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  • 1. 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.

  • 2.
    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.

  • 3. Boeger, Carsten A.
    et al.
    Chen, Ming-Huei
    Tin, Adrienne
    Olden, Matthias
    Koettgen, Anna
    de Boer, Ian H.
    Fuchsberger, Christian
    O'Seaghdha, Conall M.
    Pattaro, Cristian
    Teumer, Alexander
    Liu, Ching-Ti
    Glazer, Nicole L.
    Li, Man
    O'Conne, Jeffrey R.
    Tanaka, Toshiko
    Peralta, Carmen A.
    Kutalik, Zoltan
    Luan, Jian'an
    Zhao, Jing Hua
    Hwang, Shih-Jen
    Akylbekova, Ermeg
    Kramer, Holly
    van der Harst, Pim
    Smith, Albert V.
    Lohman, Kurt
    de Andrade, Mariza
    Hayward, Caroline
    Kollerits, Barbara
    Toenjes, Anke
    Aspelund, Thor
    Ingelsson, Erik
    Eiriksdottir, Gudny
    Launer, Lenore J.
    Harris, Tamara B.
    Shuldiner, Alan R.
    Mitchell, Braxton D.
    Arking, Dan E.
    Franceschini, Nora
    Boerwinkle, Eric
    Egan, Josephine
    Hernandez, Dena
    Reilly, Muredach
    Townsend, Raymond R.
    Lumley, Thomas
    Siscovick, David S.
    Psaty, Bruce M.
    Kestenbaum, Bryan
    Haritunians, Talin
    Bergmann, Sven
    Vollenweider, Peter
    Waeber, Gerard
    Mooser, Vincent
    Waterworth, Dawn
    Johnson, Andrew D.
    Florez, Jose C.
    Meigs, James B.
    Lu, Xiaoning
    Turner, Stephen T.
    Atkinson, Elizabeth J.
    Leak, Tennille S.
    Aasarod, Knut
    Skorpen, Frank
    Syvänen, Ann-Christine
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Molecular Medicine. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Illig, Thomas
    Baumert, Jens
    Koenig, Wolfgang
    Kraemer, Bernhard K.
    Devuyst, Olivier
    Mychaleckyj, Josyf C.
    Minelli, Cosetta
    Bakker, Stephan J. L.
    Kedenko, Lyudmyla
    Paulweber, Bernhard
    Coassin, Stefan
    Endlich, Karlhans
    Kroemer, Heyo K.
    Biffar, Reiner
    Stracke, Sylvia
    Voelzke, Henry
    Stumvol, Michael
    Maegi, Reedik
    Campbell, Harry
    Vitart, Veronique
    Hastie, Nicholas D.
    Gudnason, Vilmundur
    Kardia, Sharon L. R.
    Liu, Yongmei
    Polasek, Ozren
    Curhan, Gary
    Kronenberg, Florian
    Prokopenko, Inga
    Rudan, Igor
    Ärnlöv, Johan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Public Health and Caring Sciences, Geriatrics.
    Hallan, Stein
    Navis, Gerjan
    Parsa, Afshin
    Ferrucci, Luigi
    Coresh, Josef
    Shlipak, Michael G.
    Bul, Shelley B.
    Paterson, Andrew D.
    Wichmann, H. -Erich
    Wareham, Nicholas J.
    Loos, Ruth J. F.
    Rotter, Jerome I.
    Pramstaller, Peter P.
    Cupples, L. Adrienne
    Beckmann, Jacques S.
    Yang, Qiong
    Heid, Iris M.
    Rettig, Rainer
    Dreisbach, Albert W.
    Bochud, Murielle
    Fox, Caroline S.
    Kao, W. H. L.
    CUBN Is a Gene Locus for Albuminuria2011In: Journal of the American Society of Nephrology, ISSN 1046-6673, E-ISSN 1533-3450, Vol. 22, no 3, p. 555-570Article in journal (Refereed)
    Abstract [en]

    Identification of genetic risk factors for albuminuria may alter strategies for early prevention of CKD progression, particularly among patients with diabetes. Little is known about the influence of common genetic variants on albuminuria in both general and diabetic populations. We performed a meta-analysis of data from 63,153 individuals of European ancestry with genotype information from genome-wide association studies (CKDGen Consortium) and from a large candidate gene study (CARe Consortium) to identify susceptibility loci for the quantitative trait urinary albumin-to-creatinine ratio (UACR) and the clinical diagnosis microalbuminuria. We identified an association between a missense variant (I2984V) in the CUBN gene, which encodes cubilin, and both UACR (P = 1.1 x 10(-11)) and microalbuminuria (P = 0.001). We observed similar associations among 6981 African Americans in the CARe Consortium. The associations between this variant and both UACR and microalbuminuria were significant in individuals of European ancestry regardless of diabetes status. Finally, this variant associated with a 41% increased risk for the development of persistent microalbuminuria during 20 years of follow-up among 1304 participants with type 1 diabetes in the prospective DCCT/EDIC Study. In summary, we identified a missense CUBN variant that associates with levels of albuminuria in both the general population and in individuals with diabetes.

  • 4.
    Bruck, Katharina
    et al.
    Amsterdam Med Ctr, European Renal Assoc European Dialysis & Transpla, Dept Med Informat, Meibergdreef 9, NL-1100 DD Amsterdam, Netherlands..
    Stel, Vianda S.
    Amsterdam Med Ctr, European Renal Assoc European Dialysis & Transpla, Dept Med Informat, Meibergdreef 9, NL-1100 DD Amsterdam, Netherlands..
    Gambaro, Giovanni
    Univ Cattolica Sacro Cuore, Columbus Gemelli Univ Hosp, Div Nephrol & Dialysis, I-00168 Rome, Italy..
    Hallan, Stein
    Norwegian Univ Sci & Technol, Fac Med, St Olavs Hosp, Dept Nephrol, N-7034 Trondheim, Norway..
    Volzke, Henry
    Univ Med Greifswald, Dept Clin Epidemiol Res, Greifswald, Germany..
    Ärnlöv, Johan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Cardiovascular epidemiology.
    Kastarinen, Mika
    Kuopio Natl Inst Hlth & Welf, Dept Internal Med & Nephrol, Finnish Med Agcy, Helsinki, Finland..
    Guessous, Idris
    Univ Hosp Geneva, Dept Community Med Primary Care & Emergency Med, Geneva, Switzerland..
    Vinhas, Jose
    Setubal Hosp Ctr, Dept Med, Setubal, Portugal..
    Stengel, Benedicte
    INSERM, U1018, Res Ctr Epidemiol & Populat Hlth, Villejuif, France..
    Brenner, Hermann
    Heidelberg Univ, German Canc Res Ctr, Network Aging Res, Div Clin Epidemiol & Aging Res, Heidelberg, Germany..
    Chudek, Jerzy
    Med Univ Silesia, Dept Nephrol Endocrinol & Metab Dis, Med Fac, Dept Pathophysiol, Katowice, Poland..
    Romundstad, Solfrid
    Norwegian Univ Sci & Technol, Levanger Hosp, Hlth Trust Nord Trendelag, Dept Nephrol, N-7034 Trondheim, Norway..
    Tomson, Charles
    Freeman Rd Hosp, Dept Nephrol, Newcastle Upon Tyne, Tyne & Wear, England..
    Otero Gonzalez, Alfonso
    Univ Hosp Orense, Dept Nephrol, Orense, Spain..
    Bello, Aminu K.
    Univ Alberta, Dept Med, Edmonton, AB, Canada..
    Ferrieres, Jean
    Toulouse Univ, Sch Med, Rangueil Hosp, Dept Cardiol, Toulouse, France..
    Palmieri, Luigi
    Ist Super Sanita, Dept Epidemiol Cerebro & Cardiovasc Dis, Viale Regina Elena 299, I-00161 Rome, Italy..
    Browne, Gemma
    Univ Coll Cork, Dept Epidemiol & Publ Hlth, Cork, Ireland.;Mercy Univ Hosp, Cork, Ireland..
    Capuano, Vincenzo
    Mercato S Severino Hosp, Unite Operat Cardiol, Salerno, Italy.;Mercato S Severino Hosp, UTIC, Salerno, Italy..
    Van Biesen, Wim
    Ghent Univ Hosp, Dept Nephrol, Ghent, Belgium..
    Zoccali, Carmine
    CNR, Ist Fisiol Clin, Clin Epidemiol & Pathophysiol Renal Dis & Hyperte, Reggio Di Calabria, Italy..
    Gansevoort, Ron
    Univ Med Ctr Groningen, Grad Sch Med Sci, Dept Nephrol, NL-9713 AV Groningen, Netherlands..
    Navis, Gerjan
    Univ Med Ctr Groningen, Dept Internal Med, Div Nephrol, NL-9713 AV Groningen, Netherlands..
    Rothenbacher, Dietrich
    Univ Ulm, Inst Epidemiol & Med Biometry, D-89069 Ulm, Germany..
    Ferraro, Pietro Manuel
    Univ Cattolica Sacro Cuore, Columbus Gemelli Univ Hosp, Div Nephrol & Dialysis, I-00168 Rome, Italy..
    Nitsch, Dorothea
    London Sch Hyg & Trop Med, Dept Noncommunicable Dis Epidemiol, London WC1, England.;UCL, London, England..
    Wanner, Christoph
    Univ Hosp Wurzburg, Dept Nephrol, Wurzburg, Germany..
    Jager, Kitty J.
    Amsterdam Med Ctr, European Renal Assoc European Dialysis & Transpla, Dept Med Informat, Meibergdreef 9, NL-1100 DD Amsterdam, Netherlands..
    Consortium, European C. K. D. Burden
    CKD Prevalence Varies across the European General Population2016In: Journal of the American Society of Nephrology, ISSN 1046-6673, E-ISSN 1533-3450, Vol. 27, no 7, p. 2135-2147Article in journal (Refereed)
    Abstract [en]

