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  • 1. Abedini, Sadollah
    et al.
    Holme, Ingar
    Fellström, Bengt
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Jardine, Alan
    Cole, Ed
    Maes, Bart
    Holdaas, Hallvard
    Cerebrovascular events in renal transplant recipients2009In: Transplantation, ISSN 0041-1337, E-ISSN 1534-6080, Vol. 87, no 1, p. 112-7Article in journal (Refereed)
    Abstract [en]

    BACKGROUND: The incidence of stroke and risk factors for different subtypes of cerebrovascular (CBV) events in renal transplant recipients have not been examined in any large prospective controlled trial. METHODS: The Assessment of Lescol in Renal Transplantation was a randomized, double-blind, placebo-controlled study of the effect of fluvastatin (40-80 mg) daily on cardiovascular, and renal outcomes in renal transplant recipients. Patients initially randomized to fluvastatin or placebo in the 5 to 6 year trial was offered open-label fluvastatin in a 2-year extension to the original study. We investigated the incidence of stroke and risk factors for ischemic and hemorrhagic CBV events in 2102 renal graft recipients participating in the Assessment of Lescol in Renal Transplantation core and extension trial with a mean follow-up of 6.7 years. RESULTS: The incidence and type of CBV events did not differ between the lipid lowering arm and the placebo arm. A total of 184 (8.8%, 95% confidence interval 4.6-12.9) of 2102 patients experienced a CBV event during follow-up, corresponding to an incidence of 1.3% CBV event per year. The mortality for patients experiencing a hemorrhagic stroke was 48% (13 of 27), whereas the mortality for ischemic strokes was 6.0% (8 of 133). Diabetes mellitus, previous CBV event, age, and serum creatinine were independent risk factors for cerebral ischemic events. The risk of a hemorrhagic cerebral event was increased by diabetes mellitus, polycystic kidney disease, left ventricular hypertrophy, and systolic blood pressure. INTERPRETATION: Risk factors for CBV events in renal transplant recipients differ according to subtype.

  • 2. Abedini, Sadollah
    et al.
    Holme, Ingar
    März, Winfried
    Weihrauch, Gisela
    Fellström, Bengt
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Jardine, Alan
    Cole, Edward
    Maes, Bart
    Neumayer, Hans-Hellmut
    Grönhagen-Riska, Carola
    Ambühl, Patrice
    Holdaas, Halvard
    Inflammation in renal transplantation2009In: Journal of the American Society of Nephrology, ISSN 1046-6673, E-ISSN 1533-3450, Vol. 4, no 7, p. 1246-1254Article in journal (Refereed)
    Abstract [en]

    BACKGROUND AND OBJECTIVES: Renal transplant recipients experience premature cardiovascular disease and death. The association of inflammation, all-cause mortality, and cardiovascular events in renal transplant recipients has not been examined in a large prospective controlled trial. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: ALERT was a randomized, double-blind, placebo-controlled study of the effect of fluvastatin on cardiovascular and renal outcomes in 2102 renal transplant recipients. Patients initially randomized to fluvastatin or placebo in the 5- to 6-yr trial were offered open-label fluvastatin in a 2-yr extension to the original study. The association between inflammation markers, high-sensitivity C-reactive protein (hsCRP), and IL-6 on cardiovascular events and all-cause mortality was investigated. RESULTS: The baseline IL-6 value was 2.9 +/- 1.9 pg/ml (n = 1751) and that of hsCRP was 3.8 +/- 6.7 mg/L (n = 1910). After adjustment for baseline values for established risk factors, the hazard ratios for a major cardiac event and all-cause mortality for IL-6 were 1.08 [95% confidence interval (CI), 1.01 to 1.15, P = 0.018] and 1.11 (95% CI, 1.05 to 1.18, P < 0.001), respectively. The adjusted hazard ratio for hsCRP for a cardiovascular event was 1.10 (95% CI, 1.01 to 1.20, P = 0.027) and for all-cause mortality was 1.15 (95% CI, 1.06 to 1.1.25, P = 0.049). CONCLUSIONS: The inflammation markers IL-6 and hsCRP are independently associated with major cardiovascular events and all-cause mortality in renal transplant recipients.

