Nephrol & Hypertens, Kawasaki, Kanagawa, Japan.
    Shirai, S.
    St Marianna Univ, Sch Med, Dept Internal Med, Div Nephrol & Hypertens, Kawasaki, Kanagawa, Japan.
    Fukuda, A.
    Miyazaki Univ, Fac Med, Dept Internal Med 1, Miyazaki, Japan.
    Fujimoto, S.
    Univ Miyazaki, Fac Med, Dept Hemovasc Med & Artificial Organs, Miyazaki, Japan.
    Trimarchi, H.
    Hosp Britanico, Div Nephrol, Buenos Aires, DF, Argentina.
    Evaluating a New International Risk-Prediction Tool in IgA Nephropathy2019In: JAMA Internal Medicine, ISSN 2168-6106, E-ISSN 2168-6114, Vol. 179, no 7, p. 942-952Article in journal (Refereed)
    Abstract [en]

    Importance  Although IgA nephropathy (IgAN) is the most common glomerulonephritis in the world, there is no validated tool to predict disease progression. This limits patient-specific risk stratification and treatment decisions, clinical trial recruitment, and biomarker validation.

    Objective  To derive and externally validate a prediction model for disease progression in IgAN that can be applied at the time of kidney biopsy in multiple ethnic groups worldwide.

    Design, Setting, and Participants  We derived and externally validated a prediction model using clinical and histologic risk factors that are readily available in clinical practice. Large, multi-ethnic cohorts of adults with biopsy-proven IgAN were included from Europe, North America, China, and Japan.

    Main Outcomes and Measures  Cox proportional hazards models were used to analyze the risk of a 50% decline in estimated glomerular filtration rate (eGFR) or end-stage kidney disease, and were evaluated using the R2D measure, Akaike information criterion (AIC), C statistic, continuous net reclassification improvement (NRI), integrated discrimination improvement (IDI), and calibration plots.

    Results  The study included 3927 patients; mean age, 35.4 (interquartile range, 28.0-45.4) years; and 2173 (55.3%) were men. The following prediction models were created in a derivation cohort of 2781 patients: a clinical model that included eGFR, blood pressure, and proteinuria at biopsy; and 2 full models that also contained the MEST histologic score, age, medication use, and either racial/ethnic characteristics (white, Japanese, or Chinese) or no racial/ethnic characteristics, to allow application in other ethnic groups. Compared with the clinical model, the full models with and without race/ethnicity had better R2D (26.3% and 25.3%, respectively, vs 20.3%) and AIC (6338 and 6379, respectively, vs 6485), significant increases in C statistic from 0.78 to 0.82 and 0.81, respectively (ΔC, 0.04; 95% CI, 0.03-0.04 and ΔC, 0.03; 95% CI, 0.02-0.03, respectively), and significant improvement in reclassification as assessed by the NRI (0.18; 95% CI, 0.07-0.29 and 0.51; 95% CI, 0.39-0.62, respectively) and IDI (0.07; 95% CI, 0.06-0.08 and 0.06; 95% CI, 0.05-0.06, respectively). External validation was performed in a cohort of 1146 patients. For both full models, the C statistics (0.82; 95% CI, 0.81-0.83 with race/ethnicity; 0.81; 95% CI, 0.80-0.82 without race/ethnicity) and R2D (both 35.3%) were similar or better than in the validation cohort, with excellent calibration.

    Conclusions and Relevance  In this study, the 2 full prediction models were shown to be accurate and validated methods for predicting disease progression and patient risk stratification in IgAN in multi-ethnic cohorts, with additional applications to clinical trial design and biomarker research.

  • 10.
    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.

  • 11.
    Cameron-Christie, Sophia
    et al.
    AstraZeneca, R&D BioPharmaceut, Discovery Sci, AstraZeneca Ctr Genom Res, Cambridge, England.
    Wolock, Charles J.
    Columbia Univ, Dept Genet & Dev, New York, NY USA.
    Groopman, Emily
    Columbia Univ, Dept Med, Div Nephrol, New York, NY USA.
    Petrovski, Slave
    AstraZeneca, R&D BioPharmaceut, Discovery Sci, AstraZeneca Ctr Genom Res, Cambridge, England.
    Kamalakaran, Sitharthan
    Columbia Univ, Dept Genet & Dev, New York, NY USA.
    Povysil, Gundula
    AstraZeneca, R&D BioPharmaceut, Discovery Sci, AstraZeneca Ctr Genom Res, Cambridge, England;Columbia Univ, Med Ctr, Inst Genom Med, New York, NY USA.
    Vitsios, Dimitrios
    AstraZeneca, R&D BioPharmaceut, Discovery Sci, AstraZeneca Ctr Genom Res, Cambridge, England.
    Zhang, Mengqi
    Columbia Univ, Med Ctr, Inst Genom Med, New York, NY USA;Duke Univ, Dept Biostatist & Bioinformat, Durham, NC USA.
    Fleckner, Jan
    AstraZeneca, R&D BioPharmaceut, Discovery Sci, AstraZeneca Ctr Genom Res, Cambridge, England.
    March, Ruth E.
    AstraZeneca, R&D Oncol, Precis Med, Cambridge, England.
    Gelfman, Sahar
    Columbia Univ, Dept Genet & Dev, New York, NY USA.
    Marasa, Maddalena
    Columbia Univ, Dept Med, Div Nephrol, New York, NY USA.
    Li, Yifu
    Columbia Univ, Dept Med, Div Nephrol, New York, NY USA.
    Sanna-Cherchi, Simone
    Columbia Univ, Dept Med, Div Nephrol, New York, NY USA.
    Kiryluk, Krzysztof
    Columbia Univ, Dept Med, Div Nephrol, New York, NY USA.
    Allen, Andrew S.
    Columbia Univ, Med Ctr, Inst Genom Med, New York, NY USA;Duke Univ, Dept Biostatist & Bioinformat, Durham, NC USA.
    Fellström, Bengt
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Renal Medicine.
    Haefliger, Carolina
    AstraZeneca, R&D BioPharmaceut, Discovery Sci, AstraZeneca Ctr Genom Res, Cambridge, England.
    Platt, Adam
    AstraZeneca, R&D BioPharmaceut, Discovery Sci, AstraZeneca Ctr Genom Res, Cambridge, England.
    Goldstein, David B.
    AstraZeneca, R&D BioPharmaceut, Discovery Sci, AstraZeneca Ctr Genom Res, Cambridge, England;Columbia Univ, Dept Genet & Dev, New York, NY USA;Columbia Univ, Med Ctr, Inst Genom Med, New York, NY USA.
    Gharavi, Ali G.
    Columbia Univ, Dept Med, Div Nephrol, New York, NY USA;Columbia Univ, Med Ctr, Inst Genom Med, New York, NY USA.
    Exome-Based Rare-Variant Analyses in CKD2019In: Journal of the American Society of Nephrology, ISSN 1046-6673, E-ISSN 1533-3450, Vol. 30, no 6, p. 1109-1122Article in journal (Refereed)
    Abstract [en]