    CKD prevalence estimation is central to CKD management and prevention planning at the population level. This study estimated CKD prevalence in the European adult general population and investigated international variation in CKD prevalence by age, sex, and presence of diabetes, hypertension, and obesity. We collected data from 19 general-population studies from 13 European countries. CKD stages 1-5 was defined as eGFR <60 ml/min per 1.73 m(2), as calculated by the CKD-Epidemiology Collaboration equation, or albuminuria >30 mg/g, and CKD stages 3-5 was defined as eGFR<60 ml/min per 1.73 m(2). CKD prevalence was age- and sex-standardized to the population of the 27 Member States of the European Union (EU27). We found considerable differences in both CKD stages 1-5 and CKD stages 3-5 prevalence across European study populations. The adjusted CKD stages 1-5 prevalence varied between 3.31% (95% confidence interval [95% CI], 3.30% to 3.33%) in Norway and 17.3% (95% Cl, 16.5% to 18.1%) in northeast Germany. The adjusted CKD stages 3-5 prevalence varied between 1.0% (95% CI, 0.7% to 1.3%) in central Italy and 5.9% (95% CI, 5.2% to 6.6%) in northeast Germany. The variation in CKD prevalence stratified by diabetes, hypertension, and obesity status followed the same pattern as the overall prevalence. In conclusion, this large-scale attempt to carefully characterize CKD prevalence in Europe identified substantial variation in CKD prevalence that appears to be due to factors other than the prevalence of diabetes, hypertension, and obesity.

  • 5.
    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.

  • 6. Campistol, Josep M.
    et al.
    Eris, Josette
    Oberbauer, Rainer
    Friend, Peter
    Hutchison, Brian
    Morales, J.M.
    Claesson, Kerstin
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Transplantation Surgery.
    Stallone, Giovanni
    Russ, Graeme
    Rostaing, Lionel
    Kreis, Henri
    Burke, James T.
    Brault, Yves
    Scarola, Joseph A.
    Neylan, John F.
    Sirolimus therapy after early cyclosporine withdrawal reduces the risk for cancer in adult renal transplantation2006In: Journal of the American Society of Nephrology, ISSN 1046-6673, E-ISSN 1533-3450, Vol. 17, no 2, p. 581-589Article in journal (Refereed)
    Abstract [en]

    Sirolimus (SRL) is a mammalian target of rapamycin inhibitor that, in contrast to cyclosporine (CsA), has been shown to inhibit rather than promote cancers in experimental models. At 3 mo +/- 2 wk after renal transplantation, 430 of 525 enrolled patients were randomly assigned to remain on SRL-CsA-steroids (ST) or to have CsA withdrawn and SRL troughs increased two-fold (SRL-ST). Median times to first skin and nonskin malignancies were compared between treatments using a survival analysis. Mean annualized rates of skin malignancy were calculated, and the relative risk was determined using a Poisson model. Malignancy-free survival rates for nonskin malignancies were compared using Kaplan-Meier estimates and the log-rank test. At 5 yr, the median time to a first skin carcinoma was delayed (491 versus 1126 d; log-rank test, P = 0.007), and the risk for an event was significantly lower with SRL-ST therapy (relative risk SRL-ST to SRL-CsA-ST 0.346; 95% confidence interval 0.227 to 0.526; P < 0.001, intention-to-treat analysis). The relative risks for both basal and squamous cell carcinomas were significantly reduced. Kaplan-Meier estimates of nonskin cancer were 9.6 versus 4.0% (SRL-CsA-ST versus SRL-ST; P = 0.032, intention-to-treat analysis). Nonskin cancers included those of the lung, larynx, oropharynx, kidney, gastrointestinal tract, prostate, breast, thyroid, and cervix as well as glioma, liposarcoma, astrocytoma, leukemia, lymphoma, and Kaposi's sarcoma. Patients who received SRL-based, calcineurin inhibitor-free therapy after CsA withdrawal at month 3 had a reduced incidence of both skin and nonskin malignancies at 5 yr after renal transplantation compared with those who received SRL therapy combined with CsA. Longer follow-up and additional trials are needed to confirm these promising results.

  • 7.
    Carlsson, Axel C
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Molecular epidemiology.
    Larsson, Tobias E
    Helmersson-Karlqvist, Johanna
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Biochemial structure and function.
    Larsson, Anders
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Biochemial structure and function.
    Lind, Lars
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Cardiovascular epidemiology.
    Ärnlöv, Johan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Molecular epidemiology.
    Soluble TNF Receptors and Kidney Dysfunction in the Elderly2014In: Journal of the American Society of Nephrology, ISSN 1046-6673, E-ISSN 1533-3450, Vol. 25, no 6, p. 1313-1320Article in journal (Refereed)
    Abstract [en]

    The importance of TNF-α and its soluble receptors (sTNFR1 and sTNFR2) in the development of kidney disease is being unraveled. Yet, community-based data regarding the role of sTNFRs are lacking. We assessed serum sTNFRs and aspects of kidney damage cross-sectionally in two independent community-based cohorts of elderly participants: Prospective Investigation of the Vasculature in Uppsala Seniors (n=815; mean age, 75 years; 51% women) and Uppsala Longitudinal Study of Adult Men (n=778; mean age, 78 years). Serum sTNFR1 correlated substantially with different aspects of kidney pathology in the Uppsala Longitudinal Study of Adult Men cohort (R=-0.52 for estimated GFR, R=0.22 for urinary albumin-to-creatinine ratio, and R=0.17 for urinary kidney injury molecule-1; P<0.001 for all), with similar correlations in the Prospective Investigation of the Vasculature in Uppsala Seniors cohort. These associations remained significant after adjustment for age, sex, inflammatory markers, and cardiovascular risk factors and were also evident in participants without diabetes. Serum sTNFR2 was associated with all three markers in the Prospective Investigation of the Vasculature in Uppsala Seniors cohort (P<0.001 for all). Our findings from two independent community-based cohorts confirm and extend results of previous studies supporting circulating sTNFRs as relevant biomarkers for kidney damage and dysfunction in elderly individuals, even in the absence of diabetes.