  • 3. Abedini, Sadollah
    et al.
    Meinitzer, Andreas
    Holme, Ingar
    März, Winfried
    Weihrauch, Gisela
    Fellström, Bengt
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Jardine, Alan
    Holdaas, Halvard
    Asymmetrical dimethylarginine is associated with renal and cardiovascular outcomes and all-cause mortality in renal transplant recipients2010In: Kidney International, ISSN 0085-2538, E-ISSN 1523-1755, Vol. 77, no 1, p. 44-50Article in journal (Refereed)
    Abstract [en]

    Increased plasma levels of asymmetric dimethylarginine (ADMA) are associated with endothelial dysfunction and predict the progression to dialysis and death in patients with chronic kidney disease. The effects of these increased ADMA levels in renal transplant recipients, however, are unknown. We used the data from ALERT, a randomized, double-blind, placebo-controlled study of the effect of fluvastatin on cardiovascular and renal outcomes in 2102 renal transplant recipients with stable graft function on enrollment. Patients who were initially randomized to fluvastatin or placebo in the 5- to 6-year trial were offered open-label fluvastatin in a 2-year extension of the original study. After adjustment for baseline values for established factors in this post hoc analysis, ADMA was found to be a significant risk factor for graft failure or doubling of serum creatinine (hazard ratio 2.78), major cardiac events (hazard ratio 2.61), cerebrovascular events (hazard ratio 6.63), and all-cause mortality (hazard ratio 4.87). In this trial extension, the number of end points increased with increasing quartiles of plasma ADMA levels. All end points were significantly increased in the fourth compared to the first quartile. Our study shows that elevated plasma levels of ADMA are associated with increased morbidity, mortality, and the deterioration of graft function in renal transplant recipients.

  • 4.
    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.

  • 5. 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.

  • 6.
    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.

  • 7.
    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.

  • 8.
    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.

  • 9. 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.

  • 10.
    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.

  • 11. Baigent, Colin
    et al.
    Landray, Martin J.
    Reith, Christina
    Emberson, Jonathan
    Wheeler, David C.
    Tomson, Charles
    Wanner, Christoph
    Krane, Vera
    Cass, Alan
    Craig, Jonathan
    Neal, Bruce
    Jiang, Lixin
    Hooi, Lai Seong
    Levin, Adeera
    Agodoa, Lawrence
    Gaziano, Mike
    Kasiske, Bertram
    Walker, Robert
    Massy, Ziad A.
    Feldt-Rasmussen, Bo
    Krairittichai, Udom
    Ophascharoensuk, Vuddidhej
    Fellström, Bengt
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Holdaas, Hallvard
    Tesar, Vladimir
    Wiecek, Andrzej
    Grobbee, Diederick
    de Zeeuw, Dick
    Gronhagen-Riska, Carola
    Dasgupta, Tanaji
    Lewis, David
    Herrington, William
    Mafham, Marion
    Majoni, William
    Wallendszus, Karl
    Grimm, Richard
    Pedersen, Terje
    Tobert, Jonathan
    Armitage, Jane
    Baxter, Alex
    Bray, Christopher
    Chen, Yiping
    Chen, Zhengming
    Hill, Michael
    Knott, Carol
    Parish, Sarah
    Simpson, David
    Sleight, Peter
    Young, Alan
    Collins, Rory
    The effects of lowering LDL cholesterol with simvastatin plus ezetimibe in patients with chronic kidney disease (Study of Heart and Renal Protection): a randomised placebo-controlled trial2011In: The Lancet, ISSN 0140-6736, E-ISSN 1474-547X, Vol. 377, no 9784, p. 2181-2192Article in journal (Refereed)
    Abstract [en]

    Background Lowering LDL cholesterol with statin regimens reduces the risk of myocardial infarction, ischaemic stroke, and the need for coronary revascularisation in people without kidney disease, but its effects in people with moderate-to-severe kidney disease are uncertain. The SHARP trial aimed to assess the efficacy and safety of the combination of simvastatin plus ezetimibe in such patients. Methods This randomised double-blind trial included 9270 patients with chronic kidney disease (3023 on dialysis and 6247 not) with no known history of myocardial infarction or coronary revascularisation. Patients were randomly assigned to simvastatin 20 mg plus ezetimibe 10 mg daily versus matching placebo. The key prespecified outcome was first major atherosclerotic event (non-fatal myocardial infarction or coronary death, non-haemorrhagic stroke, or any arterial revascularisation procedure). All analyses were by intention to treat. This trial is registered at ClinicalTrials.gov, NCT00125593, and I SRCTN54137607. Findings 4650 patients were assigned to receive simvastatin plus ezetimibe and 4620 to placebo. Allocation to simvastatin plus ezetimibe yielded an average LDL cholesterol difference of 0.85 mmol/L (SE 0.02; with about two-thirds compliance) during a median follow-up of 4.9 years and produced a 17% proportional reduction in major atherosclerotic events (526 [11.3%] simvastatin plus ezetimibe vs 619 [13.4%] placebo; rate ratio [RR] 0.83, 95% CI 0.74-0.94; log-rank p=0.0021). Non-significantly fewer patients allocated to simvastatin plus ezetimibe had a non-fatal myocardial infarction or died from coronary heart disease (213 [4.6%] vs 230 [5.0%]; RR 0.92,95% CI 0.76-1.11; p=0.37) and there were significant reductions in non-haemorrhagic stroke (131 [2.8%] vs 174 [3.8%]; RR 0.75,95% CI 0.60-0.94; p=0.01) and arterial revascularisation procedures (284 [6.1%] vs 352 [7.6%]; RR 0.79, 95% CI 0.68-0.93; p=0.0036). After weighting for subgroup-specific reductions in LDL cholesterol, there was no good evidence that the proportional effects on major atherosclerotic events differed from the summary rate ratio in any subgroup examined, and, in particular, they were similar in patients on dialysis and those who were not. The excess risk of myopathy was only two per 10 000 patients per year of treatment with this combination (9 [0.2%] vs 5 [0.1%]). There was no evidence of excess risks of hepatitis (21 [0.5%] vs 18 [0.4%]), gallstones (106 [2.3%] vs 106 [2.3%]), or cancer (438 [9.4%] vs 439 [9.5%], p=0.89) and there was no significant excess of death from any non-vascular cause (668 [14.4%] vs 612 [13.2%], p=0.13). Interpretation Reduction of LDL cholesterol with simvastatin 20 mg plus ezetimibe 10 mg daily safely reduced the incidence of major atherosclerotic events in a wide range of patients with advanced chronic kidney disease.