    Background Studies have identified many common genetic associations that influence renal function and all-cause CKD, but these explain only a small fraction of variance in these traits. The contribution of rare variants has not been systematically examined. Methods We performed exome sequencing of 3150 individuals, who collectively encompassed diverse CKD subtypes, and 9563 controls. To detect causal genes and evaluate the contribution of rare variants we used collapsing analysis, in which we compared the proportion of cases and controls carrying rare variants per gene. Results The analyses captured five established monogenic causes of CKD: variants in PKD1, PKD2, and COL4A5 achieved study-wide significance, and we observed suggestive case enrichment for COL4A4 and COL4A3. Beyond known disease-associated genes, collapsing analyses incorporating regional variant intolerance identified suggestive dominant signals in CPT2 and several other candidate genes. Biallelic mutations in CPT2 cause carnitine palmitoyltransferase II deficiency, sometimes associated with rhabdomyolysis and acute renal injury. Genetic modifier analysis among cases with APOL1 risk genotypes identified a suggestive signal in AHDC1, implicated in Xia-Gibbs syndrome, which involves intellectual disability and other features. On the basis of the observed distribution of rare variants, we estimate that a two-to three-fold larger cohort would provide 80% power to implicate new genes for all-cause CKD. Conclusions This study demonstrates that rare-variant collapsing analyses can validate known genes and identify candidate genes and modifiers for kidney disease. In so doing, these findings provide a motivation for larger-scale investigation of rare-variant risk contributions across major clinical CKD categories.

  • 12.
    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)
  • 13.
    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.
    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 Surgical Sciences, Forensic 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.
    Conducting Nanocellulose Polypyrrole Membranes Intended for Hemodialysis2012In: European Cells and Materials, ISSN 1473-2262, E-ISSN 1473-2262, Vol. 23, no Suppl 5, p. 32-32Article in journal (Refereed)
  • 14.
    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)
  • 15.
    Carlsson, Daniel O
    et al.
    Uppsala University, Disciplinary Domain of Science and Technology, Technology, Department of Engineering Sciences, Nanotechnology and Functional Materials.
    Nyström, Gustav
    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.
    Shou, Qi
    Berglund, Lars A
    Fellström, Bengt
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    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.
    Development of Nanocellulose/Polypyrrole Composites Towards Blood Purification2012In: Euromembrane 2012, Queen Elizabeth II Conference Centre, London, UK, 23-27 September 2012, 2012Conference paper (Refereed)
  • 16. Coppo, Rosanna
    et al.
    D'Arrigo, Graziella
    Tripepi, Giovanni
    Russo, Maria Luisa
    Roberts, Ian S D
    Bellur, Shubha
    Cattran, Daniel
    Cook, Terence H
    Feehally, John
    Tesar, Vladimir
    Maixnerova, Dita
    Peruzzi, Licia
    Amore, Alessandro
    Lundberg, Sigrid
    Di Palma, Anna Maria
    Gesualdo, Loreto
    Emma, Francesco
    Rollino, Cristiana
    Praga, Manuel
    Biancone, Luigi
    Pani, Antonello
    Feriozzi, Sandro
    Polci, Rosaria
    Barratt, Jonathan
    Del Vecchio, Lucia
    Locatelli, Francesco
    Pierucci, Alessandro
    Caliskan, Yasar
    Perkowska-Ptasinska, Agnieszka
    Durlik, Magdalena
    Moggia, Elisabetta
    Ballarin, José C
    Wetzels, Jack F M
    Goumenos, Dimitris
    Papasotiriou, Marios
    Galesic, Kresimir
    Toric, Luka
    Papagianni, Aikaterini
    Stangou, Maria
    Benozzi, Luisa
    Cusinato, Stefano
    Berg, Ulla
    Topaloglu, Rezan
    Maggio, Milena
    Ots-Rosenberg, Mai
    D'Amico, Marco
    Geddes, Colin
    Balafa, Olga
    Quaglia, Marco
    Cravero, Raffaella
    Lino Cirami, Calogero
    Fellström, Bengt
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Renal Medicine.
    Floege, Jürgen
    Egido, Jesus
    Mallamaci, Francesca
    Zoccali, Carmine
    Is there long-term value of pathology scoring in immunoglobulin A nephropathy?: A validation study of the Oxford Classification for IgA Nephropathy (VALIGA) update2018In: Nephrology, Dialysis and Transplantation, ISSN 0931-0509, E-ISSN 1460-2385Article in journal (Refereed)
    Abstract [en]

    Background: It is unknown whether renal pathology lesions in immunoglobulin A nephropathy (IgAN) correlate with renal outcomes over decades of follow-up.

    Methods: In 1130 patients of the original Validation Study of the Oxford Classification for IgA Nephropathy (VALIGA) cohort, we studied the relationship between the MEST score (mesangial hypercellularity, M; endocapillary hypercellularity, E; segmental glomerulosclerosis, S; tubular atrophy/interstitial fibrosis, T), crescents (C) and other histological lesions with both a combined renal endpoint [50% estimated glomerular filtration rate (eGFR) loss or kidney failure] and the rate of eGFR decline over a follow-up period extending to 35 years [median 7 years (interquartile range 4.1-10.8)].

    Results: In this extended analysis, M1, S1 and T1-T2 lesions as well as the whole MEST score were independently related with the combined endpoint (P < 0.01), and there was no effect modification by age for these associations, suggesting that they may be valid in children and in adults as well. Only T lesions were associated with the rate of eGFR loss in the whole cohort, whereas C showed this association only in patients not treated with immunosuppression. In separate prognostic analyses, the whole set of pathology lesions provided a gain in discrimination power over the clinical variables alone, which was similar at 5 years (+2.0%) and for the whole follow-up (+1.8%). A similar benefit was observed for risk reclassification analyses (+2.7% and +2.4%).

    Conclusion: Long-term follow-up analyses of the VALIGA cohort showed that the independent relationship between kidney biopsy findings and the risk of progression towards kidney failure in IgAN remains unchanged across all age groups and decades after the renal biopsy.