  • 8. Chen, Yuqing
    et al.
    Mahata, Manjula
    Rao, Fangwen
    Khandrika, Srikrishna
    Courel, Maite
    Fung, Maple M
    Zhang, Kuixing
    Stridsberg, Mats
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical Chemistry.
    Ziegler, Michael G
    Hamilton, Bruce A
    Lipkowitz, Michael S
    Taupenot, Laurent
    Nievergelt, Caroline
    Mahata, Sushil K
    O'Connor, Daniel T
    Chromogranin A regulates renal function by triggering Weibel-Palade body exocytosis2009In: Journal of the American Society of Nephrology, ISSN 1046-6673, E-ISSN 1533-3450, Vol. 20, no 7, p. 1623-1632Article in journal (Refereed)
    Abstract [en]

    Chromogranin A (CHGA), a protein released from secretory granules of chromaffin cells and sympathetic nerves, triggers endothelin-1 release from endothelial cells. CHGA polymorphisms associate with an increased risk for ESRD, but whether altered CHGA-endothelium interactions may explain this association is unknown. Here, CHGA led to the release of endothelin-1 and Weibel-Palade body exocytosis in cultured human umbilical vein endothelial cells. In addition, CHGA triggered secretion of endothelin-1 from glomerular endothelial cells and TGF-beta1 from mesangial cells cocultured with glomerular endothelial cells. In humans, plasma CHGA correlated positively with endothelin-1 and negatively with GFR. GFR was highly heritable in twin pairs, and common promoter haplotypes of CHGA predicted GFR. In patients with progressive hypertensive renal disease, a CHGA haplotype predicted rate of GFR decline. In conclusion, these data suggest that CHGA acts through the glomerular endothelium to regulate renal function.

  • 9.
    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)
  • 10. Haynes, Richard
    et al.
    Lewis, David
    Emberson, Jonathan
    Reith, Christina
    Agodoa, Lawrence
    Cass, Alan
    Craig, Jonathan C.
    de Zeeuw, Dick
    Feldt-Rasmussen, Bo
    Fellström, Bengt
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Renal Medicine.
    Levin, Adeera
    Wheeler, David C.
    Walker, Rob
    Herrington, William G.
    Baigent, Colin
    Landray, Martin J.
    Effects of Lowering LDL Cholesterol on Progression of Kidney Disease2014In: Journal of the American Society of Nephrology, ISSN 1046-6673, E-ISSN 1533-3450, Vol. 25, no 8, p. 1825-1833Article in journal (Refereed)
    Abstract [en]

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

  • 11. He, Bing
    et al.
    Ebarasi, Lwaki
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Cancer and Vascular Biology.
    Zhao, Zhe
    Guo, Jing
    Ojala, Juha R. M.
    Hultenby, Kjell
    De Val, Sarah
    Betsholtz, Christer
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Cancer and Vascular Biology.
    Tryggvason, Karl
    Lmx1b and FoxC Combinatorially Regulate Podocin Expression in Podocytes2014In: Journal of the American Society of Nephrology, ISSN 1046-6673, E-ISSN 1533-3450, Vol. 25, no 12, p. 2764-2777Article in journal (Refereed)
    Abstract [en]

    Podocin is a key protein of the kidney podocyte slit diaphragm protein complex, an important part of the glomerular filtration barrier. Mutations in the human podocin gene NPHS2 cause familial or sporadic forms of renal disease owing to the disruption of filtration barrier integrity. The exclusive expression of NPHS2 in podocytes reflects its unique function and raises interesting questions about its transcriptional regulation. Here, we further define a 2.5-kb zebrafish nphs2 promoter fragment previously described and identify a 49-bp podocyte-specific transcriptional enhancer using Tol2-mediated G(0) transgenesis in zebrafish. Within this enhancer, we identified a cis-acting element composed of two adjacent DNA-binding sites (FLAT-E and forkhead) bound by transcription factors Lnnx1b and FoxC. In zebrafish, double knockdown of Lmx1b and FoxC orthologs using morpholino doses that caused no or minimal phenotypic changes upon individual knockdown completely disrupted podocyte development in 40% of injected embryos. Co-overexpression of the two genes potently induced endogenous nphs2 expression in zebrafish podocytes. We found that the NPHS2 promoter also contains a cis-acting Lmx1b-FoxC motif that binds LMX1B and FoxC2. Furthermore, a genome-wide search identified several genes that carry the Lmx1b-FoxC motif in their promoter regions. Among these candidates, motif-driven podocyte enhancer activity of CCNC and MEIS2 was functionally analyzed in vivo. Our results show that podocyte expression of some genes is combinatorially regulated by two transcription factors interacting synergistically with a common enhancer. This finding provides insights into transcriptional mechanisms required for normal and pathologic podocyte functions.

  • 12. Holdaas, Hallvard
    et al.
    Holme, Ingar
    Schmieder, Roland E.
    Jardine, Alan G.
    Zannad, Faiez
    Norby, Gudrun E.
    Fellström, Bengt C.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Rosuvastatin in Diabetic Hemodialysis Patients2011In: Journal of the American Society of Nephrology, ISSN 1046-6673, E-ISSN 1533-3450, Vol. 22, no 7, p. 1335-1341Article in journal (Refereed)
    Abstract [en]

    A randomized, placebo-controlled trial in diabetic patients receiving hemodialysis showed no effect of atorvastatin on a composite cardiovascular endpoint, but analysis of the component cardiac endpoints suggested that atorvastatin may significantly reduce risk. Because the AURORA (A Study to Evaluate the Use of Rosuvastatin in Subjects on Regular Hemodialysis: An Assessment of Survival and Cardiovascular Events) trial included patients with and without diabetes, we conducted a post hoc analysis to determine whether rosuvastatin might reduce the risk of cardiac events in diabetic patients receiving hemodialysis. Among the 7:31 participants with diabetes, traditional risk factors such as LDL-C, smoking, and BP did not associate with cardiac events (cardiac death and nonfatal myocardial infarction). At baseline, only age and high-sensitivity C-reactive protein were independent risk factors for cardiac events. Assignment to rosuvastatin associated with a nonsignificant 16.2% reduction in risk for the AURORA trial's composite primary endpoint of cardiac death, nonfatal MI, or fatal or nonfatal stroke (HR 0.84; 95% CI 0.65 to 1.07). There was no difference in overall stroke, but the rosuvastatin group had more hemorrhagic strokes than the placebo group (12 versus two strokes, respectively; HR, 5.21; 95% CI 1.17 to 23.27). Rosuvastatin treatment significantly reduced the rates of cardiac events by 32% among patients with diabetes (HR 0.68; 95% CI 0.51 to 0.90). In conclusion, among hemodialysis patients with diabetes mellitus, rosuvastatin might reduce the risk of fatal and nonfatal cardiac events.