  • 12.
    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.

  • 13.
    Barratt, Jonathan
    et al.
    Univ Leicester, Coll Med Biol Sci & Psychol, Leicester, England..
    Lafayette, Richard A.
    Stanford Univ, Dept Med, Div Nephrol, Stanford, CA USA..
    Rovin, Brad H.
    Ohio State Univ, Wexner Med Ctr, Div Nephrol, Columbus, OH USA..
    Fellström, Bengt
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Renal Medicine.
    Budesonide delayed-release capsules to reduce proteinuria in adults with primary immunoglobulin A nephropathy2023In: Expert Review of Clinical Immunology, ISSN 1744-666X, E-ISSN 1744-8409, Vol. 19, no 7, p. 699-710Article in journal (Refereed)
    Abstract [en]

    IntroductionImmunoglobulin A nephropathy (IgAN) is characterized by mesangial deposition of immune complexes containing galactose-deficient IgA1 (Gd-IgA1). This Gd-IgA1 is believed to originate from mucosally sited B cells, which are abundant in the Peyer's patches-rich distal ileum. Nefecon is a targeted-release form of budesonide developed to act in the distal ileum, thereby exerting a direct action on the mucosal tissue implicated in the pathogenesis of the disease.Areas coveredThis review discusses IgAN pathophysiology and provides an overview of the current therapeutic landscape, focusing on Nefecon, the first drug to receive accelerated US approval and conditional EU approval for the treatment of patients with IgAN at risk of rapid disease progression.Expert opinionNefecon trial data thus far have demonstrated a promising efficacy profile, with a predictable pattern of adverse events. Treatment with Nefecon for 9 months reduces proteinuria substantially (Part A of the Phase 3 trial and the Phase 2b trial). A nearly complete prevention of deterioration of renal function has been observed at 12 months in patients at greatest risk of rapid disease progression. Long-term data from Part B of the Phase 3 study will provide 24-month data, furthering understanding of the durability of the 9-month treatment course.

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  • 14.
    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.

  • 15. Bredewold, Obbo W
    et al.
    Chan, Joe
    Svensson, My
    Bruchfeld, Annette
    de Fijter, Johan W
    Furuland, Hans
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Renal Medicine.
    Grinyo, Josep M
    Hartmann, Anders
    Holdaas, Hallvard
    Hellberg, Olof
    Jardine, Alan
    Mjörnstedt, Lars
    Skov, Karin
    Smerud, Knut T
    Soveri, Inga
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Renal Medicine.
    Sørensen, Søren S
    Zonneveld, Anton-Jan van
    Fellström, Bengt
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Renal Medicine.
    Cardiovascular Risk Following Conversion to Belatacept From a Calcineurin Inhibitor in Kidney Transplant Recipients: A Randomized Clinical Trial2023In: Kidney Medicine, E-ISSN 2590-0595, Vol. 5, no 1, article id 100574Article in journal (Refereed)
    Abstract [en]

    RATIONALE & OBJECTIVE: In kidney transplant recipients (KTRs), a belatacept-based immunosuppressive regimen is associated with beneficial effects on cardiovascular (CV) risk factors compared with calcineurin inhibitor (CNI)-based regimens. Our objective was to compare the calculated CV risk between belatacept and CNI (predominantly tacrolimus) treatments using a validated model developed for KTRs.

    STUDY DESIGN: Prospective, randomized, open-label, parallel-group, investigator-initiated, international multicenter trial.

    SETTING & PARTICIPANTS: KTRs aged 18-80 years with a stable graft function (estimated glomerular filtration rate > 20 mL/min/1.73 m2), 3-60 months after transplantation, treated with tacrolimus or cyclosporine A, were eligible for inclusion.

    INTERVENTION: Continuation with a CNI-based regimen or switch to belatacept for 12 months.