  • 17. Dahle, Dag Olav
    et al.
    Mjoen, Geir
    Oqvist, Bjorn
    Scharnagl, Hubert
    Weihrauch, Gisela
    Grammer, Tanja
    Maerz, Winfried
    Abedini, Sadollah
    Norby, Gudrun E.
    Holme, Ingar
    Fellström, Bengt
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Jardine, Alan
    Holdaas, Hallvard
    Inflammation-associated graft loss in renal transplant recipients2011In: Nephrology, Dialysis and Transplantation, ISSN 0931-0509, E-ISSN 1460-2385, Vol. 26, no 11, p. 3756-3761Article in journal (Refereed)
    Abstract [en]

    Background. Although short-term graft survival has improved substantially in renal transplant recipients, long-term graft survival has not improved over the last decades. The lack of knowledge of specific causes and risk factors has hampered improvements in long-term allograft survival. There is an uncertainty if inflammation is associated with late graft loss.

    Methods. We examined, in a large prospective trial, the inflammation markers high-sensitivity C-reactive protein (hsCRP) and interleukin-6 (IL-6) and their association with chronic graft dysfunction. We collected data from the Assessment of Lescol in Renal Transplant trial, which recruited 2102 maintenance renal transplant recipients.

    Results. Baseline values were hsCRP 3.8 +/- 6.7 mg/L and IL-6 2.9 +/- 1.9 pg/mL. Adjusted for traditional risk factors, hsCRP and IL-6 were independently associated with death-censored graft loss, the composite end points graft loss or death and doubling of serum creatinine, graft loss or death.

    Conclusion. The inflammation markers hsCRP and IL-6 are associated with long-term graft outcomes in renal transplant recipients.

  • 18.
    de Laval, Philip
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Renal Medicine.
    Mobarrez, Fariborz
    Karolinska Univ Hosp, Karolinska Inst, Unit Rheumatol, Dept Med, Solna, Sweden.
    Almquist, Tora
    Danderyd Hosp, Karolinska Inst, Dept Clin Sci, Div Nephrol, Stockholm, Sweden.
    Vassil, Liina
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Renal Medicine.
    Fellström, Bengt
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Renal Medicine.
    Soveri, Inga
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Renal Medicine.
    Acute effects of haemodialysis on circulating microparticles2019In: Clinical Kidney Journal, ISSN 2048-8505, E-ISSN 2048-8513, Vol. 12, no 3, p. 456-462Article in journal (Refereed)
    Abstract [en]

    Background. Microparticles (MPs) are small cell membrane-derived vesicles regarded as both biomarkers and mediators of biological effects. Elevated levels of MPs have previously been associated with endothelial dysfunction and predict cardiovascular death in patients with end-stage renal disease. The objective of this study was to measure change in MP concentrations in contemporary haemodialysis (HD).

    Methods. Blood was sampled from 20 consecutive HD patients before and 1h into the HD session. MPs were measured by flow cytometry and phenotyped based on surface markers.

    Results. Concentrations of platelet (CD41(+)) (P = 0.039), endothelial (CD62E(+)) (P = 0.004) andmonocyte-derived MPs (CD14(+)) (P<0.001) significantly increased during HD. Similarly, endothelial-(P = 0.007) and monocyte-derived MPs (P = 0.001) expressing tissue factor (TF) significantly increased as well as MPs expressing Klotho (P = 0.003) and receptor for advanced glycation end products (RAGE) (P = 0.009). Furthermore, MPs expressing platelet activationmarkers P-selectin (P = 0.009) and CD40L (P = 0.045) also significantly increased. The increase of endothelial (P = 0.034), monocyte (P = 0.014) and RAGE(+) MPs (P = 0.032) as well as TF+ platelet-derived MPs (P = 0.043) was significantly higher in patients treated with low-flux compared with high-flux dialysers.

    Conclusion. Dialysis triggers release of MPs of various origins with marked differences between high-flux and low-flux dialysers. The MPs carry surface molecules that could possibly influence coagulation, inflammation, oxidative stress and endothelial dysfunction. The clinical impact of these findings remains to be established in future studies.

  • 19. 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)
  • 20. 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.

  • 21. Dzabic, Mensur
    et al.
    Rahbar, Afsar
    Yaiw, Koon-Chu
    Naghibi, Mansour
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology.
    Religa, Piotr
    Fellström, Bengt
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Larsson, Erik
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology.
    Söderberg-Nauclér, Cecilia
    Intragraft Cytomegalovirus Protein Expression Is Associated With Reduced Renal Allograft Survival2011In: Clinical Infectious Diseases, ISSN 1058-4838, E-ISSN 1537-6591, Vol. 53, no 10, p. 969-976Article in journal (Refereed)
    Abstract [en]

    Background: Cytomegalovirus (CMV) infection is a risk factor for acute and chronic rejection of transplanted organs and is thought to mediate rejection indirectly.

    Methods: In this retrospective observational cohort study, early- and end-stage biopsies from renal allografts lost because of chronic allograft dysfunction (n = 29) were examined for CMV antigens and DNA using immunohistochemistry, in situ hybridization, and real-time polymerase chain reaction.

    Results: CMV immediate-early and late proteins were present in 27 (93%) of 29 of the end-stage chronic allograft dysfunction biopsies and in 64% of the corresponding early biopsies but not in pretransplant biopsies from CMV-seronegative donors (n = 3). Graft survival time was reduced in patients with moderate or high CMV levels in the graft soon after transplantation compared with that in patients with no or low CMV levels in the graft. No significant difference was observed in serum creatinine obtained at the time of early biopsies.

    Conclusions: We provide evidence that intragraft CMV protein expression is associated with end-stage chronic renal allograft dysfunction, that intragraft CMV levels increase as graft function deteriorates, and that CMV protein expression in the grafts soon after transplant is associated with reduced graft survival. Thus, CMV may have a pathological role in chronic renal allograft dysfunction.

  • 22.
    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.