  • 13.
    Jeansson, Marie
    et al.
    Göteborgs Universitet.
    Björck, Karin
    Tenstad, Olav
    Haraldsson, Börje
    Adriamycin alters glomerular endothelium to induce proteinuria2009In: Journal of the American Society of Nephrology, ISSN 1046-6673, E-ISSN 1533-3450, : JASN, Vol. 20, no 1, p. 114-122Article in journal (Refereed)
    Abstract [en]

    The pathophysiology underlying the nephrotic syndrome is becoming clear for several inherited podocytopathies; the mechanisms of injury that lead to the acquired forms of this disease are not well understood. We explored these mechanisms using the mouse model of adriamycin-induced proteinuria.We estimated the fractional clearances for FITC-Ficolls, albumin, and neutral albumin in cooled, isolated,perfused kidneys (cIPK) in situ. Treatment with adriamycin led to a significant increase in the fractional clearance of albumin and of Ficoll with radii larger than 20 A. Neutral albumin (33.4 A) and similarly sized Ficoll behaved similarly to each other. In addition, adriamycin led to a significant loss of charge density and size selectivity of the glomerular barrier. The thickness of the glomerular endothelial surface layer(i.e., or the glycocalyx) in adriamycin-treated animals was only 20% of that in normal animals. Finally,several proteoglycans were downregulated in isolated glomeruli. In summary, adriamycin thins the glomerular glycocalyx, perhaps by downregulating proteoglycan synthesis, and alters glomerular charge- and size selectivity. These data suggest that the glomerular endothelium may play a role in the pathogenesis of proteinuric renal diseases.

  • 14.
    Jeansson, Marie
    et al.
    Göteborgs Universitet.
    Haraldsson, Börje
    Glomerular size and charge selectivity in the mouse after exposure to glucosaminoglycan-degrading enzymes2003In: Journal of the American Society of Nephrology, ISSN 1046-6673, E-ISSN 1533-3450, Vol. 14, no 7, p. 1756-1765Article in journal (Refereed)
    Abstract [en]

    This is the first functional study of glomerular size and charge selectivity in mice. The aim was to investigate the controversial issue of glomerular permselectivity in animals exposed to glucosaminoglycan-degrading enzymes, hyaluronidase, and heparinase. Fractional clearances (theta) for FITC-Ficoll and albumin were estimated in isoflurane anesthetized mice in vivo and in cooled isolated perfused kidneys (cIPK). In cIPK, a significant increase of theta(albumin) from 0.0023 (95% confidence interval, 0.0014 to 0.0033) in controls to 0.0130 (95% confidence interval, 0.0055 to 0.0206) was seen after hyaluronidase treatment. The theta for neutral Ficoll of similar size as albumin was 0.063 to 0.093 in all groups. According to a heterogeneous charged fiber model, the fiber volume fraction of negatively charged fibers decreased by 10% after enzyme treatments. It is concluded that glomerular size and charge selectivity in mice is similar to that previously shown for rats. Moreover, hyaluronic acid, chondroitin sulfate, and heparan sulfate are of importance for charge selectivity.

  • 15.
    Landegren, Nils
    et al.
    Uppsala University, Science for Life Laboratory, SciLifeLab. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Autoimmunity. Karolinska Inst, Karolinska Univ Hosp, Dept Med Solna, SE-17176 Stockholm, Sweden.
    Pourmousa Lindberg, Mina
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Skov, Jakob
    Uppsala University, Science for Life Laboratory, SciLifeLab. Karolinska Inst, Karolinska Univ Hosp, Dept Med Solna, SE-17176 Stockholm, Sweden.
    Hallgren, Åsa
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Autoimmunity. Uppsala University, Science for Life Laboratory, SciLifeLab. Karolinska Inst, Karolinska Univ Hosp, Dept Med Solna, SE-17176 Stockholm, Sweden.
    Eriksson, Daniel
    Uppsala University, Science for Life Laboratory, SciLifeLab. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences. Karolinska Inst, Karolinska Univ Hosp, Dept Med Solna, SE-17176 Stockholm, Sweden.
    Lisberg Toft-Bertelsen, Trine
    Univ Copenhagen, Dept Cellular & Mol Med, Copenhagen, Denmark.
    MacAulay, Nanna
    Univ Copenhagen, Dept Cellular & Mol Med, Copenhagen, Denmark.
    Hagforsen, Eva
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Dermatology and Venereology.
    Räisänen-Sokolowski, Anne
    Helsinki Univ Hosp, Dept Pathol, Helsinki, Finland.; Univ Helsinki, Helsinki, Finland.
    Saha, Heikki
    Tampere Univ Hosp, Sch Med, Dept Med, Tampere, Finland.
    Nilsson, Thomas
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Nordmark, Gunnel
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Rheumatology.
    Ohlsson, Sophie
    Lund Univ, Dept Nephrol, Lund, Sweden.
    Gustafsson, Jan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Women's and Children's Health, Pediatrics.
    Husebye, Eystein S
    Karolinska Inst, Karolinska Univ Hosp, Dept Med Solna, SE-17176 Stockholm, Sweden.; Univ Bergen, Dept Clin Sci, Bergen, Norway.; Haukeland Hosp, Dept Med, Bergen, Norway.
    Larsson, Erik
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology.
    Anderson, Mark S
    Univ Calif San Francisco, Ctr Diabet, San Francisco, CA 94143 USA.
    Perheentupa, Jaakko
    Univ Helsinki, Hosp Children & Adolescents, Helsinki, Finland.
    Rorsman, Fredrik
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Gastroenterology/Hepatology.
    Fenton, Robert A
    Aarhus Univ, Dept Biomed, Interact Prot Epithelial Transport Ctr, Aarhus, Denmark.
    Kämpe, Olle
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Autoimmunity. Karolinska Inst, Karolinska Univ Hosp, Dept Med Solna, SE-17176 Stockholm, Sweden.
    Autoantibodies Targeting a Collecting Duct-Specific Water Channel in Tubulointerstitial Nephritis.2016In: Journal of the American Society of Nephrology, ISSN 1046-6673, E-ISSN 1533-3450, Vol. 27, no 10, p. 3220-3228Article in journal (Refereed)
    Abstract [en]

    Tubulointerstitial nephritis is a common cause of kidney failure and may have diverse etiologies. This form of nephritis is sometimes associated with autoimmune disease, but the role of autoimmune mechanisms in disease development is not well understood. Here, we present the cases of three patients with autoimmune polyendocrine syndrome type 1 who developed tubulointerstitial nephritis and ESRD in association with autoantibodies against kidney collecting duct cells. One of the patients developed autoantibodies targeting the collecting duct-specific water channel aquaporin 2, whereas autoantibodies of the two other patients reacted against the HOXB7 or NFAT5 transcription factors, which regulate the aquaporin 2 promoter. Our findings suggest that tubulointerstitial nephritis developed in these patients as a result of an autoimmune insult on the kidney collecting duct cells.