    OUTCOMES: Comparison of the change in the estimated 7-year risk of major adverse CV events and all-cause mortality, changes in traditional markers of CV health, as well as measures of arterial stiffness.

    RESULTS: Among the 105 KTRs randomized, we found no differences between the treatment groups in the predicted risk for major adverse CV events or mortality. Diastolic blood pressure, measured both centrally by using a SphygmoCor device and peripherally, was lower after the belatacept treatment than after the CNI treatment. The mean changes in traditional cardiovascular (CV) risk factors, including kidney transplant function, were otherwise similar in both the treatment groups. The belatacept group had 4 acute rejection episodes; 2 were severe rejections, of which 1 led to graft loss.

    LIMITATIONS: The heterogeneous baseline estimated glomerular filtration rate and time from transplantation to trial enrollment in the participants. A limited study duration of 1 year.

    CONCLUSIONS: We found no effects on the calculated CV risk by switching to the belatacept treatment. Participants in the belatacept group had not only lower central and peripheral diastolic blood pressure but also a higher rejection rate.

    FUNDING: The trial has received a financial grant from Bristol-Myers Squibb.

    TRIAL REGISTRATION: EudraCT no. 2013-001178-20.

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  • 16.
    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.

  • 17.
    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)
  • 18.
    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 & Materials, E-ISSN 1473-2262, Vol. 23, no Suppl 5, p. 32-32Article in journal (Refereed)
  • 19.
    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)
  • 20.
    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)
  • 21. Carrero, J.J.
    et al.
    Stenvinkel, Peter
    Fellström, Bengt
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Qureshi, A.R.
    Lamb, K.
    Heimbürger, O.
    Bárány, Peter
    Radhakrishnan, K.
    Lindholm, B.
    Soveri, Inga
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Nordfors, L.
    Shiels, P.G.
    Telomere attrition is associated with inflammation, low fetuin: A levels and high mortality in prevalent haemodialysis patients2008In: Journal of Internal Medicine, ISSN 0954-6820, E-ISSN 1365-2796, Vol. 263, no 3, p. 302-312Article in journal (Refereed)
    Abstract [en]

    INTRODUCTION: Chronic kidney disease (CKD) predisposes to a 10- to 20-fold increased cardiovascular risk. Patients undergo accelerated atherogenesis and vascular ageing. We investigated whether telomere attrition, a marker of cell senescence, contributes to this increased mortality risk. METHODS: This is a cross-sectional study in prevalent haemodialysis patients [n = 175; 98 Males; median (range) age: 66 (23-86) years]. Biochemical markers of oxidative stress and inflammatory status were measured in relation to the patient's leucocyte telomere length. Overall mortality was assessed after a median of 31 (range 2-42) months. RESULTS: Telomere length was shorter in CKD men, despite women being older (average +/- SD 6.41 +/- 1.23 vs. 6.96 +/- 1.48 kb, P = 0.002). Telomere length was associated with age (rho = -0.18, P = 0.01), fetuin-A (rho = 0.26, P = 0.0004), high-sensitivity C-reactive protein (rho = -0.21, P = 0.005) and IL-6 (rho = -0.17, P = 0.02). In a multivariate logistic regression (pseudo r(2) = 0.14), telomere length was associated with age >65 years (odds ratio: 2.11; 95% CI: 1.10, 4.06), sex (2.01; 1.05, 3.86), fetuin-A (1.85; 0.97, 3.50) and white blood cell count (2.04; 1.02, 4.09). Receiver operating characteristic curves identified a telomere length < 6.28 kb as a fair predictor of mortality. Finally, reduced telomere length was associated with increased mortality, independently of age, gender and inflammation (likelihood ratio 41.6, P < 0.0001), but dependently on fetuin-A levels. CONCLUSION: Age and male gender seem to be important contributors to reduced telomere length in CKD patients, possibly via persistent inflammation. Reduced telomere length also contributes to the mortality risk of these patients through pathways that could involve circulating levels of fetuin-A.

  • 22.
    Castro Tejera, Valeria
    et al.
    Department of Molecular and Clinical Medicine, Institute of Medicine, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden..
    Öhman, Lena
    Department of Microbiology and Immunology, Institute of Biomedicine, University of Gothenburg, Gothenburg, Sweden..
    Aabakken, Lars
    Department of Transplantation Medicine, Oslo University Hospital, Rikshospitalet, Norway..
    Fellström, Bengt
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Hausken, Trygve
    Department of Clinical Medicine, Haukeland University Hospital, University of Bergen, Bergen, Norway..
    Hovde, Øistein
    Department of Medicine, Innlandet Hospital Trust, Gjøvik, Norway..
    Hreinsson, Johann P
    Department of Molecular and Clinical Medicine, Institute of Medicine, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden..
    Lindberg, Greger
    Karolinska Institutet, Department of Medicine, Karolinska University Hospital Huddinge, Stockholm, Sweden..
    Venge, Per
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Simrén, Magnus
    Department of Molecular and Clinical Medicine, Institute of Medicine, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden..
    Törnblom, Hans
    Department of Molecular and Clinical Medicine, Institute of Medicine, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden..
    Randomised clinical trial and meta-analysis: mesalazine treatment in irritable bowel syndrome-effects on gastrointestinal symptoms and rectal biomarkers of immune activity.2022In: Alimentary Pharmacology and Therapeutics, ISSN 0269-2813, E-ISSN 1365-2036, Vol. 56, no 6, p. 968-979Article in journal (Refereed)
    Abstract [en]