  • 23.
    Fellstrom, Bengt
    Uppsala University, Medicinska vetenskapsområdet, Faculty of Medicine, Department of Medical Sciences. Uppsala University, Medicinska vetenskapsområdet, Faculty of Medicine, Department of Medical Sciences.
    Cyclosporine nephrotoxicity2004In: Transplantation ProceedingsArticle in journal (Other (popular scientific, debate etc.))
  • 24.
    Fellstrom, Bengt
    Uppsala University, Medicinska vetenskapsområdet, Faculty of Medicine, Department of Medical Sciences. Uppsala University, Medicinska vetenskapsområdet, Faculty of Medicine, Department of Medical Sciences.
    Donor antigen Independent Risk Factors for Chronic Allograft Nephropathy2004In: Transplant Review, p. 61-66Article in journal (Other (popular scientific, debate etc.))
  • 25.
    Fellstrom, Bengt
    Uppsala University, Medicinska vetenskapsområdet, Faculty of Medicine, Department of Medical Sciences.
    Non-immune risk factors for chronic renal allograft dysfunction2001In: TransplantationArticle in journal (Other (popular scientific, debate etc.))
  • 26.
    Fellstrom, Bengt
    Uppsala University, Medicinska vetenskapsområdet, Faculty of Medicine, Department of Medical Sciences.
    Pathophysiology of progression of chronic graft dysfunction2001In: Transplantation Proceedings, p. 299-301Article in journal (Other (popular scientific, debate etc.))
  • 27.
    Fellstrom, Bengt
    Uppsala University, Medicinska vetenskapsområdet, Faculty of Medicine, Department of Medical Sciences.
    Progression of chronic renal transplant dysfunction2001In: Transplantation Proceedings, p. 3355-6Article in journal (Other (popular scientific, debate etc.))
  • 28.
    Fellstrom, Bengt
    Uppsala University, Medicinska vetenskapsområdet, Faculty of Medicine, Department of Medical Sciences.
    Risk factors for and Management of Post-Transplantation Cardiovascular Disease2001In: BioDrugs, p. 261-278Article in journal (Other (popular scientific, debate etc.))
  • 29.
    Fellstrom, Bengt
    et al.
    Uppsala University, Medicinska vetenskapsområdet, Faculty of Medicine, Department of Medical Sciences.
    Holdaas, H
    Uppsala University, Medicinska vetenskapsområdet, Faculty of Medicine, Department of Medical Sciences.
    Jardine, A
    Uppsala University, Medicinska vetenskapsområdet, Faculty of Medicine, Department of Medical Sciences.
    Cardiovascular Disease in Renal Transplantation-Management by Statins2004In: Transplant ReviewArticle in journal (Other (popular scientific, debate etc.))
  • 30.
    Fellstrom, Bengt
    et al.
    Uppsala University, Medicinska vetenskapsområdet, Faculty of Medicine, Department of Medical Sciences.
    Zezina, L
    Apoptosis - Friend or Foe2001In: Transplantation Proceedings, p. 2414-6Article in journal (Other (popular scientific, debate etc.))
  • 31.
    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)
  • 32.
    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)
  • 33.
    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.

  • 34.
    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)
  • 35.
    Fellström, Bengt
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Holdaas, Hallvard
    Jardine, Alan G.
    Holme, Ingar
    Nyberg, Gudrun
    Fauchald, Per
    Grönhagen-Siska, Carola
    Madsen, Sören
    Neumayer, Hans-Hellmut
    Cole, Edward
    Maes, Bart
    Ambühl, Patrice
    Olsson, Anders G.
    Hartmann, Anders
    Logan, John O.
    Pedersen, Terje R.
    Effect of fluvastatin on renal end points in the Assessment of Lescol in Renal Transplant (ALERT) trial2004In: Kidney International, ISSN 0085-2538, E-ISSN 1523-1755, Vol. 66, no 4, p. 1549-1555Article in journal (Refereed)
    Abstract [en]

    BACKGROUND: Hyperlipidemia is a risk factor for long-term renal transplant dysfunction, but no prospective clinical trials have investigated the effects of statin treatment on graft function in renal transplant recipients. The aim of the present study was to evaluate the effect of fluvastatin on long-term renal transplant function and development of chronic allograft nephropathy in the ALERT (Assessment of Lescol in Renal Transplantation) study. METHODS: ALERT was a randomized, double-blind, placebo-controlled study of the effect of fluvastatin, 40 mg and 80 mg daily, in renal transplant recipients. Patients were randomized to receive either fluvastatin (N= 1050) or placebo (N= 1052) and followed for five to six years. Renal end points included graft loss or doubling of serum creatinine or death; glomerular filtration rate (GFR) was also measured during follow-up in a subset of patients (N= 439). RESULTS: There were 283 patients (13.5%) with graft loss, mainly due to chronic rejection (82%), yielding an annual rate of 2.4%. Fluvastatin treatment significantly lowered mean low-density lipoprotein (LDL)-cholesterol levels by 32% (95% CI -33 to -30) compared with placebo, but had no significant effect on the incidence of renal graft loss or doubling of serum creatinine, or decline in GFR throughout follow-up in the whole study population. Neither was any treatment effect by fluvastatin found in any of the subgroups analyzed. CONCLUSION: Fluvastatin treatment significantly improves lipid values in renal transplant recipients but has no effect on graft loss or doubling of serum creatinine.

  • 36.
    Fellström, Bengt
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Holdaas, Hallvard
    Jardine, Alan G.
    Nyberg, Gudrun
    Grönhagen-Riska, Carola
    Madsen, Soren
    Neumayer, Hans-Hellmut
    Cole, Edward
    Maes, Bart
    Ambühl, Patrice
    Olsson, Anders G.
    Staffler, Beatrix
    Pedersen, Terje R.
    Risk factors for reaching renal endpoints in the assessment of Lescol in renal transplantation (ALERT) trial2005In: Transplantation, ISSN 0041-1337, E-ISSN 1534-6080, Vol. 79, no 2, p. 205-212Article in journal (Refereed)
    Abstract [en]

    BACKGROUND: The aim of the study was to identity risk factors for long-term renal transplant function and development of chronic allograft nephropathy (CAN) in renal transplant recipients included in the Assessment of Lescol in Renal Transplantation (ALERT) trial. METHODS: The ALERT trial was a randomized, double-blind, placebo-controlled study of the effect of fluvastatin, 40 and 80 mg/day, in renal transplant recipients who were randomized to receive fluvastatin (Lescol) (n = 1,050) or placebo (n = 1,052) over 5 to 6 years of follow-up. Renal endpoints including graft loss or doubling of serum creatinine or death were analyzed by univariate and multivariate regression analysis in the placebo group. RESULTS: There were 137 graft losses (13.5%) in the placebo group, mainly caused by CAN (82%). Univariate risk factors for graft loss or doubling of serum creatinine were as follows: serum creatinine, proteinuria, hypertension, pulse pressure, time since transplantation, donor age, human leukocyte antigen-DR mismatches, treatment for rejection, low high-density lipoprotein cholesterol, and smoking. Multivariate analysis revealed independent risk factors for graft loss as follows: serum creatinine (relative risk [RR], 3.12 per 100-microM increase), proteinuria (RR, 1.64 per 1-g/24 hr increase), and pulse pressure (RR, 1.12 per 10 mm Hg), whereas age was a protective factor. With patient death in the composite endpoint, diabetes mellitus, smoking, age, and number of transplantations were also risk factors. CONCLUSIONS: Independent risk factors for graft loss or doubling of serum creatinine or patient death are mainly related to renal transplant function, proteinuria, and blood pressure, which emphasizes the importance of renoprotective treatment regimens in this population.