  • 16.
    Liu, Peidi
    et al.
    Univ Gothenburg, Inst Neurosci & Physiol, Dept Physiol, Gothenburg, Sweden..
    Lassen, Emelie
    Univ Gothenburg, Inst Neurosci & Physiol, Dept Physiol, Gothenburg, Sweden..
    Nair, Viji
    Univ Michigan, Dept Internal Med, Div Nephrol, Ann Arbor, MI 48109 USA.;Univ Michigan, Dept Computat Med & Bioinformat, Ann Arbor, MI 48109 USA..
    Berthier, Celine C.
    Univ Michigan, Dept Internal Med, Div Nephrol, Ann Arbor, MI 48109 USA.;Univ Michigan, Dept Computat Med & Bioinformat, Ann Arbor, MI 48109 USA..
    Suguro, Miyuki
    Aichi Canc Ctr Res Inst, Div Mol Med, Nagoya, Aichi, Japan..
    Sihlbom, Carina
    Univ Gothenburg, Prote Core Facil, Gothenburg, Sweden..
    Kretzler, Matthias
    Univ Michigan, Dept Internal Med, Div Nephrol, Ann Arbor, MI 48109 USA.;Univ Michigan, Dept Computat Med & Bioinformat, Ann Arbor, MI 48109 USA..
    Betsholtz, Christer
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Vascular Biology. Karolinska Inst Novum, Integrated Cardio Metab Ctr, Huddinge, Sweden..
    Haraldsson, Borje
    Univ Gothenburg, Inst Neurosci & Physiol, Dept Physiol, Gothenburg, Sweden..
    Ju, Wenjun
    Univ Michigan, Dept Internal Med, Div Nephrol, Ann Arbor, MI 48109 USA.;Univ Michigan, Dept Computat Med & Bioinformat, Ann Arbor, MI 48109 USA..
    Ebefors, Kerstin
    Univ Gothenburg, Inst Neurosci & Physiol, Dept Physiol, Gothenburg, Sweden..
    Nystrom, Jenny
    Univ Gothenburg, Inst Neurosci & Physiol, Dept Physiol, Gothenburg, Sweden..
    Transcriptomic and Proteomic Profiling Provides Insight into Mesangial Cell Function in IgA Nephropathy2017In: Journal of the American Society of Nephrology, ISSN 1046-6673, E-ISSN 1533-3450, Vol. 28, no 10, p. 2961-2972Article in journal (Refereed)
    Abstract [en]

    IgA nephropathy (IgAN), the most common GN worldwide, is characterized by circulating galactose-deficient IgA (gd-IgA) that forms immune complexes. The immune complexes are deposited in the glomerular mesangium, leading to inflammation and loss of renal function, but the complete pathophysiology of the disease is not understood. Using an integrated global transcriptomic and proteomic profiling approach, we investigated the role of the mesangium in the onset and progression of IgAN. Global gene expression was investigated by microarray analysis of the glomerular compartment of renal biopsy specimens from patients with IgAN (n=19) and controls (n=22). Using curated glomerular cell type specific genes from the published literature, we found differential expression of a much higher percentage of mesangial cell positive standard genes than podocyte-positive standard genes in IgAN. Principal coordinate analysis of expression data revealed clear separation of patient and control samples on the basis of mesangial but not podocyte cell positive standard genes. Additionally, patient clinical parameters (serum creatinine values and eGFRs) significantly correlated with Z scores derived from the expression profile of mesangial cell positive standard genes. Among patients grouped according to Oxford MEST score, patients with segmental glomerulosclerosis had a significantly higher mesangial cell positive standard gene Z score than patients without segmental glomerulosclerosis. By investigating mesangial cell proteomics and glomerular transcriptomics, we identified 22 common pathways induced in mesangial cells by gd-IgA, most of which mediate inflammation. The genes, proteins, and corresponding pathways identified provide novel insights into the pathophysiologic mechanisms leading to IgAN.

  • 17. Maezawa, Yoshiro
    et al.
    Onay, Tuncer
    Scott, Rizaldy P
    Keir, Lindsay S
    Dimke, Henrik
    Li, Chengjin
    Eremina, Vera
    Maezawa, Yuko
    Jeansson, Marie
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Cancer and Vascular Biology. Lunenfeld-Tanenbaum Research Institute, Mount Sinai Hospital.
    Shan, Jingdong
    Binnie, Matthew
    Lewin, Moshe
    Ghosh, Asish
    Miner, Jeffrey H
    Vainio, Seppo J
    Quaggin, Susan E
    Loss of the Podocyte-Expressed Transcription Factor Tcf21/Pod1 Results in Podocyte Differentiation Defects and FSGS2014In: Journal of the American Society of Nephrology, ISSN 1046-6673, E-ISSN 1533-3450, Vol. 25, no 11, p. 2459-2470Article in journal (Refereed)
    Abstract [en]

    Podocytes are terminally differentiated cells with an elaborate cytoskeleton and are critical components of the glomerular barrier. We identified a bHLH transcription factor, Tcf21, that is highly expressed in developing and mature podocytes. Because conventional Tcf21 knockout mice die in the perinatal period with major cardiopulmonary defects, we generated a conditional Tcf21 knockout mouse to explore the role of this transcription factor in podocytes in vivo. Tcf21 was deleted from podocytes and podocyte progenitors using podocin-cre (podTcf21) and wnt4-cre (wnt4creTcf21) driver strains, respectively. Loss of Tcf21 from capillary-loop stage podocytes (podTcf21) results in simplified glomeruli with a decreased number of endothelial and mesangial cells. By 5 weeks of age, 40% of podTcf21 mice develop massive proteinuria and lesions similar to FSGS. Notably, the remaining 60% of mice do not develop proteinuria even when aged to 8 months. By contrast, earlier deletion of Tcf21 from podocyte precursors (wnt4creTcf21) results in a profound developmental arrest of podocyte differentiation and renal failure in 100% of mice during the perinatal period. Taken together, our results demonstrate a critical role for Tcf21 in the differentiation and maintenance of podocytes. Identification of direct targets of this transcription factor may provide new therapeutic avenues for proteinuric renal disease, including FSGS.

  • 18.
    Metry, George
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Wikström, Björn
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Valind, Sven
    Sandhagen, Bo
    Linde, Torbjörn
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Beshara, Soheir
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Långström, Bengt
    Danielson, Bo G.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Effect of normalization of hematocrit on brain circulation and metabolism in hemodialysis patients1999In: Journal of the American Society of Nephrology, ISSN 1046-6673, E-ISSN 1533-3450, Vol. 10, no 4, p. 854-863Article in journal (Refereed)
    Abstract [en]

    Full correction of anemia with recombinant human erythropoietin (rhEPO) has been reported to reduce the risk of cardiovascular morbidity and mortality and improve the quality of life in hemodialysis (HD) patients. Effects of normalization of hematocrit on cerebral blood flow and oxygen metabolism were investigated by positron emission tomography. Regional cerebral blood flow (rCBF), cerebral blood volume (rCBV), oxygen extraction ratio (rOER), and metabolic rate for oxygen (rCMRO2) were measured in seven HD patients before and after correction of anemia and compared with those in six healthy control subjects. In addition, blood rheology before and on rhEPO therapy was measured in HD patients, which included blood viscosity, plasma viscosity, erythrocyte fluidity, and erythrocyte aggregability. The results showed that plasma viscosity was high (1.51+/-0.19 mPa x s) and erythrocyte fluidity was low (85.8+/-4.8 Pa(-1) x s(-1)), while whole blood viscosity was within the normal range (3.72+/-0.38 mPa x s) before rhEPO therapy. After treatment, the hematocrit rose significantly from 29.3+/-3.3 to 42.4+/-2.2% (P<0.001), accompanied by a significant increase in the whole blood viscosity to 4.57+/-0.16 mPa x s, nonsignificant decrease in erythrocyte fluidity to 79.9+/-7.4 mPa(-1) x s(-1) and nonsignificant change in plasma viscosity (1.46+/-1.3 mPa x s). Positron emission tomography measurements revealed that by normalization of hematocrit, rCBF significantly decreased from 65+/-11 to 48+/-12 ml/min per 100 cm3 (P<0.05). However, arterial oxygen content (caO2) significantly increased from 5.7+/-0.7 to 8.0+/-0.4 mmol/L (P<0.0001), rOER of the hemispheres significantly increased from 44+/-3 to 51+/-6% (P<0.05) and became significantly higher than healthy control subjects (P<0.05). In addition, rCBV significantly increased from 3.5+/-0.5 to 4.6+/-0.6 ml/100 cc brain tissue. The results showed that oxygen supply to the brain tissue increased with normalization of hematocrit, but it was accompanied by increased oxygen extraction in the brain tissue. This may be assumed to be related to the decrease of erythrocyte velocity in the cerebral capillaries as a result of the decreased blood deformability and the increased plasma viscosity.