    BACKGROUND: Low-grade immune activation in the gut is a potential treatment target in irritable bowel syndrome (IBS).

    AIMS: To determine improvement in IBS symptoms after mesalazine treatment, and the utility of measures of immune activity in the rectal mucosa METHODS: This was a randomised, double-blind, placebo-controlled, parallel-arm, multicentre trial in subjects with IBS (Rome III criteria), with an eight-week treatment period of mesalazine 2400 mg or plcebo once-daily. The primary endpoint was the global assessment of satisfactory relief of IBS symptoms in ≥50% of weeks during intervention. IBS symptoms were also measured with the IBS severity scoring system; immune activity was measured by mucosal patch technology. A post hoc meta-analysis of randomised placebo-controlled trials of mesalazine in IBS was added.

    RESULTS: Of 181 included patients, 91 received mesalazine and 90 received placebo. The primary endpoint was met by 32 (36%) patients after mesalazine and 27 (30%) after placebo (p = 0.40). There were no differences in response rates related to IBS subtype or post-infection symptom onset. More reduction of abdominal bloating was noted in the mesalazine group (p = 0.02). The meta-analysis showed no effect of mesalazine on IBS symptoms. No mucosal patch technology measure could predict response to mesalazine, and found no differences in the effects of intervention on levels of immune markers.

    CONCLUSIONS: Mesalazine is ineffective in reducing IBS symptoms. Rectal measures of immune activity by the mucosal patch technology cannot predict a higher chance of response to mesalazine.

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  • 23. 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) update2020In: Nephrology, Dialysis and Transplantation, ISSN 0931-0509, E-ISSN 1460-2385, Vol. 35, no 6, p. 1002-1009Article 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.

  • 24. 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.

  • 25.
    de Gonzalo-Calvo, David
    et al.
    Hannover Med Sch, Inst Mol & Translat Therapeut Strategies IMTTS, Carl Neuberg Str 1, D-30625 Hannover, Germany.;IRBLleida, Univ Hosp Arnau de Vilanova & Santa Maria, Translat Res Resp Med, Lleida, Spain.;Inst Hlth Carlos III, CIBER Resp Dis CIBERES, Madrid, Spain..
    Martinez-Camblor, Pablo
    Dartmouth Coll, Geisel Sch Med, Hanover, NH 03755 USA..
    Baer, Christian
    Hannover Med Sch, Inst Mol & Translat Therapeut Strategies IMTTS, Carl Neuberg Str 1, D-30625 Hannover, Germany.;Hannover Med Sch, REBIRTH Ctr Translat Regenerat Med, Hannover, Germany..
    Duarte, Kevin
    Univ Lorraine, INSERM, Ctr Invest Clin Plurithemat 1433, Inserm U1116, Nancy, France.;CHRU Nancy, Nancy, France.;F CRIN INI CRCT Network, Nancy, France..
    Girerd, Nicolas
    Univ Lorraine, INSERM, Ctr Invest Clin Plurithemat 1433, Inserm U1116, Nancy, France.;CHRU Nancy, Nancy, France.;F CRIN INI CRCT Network, Nancy, France..
    Fellström, Bengt
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Renal Medicine.
    Schmieder, Roland E.
    Friedrich Alexander Univ Erlangen Nurnberg FAU, Univ Hosp, Dept Nephrol & Hypertens, Erlangen, Germany..
    Jardine, Alan G.
    Univ Glasgow, Inst Cardiovasc & Med Sci, Glasgow, Lanark, Scotland..
    Massy, Ziad A.
    Ambroise Pare Univ, AP HP, Med Ctr, Div Nephrol, F-92100 Paris, France.;Paris Sud Univ, Paris Saclay Univ, CESP Ctr Rech Epidemiol & Sante Populat, INSERM U1018,Team 5, F-94800 Villejuif, France.;Paris Ouest Versailles St Quentin en Yvelines Uni, F-94800 Villejuif, France..
    Holdaas, Hallvard
    Oslo Univ Hosp, Rikshosp, Dept Transplantat Med, Oslo, Norway..
    Rossignol, Patrick
    Univ Lorraine, INSERM, Ctr Invest Clin Plurithemat 1433, Inserm U1116, Nancy, France.;CHRU Nancy, Nancy, France.;F CRIN INI CRCT Network, Nancy, France..
    Zannad, Faiez
    Univ Lorraine, INSERM, Ctr Invest Clin Plurithemat 1433, Inserm U1116, Nancy, France.;CHRU Nancy, Nancy, France.;F CRIN INI CRCT Network, Nancy, France..
    Thum, Thomas
    Hannover Med Sch, Inst Mol & Translat Therapeut Strategies IMTTS, Carl Neuberg Str 1, D-30625 Hannover, Germany.;Hannover Med Sch, REBIRTH Ctr Translat Regenerat Med, Hannover, Germany..
    Improved cardiovascular risk prediction in patients with end-stage renal disease on hemodialysis using machine learning modeling and circulating microribonucleic acids2020In: Theranostics, E-ISSN 1838-7640, Vol. 10, no 19, p. 8665-8676Article in journal (Refereed)
    Abstract [en]