  • 37.
    Fellström, Bengt
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Renal Medicine.
    Holmdahl, J.
    Univ Gothenburg, Sahlgrenska Acad, Dept Nephrol, Gothenburg, Sweden.
    Sundvall, N.
    Sunderby Hosp, Unit Nephrol, Lulea, Sweden.
    Cockburn, E.
    Astellas Pharma, Kastrup, Denmark.
    Kilany, S.
    Astellas Pharma, Kastrup, Denmark.
    Wennberg, L.
    Karolinska Univ Hosp, Div Transplantat Surg, Huddinge, Sweden;Karolinska Univ Hosp, CLINTEC, Huddinge, Sweden;Karolinska Inst, Stockholm, Sweden.
    Adherence of Renal Transplant Recipients to Once-daily, Prolonged-Release and Twice-daily, Immediate-release Tacrolimus-based Regimens in a Real-life Setting in Sweden2018In: Transplantation Proceedings, ISSN 0041-1345, E-ISSN 1873-2623, Vol. 50, no 10, p. 3275-3282Article in journal (Refereed)
    Abstract [en]

    Background. In this study we investigated medication adherence of kidney transplant patients (KTPs) to an immediate-release tacrolimus (IR-T) regimen and, after conversion, to a prolonged-release tacrolimus (PR-T) regimen in routine clinical practice. Methods. This was a non-interventional, observational, multicenter Swedish study. We included adult KTPs with stable graft function, remaining on IR-T or converting from IR-T to PR-T. Data were collected at baseline, and months 3, 6, and 12 post-baseline. The primary endpoint was adherence using the Basel Assessment of Adherence to Immunosuppressive Medication Scale (BAASIS). Secondary assessments included tacrolimus dose and trough levels, clinical laboratory parameters (eg, estimated glomerular filtration rate), and adverse drug reactions (ADRs). Results. Overall, data from 233 KTPs were analyzed (PR-T, n = 175; IR-T, n = 58). Mean change in PR-T dose from baseline (4.8 mg/d) to month 12 was -0.2 mg/d, and for IR-T (4.2 mg/d) was-0.4 mg/d; tacrolimus trough levels remained similar. Overall adherence was similar between baseline and month 12 in both groups (PR-T: 54.4% vs 57.0%, respectively; IR-T: 65.5% vs 69.4%); timing adherence followed a similar pattern. The probability of taking adherence improved between baseline and month 12 (odds ratio, 1.97; P =.0092) in the PR-T group only. Mean BAASIS visual analog scale score at baseline was 94.3 11.1% (PR-T) and 95.3 7.6% (IR-T), and >95% at subsequent visits. Laboratory parameters remained stable. Eight (4.6%) patients receiving PR-T (none receiving IR-T) had ADRs considered probably/possibly treatment-related. Conclusion. Disparity existed between high, patient-perceived and low, actual adherence. Overall adherence to the immunosuppressive regimen (measured by BAASIS) did not improve significantly over 12 months in stable KTPs converting to PR-T or remaining on IR-T; renal function remained stable.

  • 38.
    Fellström, Bengt
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Jardine, Alan G.
    Soveri, Inga
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Cole, E.
    Neumayer, Hans-Helmutt
    Maes, Bart
    Gimpelewicz, Claudio
    Holdaas, Hallvard
    Renal dysfunction is a strong and independent risk factor for mortality and cardiovascular complications in renal transplantation2005In: American Journal of Transplantation, ISSN 1600-6135, E-ISSN 1600-6143, Vol. 5, no 8, p. 1986-1991Article in journal (Refereed)
    Abstract [en]

    Renal transplant recipients (RTR) have shortened life expectancy, primarily due to premature cardiovascular disease (CVD). Traditional CVD risk factors are highly prevalent. In addition, several non-traditional risk factors may contribute to the high risk. The aim of the study was to evaluate the effects of renal dysfunction on mortality and cardiovascular complications in 1052 placebo-treated patients of the Assessment of LEscol in Renal Transplantation (ALERT) trial. Follow-up was 5-6 years and endpoints included cardiac death, non-cardiovascular death, all-cause mortality, major adverse cardiac event (MACE), non-fatal myocardial infarction (MI) and stroke. The effects of serum creatinine at baseline on these endpoints were evaluated. Elevated serum creatinine in RTR was a strong and independent risk factor for MACE, cardiac, non-cardiovascular, and all-cause mortality, but not for stroke or non-fatal MI alone. Serum creatinine was associated with increased mortality and MACE, independent of established CVD risk factors. Graft loss resulted in increased incidences of non-cardiovascular death, all-cause mortality, MACE and non-fatal MI. In conclusion, elevated serum creatinine is a strong risk factor for all-cause, non-cardiovascular and cardiac mortality, and MACE, independent of traditional risk factors, but not for stroke or non-fatal MI alone.

  • 39.
    Fellström, Bengt
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Jardine, Alan G.
    Soveri, Inga
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Cole, Edward
    Grönhagen-Riska, Carola
    Neumayer, Hans H.
    Maes, Bart
    Gimpelewicz, Claudio
    Holdaas, Hallvard
    Renal dysfunction as a risk factor for mortality and cardiovascular disease in renal transplantation: experience from the Assessment of Lescol in Renal Transplantation trial2005In: Transplantation, ISSN 0041-1337, E-ISSN 1534-6080, Vol. 79, no 9, p. 1160-1163Article in journal (Refereed)
    Abstract [en]

    BACKGROUND: Renal-transplant recipients have shortened life expectancy primarily because of premature cardiovascular disease. Traditional and nontraditional risk factors for cardiovascular disease are prevalent in renal patients. In renal-transplant recipients, immunosuppressive therapy can be nephrotoxic and aggravate cardiovascular disease risk factors. Renal dysfunction has been established as a risk factor for cardiovascular disease and mortality in different populations. We evaluated the effects of baseline renal-transplant function on mortality and cardiovascular and renal endpoints in 1,052 placebo-treated patients of the Assessment of Lescol in Renal Transplantation trial. METHODS: All renal-transplant recipients were on cyclosporine-based immunosuppressive therapy. Follow-up was 5 to 6 years, and endpoints included cardiac death, noncardiovascular death, all-cause mortality, major adverse cardiac event (MACE), stroke, nonfatal myocardial infarction, and graft loss. RESULTS: Baseline serum creatinine was strongly and independently associated with increased cardiac, noncardiovascular, and all-cause mortality, as well as MACE and graft loss. Serum creatinine was not a risk factor for stroke or nonfatal myocardial infarction. CONCLUSIONS: Elevated baseline serum creatinine in renal-transplant recipients is a strong and independent risk factor for all-cause, noncardiovascular and cardiac mortality, MACE, and graft loss.