  • 19.
    Nordquist, Lina
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology, Integrative Physiology.
    Friederich-Persson, Malou
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology, Integrative Physiology.
    Fasching, Angelica
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology, Integrative Physiology.
    Liss, Per
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Radiology, Oncology and Radiation Science, Radiology.
    Shoji, Kumi
    Nangaku, Masaomi
    Hansell, Peter
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology, Integrative Physiology.
    Palm, Fredrik
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology, Integrative Physiology.
    Activation of Hypoxia-Inducible Factors Prevents Diabetic Nephropathy2015In: Journal of the American Society of Nephrology, ISSN 1046-6673, E-ISSN 1533-3450, Vol. 26, no 2, p. 328-338Article in journal (Refereed)
    Abstract [en]

    Hyperglycemia results in increased oxygen consumption and decreased oxygen tension in the kidney. We tested the hypothesis that activation of hypoxia-inducible factors (HIFs) protects against diabetes-induced alterations in oxygen metabolism and kidney function. Experimental groups consisted of control and streptozotocin-induced diabetic rats treated with or without chronic cobalt chloride to activate HIFs. We elucidated the involvement of oxidative stress by studying the effects of acute administration of the superoxide dismutase mimetic tempol. Compared with controls, diabetic rats displayed tissue hypoxia throughout the kidney, glomerular hyperfiltration, increased oxygen consumption, increased total mitochondrial leak respiration, and decreased tubular sodium transport efficiency. Diabetic kidneys showed proteinuria and tubulointerstitial damage. Cobalt chloride activated HIFs, prevented the diabetes-induced alterations in oxygen metabolism, mitochondrial leak respiration, and kidney function, and reduced proteinuria and tubulointerstitial damage. The beneficial effects of tempol were less pronounced after activation of HIFs, indicating improved oxidative stress status. In conclusion, activation of HIFs prevents diabetes-induced alteration in kidney oxygen metabolism by normalizing glomerular filtration, which reduces tubular electrolyte load, preventing mitochondrial leak respiration and improving tubular transport efficiency. These improvements could be related to reduced oxidative stress and account for the reduced proteinuria and tubulointerstitial damage. Thus, pharmacologic activation of the HIF system may prevent development of diabetic nephropathy.

  • 20. Parsa, Afshin
    et al.
    Fuchsberger, Christian
    Koettgen, Anna
    O'Seaghdha, Conall M.
    Pattaro, Cristian
    de Andrade, Mariza
    Chasman, Daniel I.
    Teumer, Alexander
    Endlich, Karlhans
    Olden, Matthias
    Chen, Ming-Huei
    Tin, Adrienne
    Kim, Young J.
    Taliun, Daniel
    Li, Man
    Feitosa, Mary
    Gorski, Mathias
    Yang, Qiong
    Hundertmark, Claudia
    Foster, Meredith C.
    Glazer, Nicole
    Isaacs, Aaron
    Rao, Madhumathi
    Smith, Albert V.
    O'Connell, Jeffrey R.
    Struchalin, Maksim
    Tanaka, Toshiko
    Li, Guo
    Hwang, Shih-Jen
    Atkinson, Elizabeth J.
    Lohman, Kurt
    Cornelis, Marilyn C.
    Johansson, Åsa
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Genomics.
    Toenjes, Anke
    Dehghan, Abbas
    Couraki, Vincent
    Holliday, Elizabeth G.
    Sorice, Rossella
    Kutalik, Zoltan
    Lehtimaeki, Terho
    Esko, Tonu
    Deshmukh, Harshal
    Ulivi, Sheila
    Chu, Audrey Y.
    Murgia, Federico
    Trompet, Stella
    Imboden, Medea
    Kollerits, Barbara
    Pistis, Giorgio
    Harris, Tamara B.
    Launer, Lenore J.
    Aspelund, Thor
    Eiriksdottir, Gudny
    Mitchell, Braxton D.
    Boerwinkle, Eric
    Schmidt, Helena
    Hofer, Edith
    Hu, Frank
    Demirkan, Ayse
    Oostra, Ben A.
    Turner, Stephen T.
    Ding, Jingzhong
    Andrews, Jeanette S.
    Freedman, Barry I.
    Giulianini, Franco
    Koenig, Wolfgang
    Illig, Thomas
    Doering, Angela
    Wichmann, H. -Erich
    Zgaga, Lina
    Zemunik, Tatijana
    Boban, Mladen
    Minelli, Cosetta
    Wheeler, Heather E.
    Igl, Wilmar
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology.
    Zaboli, Ghazal
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology.
    Wild, Sarah H.
    Wright, Alan F.
    Campbell, Harry
    Ellinghaus, David
    Noethlings, Ute
    Jacobs, Gunnar
    Biffar, Reiner
    Ernst, Florian
    Homuth, Georg
    Kroemer, Heyo K.
    Nauck, Matthias
    Stracke, Sylvia
    Voelker, Uwe
    Voelzke, Henry
    Kovacs, Peter
    Stumvoll, Michael
    Maegi, Reedik
    Hofman, Albert
    Uitterlinden, Andre G.
    Rivadeneira, Fernando
    Aulchenko, Yurii S.
    Polasek, Ozren
    Hastie, Nick
    Vitart, Veronique
    Helmer, Catherine
    Wang, Jie Jin
    Stengel, Benedicte
    Ruggiero, Daniela
    Bergmann, Sven
    Kaehoenen, Mika
    Viikari, Jorma
    Nikopensius, Tiit
    Province, Michael
    Colhoun, Helen
    Doney, Alex
    Robino, Antonietta
    Kraemer, Bernhard K.
    Portas, Laura
    Ford, Ian
    Buckley, Brendan M.
    Adam, Martin
    Thun, Gian-Andri
    Paulweber, Bernhard
    Haun, Margot
    Sala, Cinzia
    Mitchell, Paul
    Ciullo, Marina
    Vollenweider, Peter
    Raitakari, Olli
    Metspalu, Andres
    Palmer, Colin
    Gasparini, Paolo
    Pirastu, Mario
    Jukema, J. Wouter
    Probst-Hensch, Nicole M.
    Kronenberg, Florian
    Toniolo, Daniela
    Gudnason, Vilmundur
    Shuldiner, Alan R.
    Coresh, Josef
    Schmidt, Reinhold
    Ferrucci, Luigi
    Van Duijn, Cornelia M.
    Borecki, Ingrid
    Kardia, Sharon L. R.
    Liu, Yongmei
    Curhan, Gary C.
    Rudan, Igor
    Gyllensten, Ulf
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Genomics.
    Wilson, James F.
    Franke, Andre
    Pramstaller, Peter P.
    Rettig, Rainer
    Prokopenko, Inga
    Witteman, Jacqueline
    Hayward, Caroline
    Ridker, Paul M.
    Bochud, Murielle
    Heid, Iris M.
    Siscovick, David S.
    Fox, Caroline S.
    Kao, W. Linda
    Boeger, Carsten A.
    Common Variants in Mendelian Kidney Disease Genes and Their Association with Renal Function2013In: Journal of the American Society of Nephrology, ISSN 1046-6673, E-ISSN 1533-3450, Vol. 24, no 12, p. 2105-2117Article in journal (Refereed)
    Abstract [en]

    Many common genetic variants identified by genome-wide association studies for complex traits map to genes previously linked to rare inherited Mendelian disorders. A systematic analysis of common single-nucleotide polymorphisms (SNPs) in genes responsible for Mendelian diseases with kidney phenotypes has not been performed. We thus developed a comprehensive database of genes for Mendelian kidney conditions and evaluated the association between common genetic variants within these genes and kidney function in the general population. Using the Online Mendelian Inheritance in Man database, we identified 731 unique disease entries related to specific renal search terms and confirmed a kidney phenotype in 218 of these entries, corresponding to mutations in 258 genes. We interrogated common SNPs (minor allele frequency >5%) within these genes for association with the estimated GFR in 74,354 European-ancestry participants from the CKDGen Consortium. However, the top four candidate SNPs (rs6433115 at LRP2, rs1050700 at TSC1, rs249942 at PALB2, and rs9827843 at ROBO2) did not achieve significance in a stage 2 meta-analysis performed in 56,246 additional independent individuals, indicating that these common SNPs are not associated with estimated GFR. The effect of less common or rare variants in these genes on kidney function in the general population and disease-specific cohorts requires further research.