    Rationale: To test whether novel biomarkers, such as microribonucleic acids (miRNAs), and nonstandard predictive models, such as decision tree learning, provide useful information for medical decision-making in patients on hemodialysis (HD). Methods: Samples from patients with end-stage renal disease receiving HD included in the AURORA trial were investigated (n=810). The study included two independent phases: phase I (matched cases and controls, n=410) and phase II (unmatched cases and controls, n=400). The composite endpoint was cardiovascular death, nonfatal myocardial infarction or nonfatal stroke. miRNA quantification was performed using miRNA sequencing and RT-qPCR. The CART algorithm was used to construct regression tree models. A bagging-based procedure was used for validation. Results: In phase I, miRNA sequencing in a subset of samples (n=20) revealed miR-632 as a candidate (fold change=2.9). miR-632 was associated with the endpoint, even after adjusting for confounding factors (HR from 1.43 to 1.53). These findings were not reproduced in phase II. Regression tree models identified eight patient subgroups with specific risk patterns. miR-186-5p and miR-632 entered the tree by redefining two risk groups: patients older than 64 years and with hsCRP<0.827 mg/L and diabetic patients younger than 64 years. miRNAs improved the discrimination accuracy at the beginning of the follow-up (24 months) compared to the models without miRNAs (integrated AUC [iAUC]=0.71). Conclusions: The circulating miRNA profile complements conventional risk factors to identify specific cardiovascular risk patterns among patients receiving maintenance HD.

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  • 26.
    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.

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  • 27. 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)
  • 28. 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.

  • 29. 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.

  • 30.
    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.

  • 31.
    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.))
  • 32.
    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.))
  • 33.
    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.))
  • 34.
    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.))
  • 35.
    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.))
  • 36.
    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.))
  • 37.
    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.))
  • 38.
    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.))
  • 39.
    Fellström , Bengt
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Jardine, Alan G.
    Scmieder, R.E.
    Holdaas, H.
    Bannister, K.
    Beutler, J.
    Chae, D.W.
    Chevalie, A.
    Cobbe, S.M.
    Grönhagen-Riska, C.
    De Lima, J.J.
    Lins, R.
    Mayer, G.
    McMahon, A.W.
    Parving, H.H.
    Remuzzi, G.
    Samuelsson, O.
    Sonkodi, S.
    Sci, D.
    Süleymanlar, G.
    Tsakiris, D.
    Tesar, V.
    Todorov, V.
    Wiecek, A.
    Wüthrich, R.P.
    Gottlow, M.
    Johnsson, E.
    Zannard, F.
    Rosuvastatin and Cardiovascuular Events in Patients Undergoing Hemodialysis2009In: New England Journal of Medicine, ISSN 0028-4793, E-ISSN 1533-4406, Vol. 360, no 14, p. 1395-1407Article in journal (Refereed)
    Abstract [en]

    BACKGROUND: Statins reduce the incidence of cardiovascular events in patients at high cardiovascular risk. However, a benefit of statins in such patients who are undergoing hemodialysis has not been proved. METHODS: We conducted an international, multicenter, randomized, double-blind, prospective trial involving 2776 patients, 50 to 80 years of age, who were undergoing maintenance hemodialysis. We randomly assigned patients to receive rosuvastatin, 10 mg daily, or placebo. The combined primary end point was death from cardiovascular causes, nonfatal myocardial infarction, or nonfatal stroke. Secondary end points included death from all causes and individual cardiac and vascular events. RESULTS: After 3 months, the mean reduction in low-density lipoprotein (LDL) cholesterol levels was 43% in patients receiving rosuvastatin, from a mean baseline level of 100 mg per deciliter (2.6 mmol per liter). During a median follow-up period of 3.8 years, 396 patients in the rosuvastatin group and 408 patients in the placebo group reached the primary end point (9.2 and 9.5 events per 100 patient-years, respectively; hazard ratio for the combined end point in the rosuvastatin group vs. the placebo group, 0.96; 95% confidence interval [CI], 0.84 to 1.11; P=0.59). Rosuvastatin had no effect on individual components of the primary end point. There was also no significant effect on all-cause mortality (13.5 vs. 14.0 events per 100 patient-years; hazard ratio, 0.96; 95% CI, 0.86 to 1.07; P=0.51). CONCLUSIONS: In patients undergoing hemodialysis, the initiation of treatment with rosuvastatin lowered the LDL cholesterol level but had no significant effect on the composite primary end point of death from cardiovascular causes, nonfatal myocardial infarction, or nonfatal stroke.