  • 40.
    Fellström, Bengt
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Zannad, Faiez
    Schmieder, Roland
    Holdaas, Hallvard
    Jardine, Alan G.
    Effect of Rosuvastatin on Outcomes in Chronic Haemodialysis Patients: Baseline Data from the AURORA Study2007In: Kidney and Blood Pressure Research, ISSN 1420-4096, E-ISSN 1423-0143, Vol. 30, no 5, p. 314-322Article in journal (Refereed)
    Abstract [en]

    Background: Cardiovascular disease (CVD) is the leading cause of death in patients with end-stage renal disease (ESRD). Aims: AURORA (A study to evaluate the Use of Rosuvastatin in subjects On Regular haemodialysis: an Assessment of survival and cardiovascular events) is the first large-scale international trial to assess the effects of statins on cardiovascular outcomes in patients with ESRD on chronic haemodialysis. Preliminary baseline data from the randomised population are presented. Methods: A total of 2,775 patients from 280 centres in 25 countries were randomised into the study. Patients aged 50-80 years on regular chronic haemodialysis for at least 3 months before screening were eligible for inclusion. They were randomised 1:1 to receive either rosuvastatin 10 mg or placebo daily and assessed throughout the study. Results: The mean age at baseline was 64 years. Most patients were male (62%) and 85% were white. The median time since commencing renal replacement was 32 months. Mean total cholesterol (TC) and low-density lipoprotein cholesterol (LDL-C) levels were 4.53 mmol/l (175 mg/dl) and 2.57 mmol/l (99 mg/dl), respectively. Conclusion: Results from the AURORA trial will impact on the current guidelines and use of statins in this patient population.

  • 41.
    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.

  • 42.
    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.
    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.
    Hemocompatibility of Nanocellulose Polypyrrole Membranes Intended for Hemodialysis2012In: 9th World Biomaterials Congress, June 1-5, 2012, Chengdu, China, 2012Conference paper (Refereed)
  • 43.
    Ferraz, Natalia
    et al.
    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.
    Fellström, Bengt
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Pradhan, Sulena
    Uppsala University, Disciplinary Domain of Science and Technology, Technology, Department of Engineering Sciences, Nanotechnology and Functional Materials.
    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.
    In vitro and in vivo toxicity of rinsed and aged nanocellulose-polypyrrole composites2012In: Journal of Biomedical Materials Research. Part A, ISSN 1549-3296, E-ISSN 1552-4965, Vol. 100A, no 8, p. 2128-2138Article in journal (Refereed)
    Abstract [en]

    Novel composites of nanocellulose and the conducting polymer polypyrrole (PPy) are herein suggested as potential candidates for active ion-extraction membranes in electrochemically controlled hemodialysis. This work has defined processing parameters to obtain a biocompatible nanocellulose-PPy composite and for the first time, the effect of the composite ageing on cell viability has been studied.

    The influence of rinsing and extraction process steps, as well as ageing under different conditions (i.e. in air, at –20 ˚C and in argon), on the electroactivity and cytotoxicity of a PPy-nanocellulose composite has been investigated. The biocompatibility evaluation was based on indirect toxicity assays with fibroblasts and monocyte cell lines and an acute toxicity test in mice, while the electroactivity was evaluated by cyclic voltammetry experiments.

    The as-prepared composite did not induce any cytotoxic response in vitro or in vivo. Extensive rinsing and 48 hour incubation in biological buffer previous to the preparation of the culture medium extracts were, however, necessary to obtain a non-cytotoxic composite. The as-prepared composite was also found to exhibit acceptable electrochemical performance, which was retained upon 4 weeks storage in argon atmosphere.  It was shown that ageing of the composite had a negative effect on biocompatibility, regardless of the storage condition. Thus, to allow for long time storage of electroactive nanocellulose-PPy hemodialysis membranes, the degradation of PPy upon storage must be controlled. The present results show that the biocompatibility of PPy composites depends on the rinsing and pre-treatment of the composite material as well as the aging of the material.