  • 21. Pascual, Julio
    et al.
    Berger, Stefan P
    Witzke, Oliver
    Tedesco, Helio
    Mulgaonkar, Shamkant
    Qazi, Yasir
    Chadban, Steven
    Oppenheimer, Federico
    Sommerer, Claudia
    Oberbauer, Rainer
    Watarai, Yoshihiko
    Legendre, Christophe
    Citterio, Franco
    Henry, Mitchell
    Srinivas, Titte R
    Luo, Wen-Lin
    Marti, AnaMaria
    Bernhardt, Peter
    Vincenti, Flavio
    Everolimus with Reduced Calcineurin Inhibitor Exposure in Renal Transplantation.2018In: Journal of the American Society of Nephrology, ISSN 1046-6673, E-ISSN 1533-3450, Vol. 29, no 7, p. 1979-1991Article in journal (Refereed)
    Abstract [en]

    Background Everolimus permits reduced calcineurin inhibitor (CNI) exposure, but the efficacy and safety outcomes of this treatment after kidney transplant require confirmation.Methods In a multicenter noninferiority trial, we randomized 2037 de novo kidney transplant recipients to receive, in combination with induction therapy and corticosteroids, everolimus with reduced-exposure CNI (everolimus arm) or mycophenolic acid (MPA) with standard-exposure CNI (MPA arm). The primary end point was treated biopsy-proven acute rejection or eGFR<50 ml/min per 1.73 m2 at post-transplant month 12 using a 10% noninferiority margin.Results In the intent-to-treat population (everolimus n=1022, MPA n=1015), the primary end point incidence was 48.2% (493) with everolimus and 45.1% (457) with MPA (difference 3.2%; 95% confidence interval, -1.3% to 7.6%). Similar between-treatment differences in incidence were observed in the subgroups of patients who received tacrolimus or cyclosporine. Treated biopsy-proven acute rejection, graft loss, or death at post-transplant month 12 occurred in 14.9% and 12.5% of patients treated with everolimus and MPA, respectively (difference 2.3%; 95% confidence interval, -1.7% to 6.4%). De novo donor-specific antibody incidence at 12 months and antibody-mediated rejection rate did not differ between arms. Cytomegalovirus (3.6% versus 13.3%) and BK virus infections (4.3% versus 8.0%) were less frequent in the everolimus arm than in the MPA arm. Overall, 23.0% and 11.9% of patients treated with everolimus and MPA, respectively, discontinued the study drug because of adverse events.Conclusions In kidney transplant recipients at mild-to-moderate immunologic risk, everolimus was noninferior to MPA for a binary composite end point assessing immunosuppressive efficacy and preservation of graft function.

  • 22.
    Robinson-Cohen, Cassianne
    et al.
    Vanderbilt Univ, Med Ctr, Dept Med, Div Nephrol, Nashville, TN 37232 USA.
    Bartz, Traci M.
    Univ Washington, Cardiovasc Hlth Res Unit, Dept Biostat, Seattle, WA 98195 USA;Univ Washington, Cardiovasc Hlth Res Unit, Dept Med, Seattle, WA 98195 USA.
    Lai, Dongbing
    Indiana Univ, Dept Med, Indianapolis, IN 46204 USA;Indiana Univ, Dept Mol Genet, Indianapolis, IN 46204 USA.
    Ikizler, T. Alp
    Vanderbilt Univ, Med Ctr, Dept Med, Div Nephrol, Nashville, TN 37232 USA.
    Peacock, Munro
    Imel, Erik A.
    Michos, Erin D.
    Johns Hopkins Sch Med, Div Cardiol, Baltimore, MD USA.
    Foroud, Tatiana M.
    Indiana Univ, Dept Med, Indianapolis, IN 46204 USA;Indiana Univ, Dept Mol Genet, Indianapolis, IN 46204 USA.
    Åkesson, Kristina
    Lund Univ, Dept Clin Sci Malmo, Clin & Mol Osteoporosis Res Unit, Malmo, Sweden;Skane Univ Hosp, Dept Orthopaed, Malmo, Sweden.
    Taylor, Kent D.
    Harbor Univ Calif, Los Angeles Med Ctr, Los Angeles Biomed Res Inst Harbor, Dept Pediat,Inst Translat Gen & Populat Sci, Torrance, CA USA.
    Malmgren, Linnea
    Lund Univ, Dept Clin Sci Malmo, Clin & Mol Osteoporosis Res Unit, Malmo, Sweden;Skane Univ Hosp, Dept Orthopaed, Malmo, Sweden.
    Matsushita, Kunihiro
    Johns Hopkins Sch Med, Div Cardiol, Baltimore, MD USA;Johns Hopkins Univ, Johns Hopkins Bloomberg Sch Publ Hlth, Dept Epidemiol, Baltimore, MD USA;Johns Hopkins Univ, Welch Ctr Prevent Epidemiol & Clin Res, Baltimore, MD USA.
    Nethander, Maria
    Univ Gothenburg, Sahlgrenska Acad, Inst Med, Dept Med,Bioinformat Core Facil, Gothenburg, Sweden.
    Eriksson, Joel
    Univ Gothenburg, Sahlgrenska Acad, Inst Med, Ctr Bone & Arthrit Res,Dept Internal Med & Clin N, Gothenburg, Sweden.
    Ohlsson, Claes
    Univ Gothenburg, Sahlgrenska Acad, Inst Med, Ctr Bone & Arthrit Res,Dept Internal Med & Clin N, Gothenburg, Sweden.
    Mellström, Daniel
    Univ Gothenburg, Sahlgrenska Acad, Inst Med, Ctr Bone & Arthrit Res,Dept Internal Med & Clin N, Gothenburg, Sweden.
    Wolf, Myles
    Duke Univ, Sch Med, Div Nephrol, Dept Med, Durham, NC USA;Duke Univ, Sch Med, Duke Clin Res Inst, Durham, NC USA.
    Ljunggren, Östen
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Endocrinology and mineral metabolism.
    McGuigan, Fiona
    Lund Univ, Dept Clin Sci Malmo, Clin & Mol Osteoporosis Res Unit, Malmo, Sweden;Skane Univ Hosp, Dept Orthopaed, Malmo, Sweden.
    Rotter, Jerome I.
    Harbor Univ Calif, Los Angeles Med Ctr, Los Angeles Biomed Res Inst Harbor, Dept Pediat,Inst Translat Gen & Populat Sci, Torrance, CA USA.
    Karlsson, Magnus
    Lund Univ, Dept Clin Sci Malmo, Clin & Mol Osteoporosis Res Unit, Malmo, Sweden;Skane Univ Hosp, Dept Orthopaed, Malmo, Sweden.
    Econs, Michael J.
    Indiana Univ, Dept Med, Indianapolis, IN 46204 USA;Indiana Univ, Dept Mol Genet, Indianapolis, IN 46204 USA.
    Ix, Joachim H.
    Univ Calif San Diego, Dept Med, Div Nephrol Hypertens, San Diego, CA 92103 USA;Vet Affairs San Diego Healthcare Syst, Nephrol Sect, San Diego, CA USA.
    Lutsey, Pamela L.
    Univ Minnesota, Sch Publ Hlth, Div Epidemiol & Community Hlth, Minneapolis, MN USA.
    Psaty, Bruce M.
    Univ Washington, Cardiovasc Hlth Res Unit, Dept Med, Seattle, WA 98195 USA;Univ Washington, Cardiovasc Hlth Res Unit, Dept Epidemiol, Seattle, WA 98195 USA;Univ Washington, Cardiovasc Hlth Res Unit, Dept Hlth Serv, Seattle, WA 98195 USA;Kaiser Permanente, Washington Hlth Res Inst, Seattle, WA USA.
    de Boer, Ian H.
    Univ Washington, Kidney Res Inst, Div Nephrol, Dept Med, Seattle, WA 98195 USA.
    Kestenbaum, Bryan R.
    Univ Washington, Kidney Res Inst, Div Nephrol, Dept Med, Seattle, WA 98195 USA.
    Genetic Variants Associated with Circulating Fibroblast Growth Factor 232018In: Journal of the American Society of Nephrology, ISSN 1046-6673, E-ISSN 1533-3450, Vol. 29, no 10, p. 2583-2592Article in journal (Refereed)
    Abstract [en]