  • 40.
    Fellström, Bengt
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Cardioprotective role of statins in chronic kidney disease: do we have the answer?2011In: Kidney International, ISSN 0085-2538, E-ISSN 1523-1755, Vol. 79, no 9, p. 931-932Article in journal (Other academic)
    Abstract [en]

    The observational study by Szummer et al. shows that patients with advanced chronic kidney disease (CKD) are treated less with statins after myocardial infarction, even though statins benefit survival in CKD classes 1-4. The study's limitations are obvious, but such a population may be more representative. The results indicate that statins should be used more frequently after myocardial infarction in CKD classes lower than 5, a conclusion supported by the recently presented Study of Heart and Renal Protection (SHARP).

  • 41.
    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)
  • 42.
    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)
  • 43.
    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.

  • 44.
    Fellström, Bengt C.
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Jardine, Alan
    Holdaas, Hallvard
    Chronic allograft nepropathy2009In: Evidence-based nephrology / [ed] Donald A. Molony, Jonathan C. Craig, Oxford: Wiley-Blackwell , 2009, , p. 1-9p. 599-608Chapter in book (Other academic)
  • 45.
    Fellström, Bengt
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Renal Medicine.
    Helmersson, Johanna
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical Chemistry.
    Lind, Lars
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical Epidemiology.
    Soveri, Inga
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Renal Medicine.
    Thulin, Måns
    Centre for Statistics, The Swedish University of Agricultural Sciences, Uppsala, Sweden..
    Ärnlöv, Johan
    Division of Family Medicine and Primary Care, Department of Neurobiology, Care Sciences and Society (NVS), Karolinska Institutet, Stockholm, Sweden..
    Kultima, Kim
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical Chemistry.
    Larsson, Anders
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical Chemistry.
    Strong Associations Between Early Tubular Damage and Urinary Cytokine, Chemokine, and Growth Factor Levels in Elderly Males and Females2021In: Journal of Interferon and Cytokine Research, ISSN 1079-9907, E-ISSN 1557-7465, Vol. 41, no 8, p. 283-290Article in journal (Refereed)
    Abstract [en]

    Acute tubular necrosis is associated with high mortality rates and it is important to develop new biomarkers for tubular damage. The aim of this study was to investigate the effect of early tubular damage on a large number of urinary cytokines, chemokines, and growth factors. We selected 90 urine samples from the Prospective Investigation of the Vasculature in Uppsala Seniors Study (41 males and 49 females). The tubular damage markers cystatin C, neutrophil gelatinase-associated lipocalin (NGAL), and kidney injury molecule-1 (KIM-1) were analyzed in the urine samples and urinary cytokine levels were analyzed with 2 multiplex assays (proximity extension assay). After adjustment for sex, body mass index, estimated glomerular filtration rate, smoking, and multiplicity testing using the false discovery rate approach, there remained 26 cytokines that correlated significantly with urine cystatin C, 27 cytokines that correlated with NGAL, and 66 cytokines that correlated with KIM-1. Tubular damage shows a strong association with urinary cytokines, chemokines, and growth factors. Our findings indicate that multiplex proteomics could be a promising new approach to explore the complex effects of tubular damage.

  • 46.
    Fellström, Bengt
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Renal Medicine.
    Helmersson Karlqvist, Johanna
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical Chemistry.
    Lind, Lars
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical Epidemiology.
    Soveri, Inga
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Renal Medicine.
    Thulin, Måns
    Centre for Statistics, The Swedish University of Agricultural Sciences, SE-752 36 Uppsala, Sweden..
    Ärnlöv, Johan
    Division of Family Medicine and Primary Care, Department of Neurobiology, Care Sciences and Society (NVS), Karolinska Institutet, 14152 Huddinge, Sweden..
    Kultima, Kim
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical Chemistry.
    Larsson, Anders
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical Chemistry.
    Albumin Urinary Excretion Is Associated with Increased Levels of Urinary Chemokines, Cytokines, and Growth Factors Levels in Humans2021In: Biomolecules, E-ISSN 2218-273X, Vol. 11, no 3, article id 396Article in journal (Refereed)
    Abstract [en]