  • 44.
    Groopman, Emily E.
    et al.
    Hammer Hlth Sci, Dept Med, New York, NY USA.
    Marasa, Maddalena
    Hammer Hlth Sci, Dept Med, New York, NY USA.
    Cameron-Christie, Sophia
    AstraZeneca Ctr Genom Res Precis Med & Genom, Innovat Med & Early Dev IMED Biotech Uni, Cambridge, England.
    Petrovski, Slavé
    AstraZeneca Ctr Genom Res Precis Med & Genom, Innovat Med & Early Dev IMED Biotech Uni, Cambridge, England.
    Aggarwal, Vimla S.
    Hammer Hlth Sci, Div Nephrol, Dept Pathol, New York, NY USA.
    Milo-Rasouly, Hila
    Hammer Hlth Sci, Dept Med, New York, NY USA.
    Li, Yifu
    Hammer Hlth Sci, Dept Med, New York, NY USA.
    Zhang, Junying
    Hammer Hlth Sci, Dept Med, New York, NY USA.
    Nestor, Jordan
    Hammer Hlth Sci, Dept Med, New York, NY USA.
    Krithivasan, Priya
    Hammer Hlth Sci, Dept Med, New York, NY USA.
    Lam, Wan Yee
    Hammer Hlth Sci, Dept Med, New York, NY USA.
    Mitrotti, Adele
    Hammer Hlth Sci, Dept Med, New York, NY USA.
    Piva, Stacy
    Hammer Hlth Sci, Dept Med, New York, NY USA.
    Kil, Byum H.
    Hammer Hlth Sci, Dept Med, New York, NY USA.
    Chatterjee, Debanjana
    Hammer Hlth Sci, Dept Med, New York, NY USA.
    Reingold, Rachel
    Hammer Hlth Sci, Dept Med, New York, NY USA.
    Bradbury, Drew
    Hammer Hlth Sci, Dept Med, New York, NY USA.
    DiVecchia, Michael
    Hammer Hlth Sci, Dept Med, New York, NY USA.
    Snyder, Holly
    Hammer Hlth Sci, Dept Med, New York, NY USA.
    Mu, Xueru
    Hammer Hlth Sci, Dept Med, New York, NY USA.
    Mehl, Karla
    Hammer Hlth Sci, Dept Med, New York, NY USA.
    Balderes, Olivia
    Hammer Hlth Sci, Dept Med, New York, NY USA.
    Fasel, David A.
    Hammer Hlth Sci, Dept Biomed Informat, New York, NY USA.
    Weng, Chunhua
    Hammer Hlth Sci, Dept Biomed Informat, New York, NY USA.
    Radhakrishnan, Jai
    Hammer Hlth Sci, Dept Med, New York, NY USA.
    Canetta, Pietro
    Hammer Hlth Sci, Dept Med, New York, NY USA.
    Appel, Gerald B.
    Hammer Hlth Sci, Dept Med, New York, NY USA.
    Bomback, Andrew S.
    Hammer Hlth Sci, Dept Med, New York, NY USA.
    Ahn, Wooin
    Hammer Hlth Sci, Dept Med, New York, NY USA.
    Uy, Natalie S.
    Hammer Hlth Sci, Dept Pediat, New York, NY USA.
    Alam, Shumyle
    Hammer Hlth Sci, Dept Urol, New York, NY USA.
    Cohen, David J.
    Hammer Hlth Sci, Dept Med, New York, NY USA.
    Crew, Russell J.
    Hammer Hlth Sci, Dept Med, New York, NY USA.
    Dube, Geoffrey K.
    Hammer Hlth Sci, Dept Med, New York, NY USA.
    Rao, Maya K.
    Hammer Hlth Sci, Dept Med, New York, NY USA.
    Kamalakaran, Sitharthan
    Hammer Hlth Sci, Inst Genom Med, New York, NY USA.
    Copeland, Brett
    Hammer Hlth Sci, Inst Genom Med, New York, NY USA.
    Ren, Zhong
    Hammer Hlth Sci, Inst Genom Med, New York, NY USA.
    Bridgers, Joshua
    Hammer Hlth Sci, Inst Genom Med, New York, NY USA.
    Malone, Colin D.
    Hammer Hlth Sci, Inst Genom Med, New York, NY USA.
    Mebane, Caroline M.
    Hammer Hlth Sci, Inst Genom Med, New York, NY USA.
    Dagaonkar, Neha
    Hammer Hlth Sci, Inst Genom Med, New York, NY USA.
    Fellström, Bengt C.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Renal Medicine.
    Haefliger, Carolina
    AstraZeneca Ctr Genom Res Precis Med & Genom, Innovat Med & Early Dev IMED Biotech Uni, Cambridge, England.
    Mohan, Sumit
    Hammer Hlth Sci, Dept Med, New York, NY USA;Columbia Univ, Dept Epidemiol, Mailman Sch Publ Hlth, New York, NY USA.
    Sanna-Cherchi, Simone
    Hammer Hlth Sci, Dept Med, New York, NY USA.
    Kiryluk, Krzysztof
    Hammer Hlth Sci, Dept Med, New York, NY USA.
    Fleckner, Jan
    AstraZeneca Ctr Genom Res Precis Med & Genom, Innovat Med & Early Dev IMED Biotech Uni, Cambridge, England.
    March, Ruth
    AstraZeneca Ctr Genom Res Precis Med & Genom, Innovat Med & Early Dev IMED Biotech Uni, Cambridge, England.
    Platt, Adam
    AstraZeneca Ctr Genom Res Precis Med & Genom, Innovat Med & Early Dev IMED Biotech Uni, Cambridge, England.
    Goldstein, David B.
    Hammer Hlth Sci, Inst Genom Med, New York, NY USA;Hammer Hlth Sci, Dept Genet & Dev, New York, NY USA.
    Gharavi, Ali G.
    Hammer Hlth Sci, Dept Med, New York, NY USA;Hammer Hlth Sci, Inst Genom Med, New York, NY USA.
    Diagnostic Utility of Exome Sequencing for Kidney Disease2019In: New England Journal of Medicine, ISSN 0028-4793, E-ISSN 1533-4406, Vol. 380, no 2, p. 142-151Article in journal (Refereed)
    Abstract [en]

    BACKGROUND Exome sequencing is emerging as a first-line diagnostic method in some clinical disciplines, but its usefulness has yet to be examined for most constitutional disorders in adults, including chronic kidney disease, which affects more than 1 in 10 persons globally.

    METHODS We conducted exome sequencing and diagnostic analysis in two cohorts totaling 3315 patients with chronic kidney disease. We assessed the diagnostic yield and, among the patients for whom detailed clinical data were available, the clinical implications of diagnostic and other medically relevant findings.

    RESULTS In all, 3037 patients (91.6%) were over 21 years of age, and 1179 (35.6%) were of self-identified non-European ancestry. We detected diagnostic variants in 307 of the 3315 patients (9.3%), encompassing 66 different monogenic disorders. Of the disorders detected, 39 (59%) were found in only a single patient. Diagnostic variants were detected across all clinically defined categories, including congenital or cystic renal disease (127 of 531 patients [23.9%]) and nephropathy of unknown origin (48 of 281 patients [17.1%]). Of the 2187 patients assessed, 34 (1.6%) had genetic findings for medically actionable disorders that, although unrelated to their nephropathy, would also lead to subspecialty referral and inform renal management.

    CONCLUSIONS Exome sequencing in a combined cohort of more than 3000 patients with chronic kidney disease yielded a genetic diagnosis in just under 10% of cases.

  • 45. 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.

  • 46. Herrington, William
    et al.
    Emberson, Jonathan
    Mihaylova, Borislava
    Blackwell, Lisa
    Reith, Christina
    Solbu, Marit
    Mark, Patrick
    Fellström, Bengt
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Renal Medicine.
    Jardine, Alan
    Wanner, Christoph
    Holdaas, Hallvard
    Fulcher, Jordan
    Haynes, Richard
    Landray, Martin
    Keech, Anthony
    Simes, John
    Collins, Rory
    Baigent, Colin
    Impact of renal function on the effects of LDL cholesterol lowering with statin-based regimens: a meta-analysis of individual participant data from 28 randomised trials2016In: The Lancet Diabetes and Endocrinology, ISSN 2213-8587, E-ISSN 2213-8595, Vol. 4, no 10, p. 829-839, article id S2213-8587(16)30156-5Article in journal (Refereed)
    Abstract [en]

    BACKGROUND: Statin therapy is effective for the prevention of coronary heart disease and stroke in patients with mild-to-moderate chronic kidney disease, but its effects in individuals with more advanced disease, particularly those undergoing dialysis, are uncertain.