    Background: Fibroblast growth factor 23 (FGF23), a bone-derived hormone that regulates phosphorus and vitamin D metabolism, contributes to the pathogenesis of mineral and bone disorders in CKD and is an emerging cardiovascular risk factor. Central elements of FGF23 regulation remain incompletely understood; genetic variation may help explain interindividual differences.

    Methods: We performed a meta-analysis of genome-wide association studies of circulating FGF23 concentrations among 16,624 participants of European ancestry from seven cohort studies, excluding participants with eGFR<30 ml/min per 1.73 m(2) to focus on FGF23 under normal conditions. We evaluated the association of single-nucleotide polymorphisms (SNPs) with natural log-transformed FGF23 concentration, adjusted for age, sex, study site, and principal components of ancestry. A second model additionally adjusted for BMI and eGFR.

    Results: We discovered 154 SNPs from five independent regions associated with FGF23 concentration. The SNP with the strongest association, rs17216707 (P=3.0x10(-24)), lies upstream of CYP24A1, which encodes the primary catabolic enzyme for 1,25-dihydroxyvitamin D and 25-hydroxyvitamin D. Each additional copy of the T allele at this locus is associated with 5% higher FGF23 concentration. Another locus strongly associated with variations in FGF23 concentration is rs11741640, within RGS14 and upstream of SLC34A1 (a gene involved in renal phosphate transport). Additional adjustment for BMI and eGFR did not materially alter the magnitude of these associations. Another top locus (within ABO, the ABO blood group transferase gene) was no longer statistically significant at the genome-wide level.

    Conclusions: Common genetic variants located near genes involved in vitamin D metabolism and renal phosphate transport are associated with differences in circulating FGF23 concentrations.

  • 23. Salem, Rany M.
    et al.
    Cadman, Peter E.
    Chen, Yuqing
    Rao, Fangwen
    Wen, Gen
    Harnilton, Bruce A.
    Rana, Brincla K.
    Smith, Douglas W.
    Stridsberg, Mats
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical Chemistry.
    Ward, Harry J.
    Mahata, Manjula
    Mahata, Sushi K.
    Bowden, Donald W.
    Hicks, Pamela J.
    Freeclman, Barry I.
    Schork, Nicholas J.
    O'Connor, Daniel T.
    Chromogranin a polymorphisms are associated with hypertensive renal disease2008In: Journal of the American Society of Nephrology, ISSN 1046-6673, E-ISSN 1533-3450, Vol. 19, no 3, p. 600-614Article in journal (Refereed)
    Abstract [en]

    Chromogranin A is released together with epinephrine and norepinephrine from catecholaminergic cells. Specific endopeptidases cleave chromogranin A into biologically active peptide fragments, including catestatin, which inhibits catecholamine release. Previous studies have suggested that a deficit in this sympathetic “braking” system might be an early event in the pathogenesis of human hypertension. Whether chromogranin A (CHGA) polymorphisms predict end-organ complications of hypertension, such as end-stage renal disease, is unknown. Among blacks, we studied common genetic variants spanning the CHGA locus in 2 independent case-control studies of hypertensive ESRD. Two haplotypes were significantly more frequent among subjects with hypertensive ESRD: 1) in the promoter (5′) region, G-462A→T-415C→C-89A, haplotype ATC (adjusted odds ratio = 2.65; P = 0.037), and 2) at the 3′-end, C11825T (3′-UTR, C+87T)→G12602C, haplotype TC (adjusted odds ratio = 2.73, P = 0.0196). Circulating levels of catestatin were lower among those with hypertensive ESRD than controls, an unexpected finding given that peptide levels are usually elevated in ESRD because of reduced renal elimination. We found that the 3′-UTR + 87T variant decreased reporter gene expression, providing a possible mechanistic explanation for diminished catestatin. In summary, common variants in chromogranin A associate with the risk of hypertensive ESRD in blacks.

  • 24. Stenvinkel, Peter
    et al.
    Rodriguez-Ayala, Ernesto
    Massy, Ziad A.
    Qureshi, Abdul Rashid
    Barany, Peter
    Fellström, Bengt
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Heimburger, Olof
    Lindholm, Bengt
    Alvestrand, Anders
    Statin treatment and diabetes affect myeloperoxidase activity in maintenance hemodialysis patients2006In: Journal of the American Society of Nephrology, ISSN 1046-6673, E-ISSN 1533-3450, Vol. 1, no 2, p. 281-287Article in journal (Refereed)
    Abstract [en]

    Myeloperoxidase (MPO), which is secreted during activation of neutrophils, may serve as one mechanistic link among persistent inflammation, oxidative stress, and cardiovascular disease. This study related MPO activity to inflammatory and oxidative stress biomarkers, comorbidity, and ongoing medication in prevalent hemodialysis (HD) patients. In a cross-sectional evaluation of 115 prevalent (vintage 25 mo) HD patients (62 men; 63 +/- 1 yr), data on comorbidity (Davies score), diabetes, medication (statins and antiltypertensive drugs), nutritional status (subjective global assessment), blood lipids (cholesterol, HDL cholesterol, and triglycerides), inflammatory biomarkers (serum albumin, C-reactive protein, TNF-alpha, and IL-6), oxidative stress biomarkers (pentosidine, 8-hydroxydeoxyguanosine, and MPO activity) were recorded. Patients with MPO activity greater than the median had significantly (P < 0.05) lower serum albumin levels (33.2 +/- 0.7 versus 35.0 +/- 0.5 g/L), higher 8-hydroxydeoxyguanosine levels (1.26 +/- 0.08 versus 1.05 +/- 0.06 ng/mb, and a lower prevalence of statin treatment (18 versus 36%). Therefore, the median MPO activity was significantly (P < 0.05) lower (17.7 versus 26.6 Delta OD630/min per mg protein) in the subgroup of 31 HD patients with ongoing statin treatment. In a multiple regression model, correction for the impact of age, gender, vintage, serum cholesterol, serum albumin, comorbidity, diabetes, and statin use, only diabetes (P < 0.01) and statin use (P < 0.01) were significantly associated to MPO activity. Fourteen patients who had diabetes and were receiving statin treatment had markedly (P = 0.001) lower median (19.9 versus 41.2 Delta OD630/min per mg protein) MPO activity compared with 18 who had diabetes and were not taking statins. This cross-sectional study suggests that both diabetes and statin treatment affect MPO activity in prevalent HD patients.

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