    The aim of the present study was to study the associations between urine albumin excretion, and a large number of urinary chemokines, cytokines, and growth factors in a normal population. We selected 90 urine samples from individuals without CVD, diabetes, stroke or kidney disease belonging to the Prospective Investigation of the Vasculature in Uppsala Seniors Study (41 males and 49 females, all aged 75 years). Urinary cytokine levels were analyzed with two multiplex assays (proximity extension assays) and the cytokine levels were correlated with urine albumin. After adjustment for sex, body mass index (BMI), estimated glomerular filtration rate (eGFR), smoking and multiplicity testing, 11 biomarkers remained significantly associated with urine albumin: thrombospondin 2, interleukin 6, interleukin 8, hepatocyte growth factor, matrix metalloproteinase-12 (MMP-12), C-X-C motif chemokine 9, tumor necrosis factor receptor superfamily member 11B, osteoprotegerin, growth-regulated alpha protein, C-X-C motif chemokine 6, oncostatin-M (OSM) and fatty acid-binding protein, intestinal, despite large differences in molecular weights. In this study, we found associations between urinary albumin and both small and large urine proteins. Additional studies are warranted to identify cytokine patterns and potential progression markers in various renal diseases.

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  • 47.
    Fellström, Bengt
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Renal Medicine.
    Helmersson-Karlqvist, Johanna
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical Chemistry.
    Lind, Lars
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical Epidemiology.
    Soveri, Inga
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Renal Medicine.
    Wu, Ping-Hsun
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Endocrinology and mineral metabolism.
    Thulin, Måns
    Uppsala University, Disciplinary Domain of Humanities and Social Sciences, Faculty of Social Sciences, Department of Statistics.
    Ärnlöv, Johan
    Dalarna Univ, Dept Sch Hlth & Social Studies, Falun, Sweden;Karolinska Inst, Div Family Med, Dept Neurobiol Care Sci & Soc, Huddinge, Sweden.
    Larsson, Anders
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical Chemistry.
    Associations Between Apolipoprotein A1, High-Density Lipoprotein Cholesterol, and Urinary Cytokine Levels in Elderly Males and Females2020In: Journal of Interferon and Cytokine Research, ISSN 1079-9907, E-ISSN 1557-7465, Vol. 40, no 2, p. 71-74Article in journal (Refereed)
    Abstract [en]

    There exists a close relationship between cardiovascular diseases and chronic kidney disease. Apolipoprotein A1 and high-density lipoprotein (HDL) cholesterol are widely used as cardiovascular risk markers but they also have anti-inflammatory properties. The aim of this study was to investigate any associations between HDL levels and cytokine levels in urine. We randomly selected 90 urine samples from the Prospective Investigation of the Vasculature in Uppsala Seniors Study (41 males and 49 females). The samples were analyzed with 2 multiplex assays, Multiplex Inflammation I and Cardiovascular II kits (Olink Bioscience, Uppsala, Sweden). We analyzed the correlations between 158 cytokines in urine with apolipoprotein A1, HDL cholesterol, apolipoprotein B, and low-density lipoprotein cholesterol. There were strong correlations for apolipoprotein A1 and HDL cholesterol with individual cytokines. After adjustment for multiplicity testing, there were 33 significant correlations between apolipoprotein A1 and cytokine levels and 14 of these were also significantly correlated with HDL cholesterol. The strongest associations were observed for IL-1 alpha, SPON2, RAGE, PAR-1, TRAIL-R2, IL-4RA, TNFRSF11A, and SCF. A total of 28 out of 33 correlations were negative, indicating a negative relationship between apolipoprotein A1 and urinary cytokines. The study shows a negative correlation between apolipoprotein A1 and HDL cholesterol and urinary cytokine levels. The finding is in agreement with the anti-inflammatory properties of HDL.

  • 48.
    Fellström, Bengt
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Holdaas, Hallvard
    Jardine, Alan
    Cardiovascular risk in renal transplantation2008In: Trends in Transplantation, ISSN 1887-455X, Vol. 2, no 2, p. 92-100Article, book review (Other academic)
    Abstract [en]

    Renal transplant patients suffer from a higher risk of cardiovascular morbidity and mortality. The risk-factor spectrum is different from the general population; several risk factors are transplantation specific, and to a large extent dependent on the immunosuppressive drugs used to prevent rejection. Due to the complexity of the risk factors, the variable impact of each factor on different cardiovascular outcomes and the inter-relationships between risk factors, it is difficult to judge the overall cardiovascular risk in a single renal transplant patient. In this paper we review risk-factor data from the literature, limited to single risk factors and their impact on single cardiovascular outcomes. We believe that a cardiovascular risk calculator specific to the renal transplant population, which takes into account all the important risk factors for a cardiovascular event, based upon a high quality database such as the ALERT data set, may provide a solid guidance to means to assess the overall cardiovascular risk in renal transplant recipients.

  • 49.
    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)
  • 50.
    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.

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