    METHODS: We did a meta-analysis of individual participant data from 28 trials (n=183 419), examining effects of statin-based therapy on major vascular events (major coronary event [non-fatal myocardial infarction or coronary death], stroke, or coronary revascularisation) and cause-specific mortality. Participants were subdivided into categories of estimated glomerular filtration rate (eGFR) at baseline. Treatment effects were estimated with rate ratio (RR) per mmol/L reduction in LDL cholesterol.

    FINDINGS: Overall, statin-based therapy reduced the risk of a first major vascular event by 21% (RR 0·79, 95% CI 0·77-0·81; p<0·0001) per mmol/L reduction in LDL cholesterol. Smaller relative effects on major vascular events were observed as eGFR declined (p=0·008 for trend; RR 0·78, 99% CI 0·75-0·82 for eGFR ≥60 mL/min per 1·73 m(2); 0·76, 0·70-0·81 for eGFR 45 to <60 mL/min per 1·73 m(2); 0·85, 0·75-0·96 for eGFR 30 to <45 mL/min per 1·73 m(2); 0·85, 0·71-1·02 for eGFR <30 mL/min per 1·73 m(2) and not on dialysis; and 0·94, 0·79-1·11 for patients on dialysis). Analogous trends by baseline renal function were seen for major coronary events (p=0·01 for trend) and vascular mortality (p=0·03 for trend), but there was no significant trend for coronary revascularisation (p=0·90). Reducing LDL cholesterol with statin-based therapy had no effect on non-vascular mortality, irrespective of eGFR.

    INTERPRETATION: Even after allowing for the smaller reductions in LDL cholesterol achieved by patients with more advanced chronic kidney disease, and for differences in outcome definitions between dialysis trials, the relative reductions in major vascular events observed with statin-based treatment became smaller as eGFR declined, with little evidence of benefit in patients on dialysis. In patients with chronic kidney disease, statin-based regimens should be chosen to maximise the absolute reduction in LDL cholesterol to achieve the largest treatment benefits.

    FUNDING: UK Medical Research Council, British Heart Foundation, Cancer Research UK, European Community Biomed Programme, Australian National Health and Medical Research Council, Australian National Heart Foundation.

  • 47. 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.

  • 48. Holdaas, Hallvard
    et al.
    Fellstrom, Bengt
    Uppsala University, Medicinska vetenskapsområdet, Faculty of Medicine, Department of Medical Sciences.
    Holme, I
    Nyberg, Gudrun
    Fauchald, P
    Jardine, AG
    Effects of fluvastatin on cardiac events in renal transplant recipients2001In: J Cardiovasc Risk, p. 63-71Article in journal (Other (popular scientific, debate etc.))
  • 49. Holdaas, Hallvard
    et al.
    Fellstrom, Bengt
    Uppsala University, Medicinska vetenskapsområdet, Faculty of Medicine, Department of Medical Sciences.
    Jardine, Alan G
    Holme, Ingar
    Nyberg, Gudrun
    Fauchald, Per
    Gronhagen-Riska, Carola
    Madsen, Søren
    Neumayer, Hans-Hellmut
    Cole, Edward
    Maes, Bart
    Ambuhl, Patrice
    Olsson, Anders G
    Hartmann, Anders
    Solbu, Dag O
    Pedersen, Terje R
    Effect of fluvastatin on cardiac outcomes in renal transplant recipients: a multicentre, randomised, placebo-controlled trial.2003In: Lancet, ISSN 1474-547X, Vol. 361, no 9374, p. 2024-31Article in journal (Other scientific)
  • 50. Holdaas, Hallvard
    et al.
    Fellström, Bengt
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Jardine, Alan G.
    Nyberg, Gudrun
    Grönhagen-Riska, Carola
    Madsen, Sören
    Heumayer, Hans-Hellmut
    Cole, Edward
    Maes, Bart
    Ambühl, Patrice
    Logan, John O.
    Staffler, Beatrix
    Gimpelewicz, Claudio
    Beneficial effect of early initiation of lipid-lowering therapy following renal transplantation2005In: Nephrology, Dialysis and Transplantation, ISSN 0931-0509, E-ISSN 1460-2385, Vol. 20, no 5, p. 974-980Article in journal (Refereed)
    Abstract [en]

    BACKGROUND: Renal transplant recipients have a significantly reduced life expectancy, largely due to premature cardiovascular disease. The aim of the current analysis was to investigate the importance of time of initiation of therapy after transplantation, on the benefits of statin therapy. METHODS: 2102 renal transplant recipients with total cholesterol levels of 4.0-9.0 mmol/l were randomly assigned to treatment with fluvastatin (n = 1050) or placebo (n = 1052) and followed for a mean time of 5.1 years. The end-points were major cardiac events. The average median time from transplantation to randomization was 4.5 years (range: 0.5-29 years). RESULTS: In patients starting treatment with fluvastatin <4.5 years after renal transplantation, the incidence of cardiac events was 4.6% over 5.1 years vs 9.2% in those on placebo (P = 0.007). Fluvastatin significantly reduced the risk of cardiac death and non-fatal myocardial infarction by 56% [risk ratio (RR): 0.44; 95% confidence interval (95% CI): 0.26-0.74; P = 0.002]. In a more detailed analysis patients were grouped into 2-year intervals (since the last transplantation). The frequency of cardiac death and non-fatal myocardial infarction was reduced by 3.2%, 5.1%, 9.6% and 8.2% with fluvastatin treatment as compared to 6%, 10.4%, 13.4% and 9.6% with placebo when treatment was initiated at 0-2, 2-4, 4-6 and >6 years, respectively. The risk reduction for patients initiating therapy with fluvastatin at years 0-2 (compared with >6 years) following transplantation was 59% (RR: 0.41; 95% CI: 0.18-0.92; P = 0.0328). This is also reflected in total time on renal replacement therapy: in patients in the first quartile (<47 months) fluvastatin use was associated with a risk reduction of 64% compared with 19% for patients in the fourth quartile (>120 months) (P = 0.033). CONCLUSIONS: Our data support an early introduction of fluvastatin therapy in a population of transplant recipients at high risk of premature coronary heart disease.

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