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  1. Article ; Online: Cardio-renal protective effect of the xanthine oxidase inhibitor febuxostat in the 5/6 nephrectomy model with hyperuricemia.

    Omizo, Hiroki / Tamura, Yoshifuru / Morimoto, Chikayuki / Ueno, Masaki / Hayama, Yuto / Kuribayashi-Okuma, Emiko / Uchida, Shunya / Shibata, Shigeru

    Scientific reports

    2020  Volume 10, Issue 1, Page(s) 9326

    Abstract: Although hyperuricemia has been shown to be associated with the progression of cardiovascular disorder and chronic kidney disease (CKD), there is conflicting evidence as to whether xanthine oxidase (XO) inhibitors confer organ protection besides lowering ...

    Abstract Although hyperuricemia has been shown to be associated with the progression of cardiovascular disorder and chronic kidney disease (CKD), there is conflicting evidence as to whether xanthine oxidase (XO) inhibitors confer organ protection besides lowering serum urate levels. In this study, we addressed the cardio-renal effects of XO inhibition in rodent CKD model with hyperuricemia. Sprague-Dawley rats underwent 5/6 nephrectomy and received a uricase inhibitor oxonic acid for 8 weeks (RK + HUA rats). In some rats, a XO inhibitor febuxostat was administered orally. Compared with control group, RK + HUA group showed a significant increase in albuminuria and renal injury. Febuxostat reduced serum uric acid as well as urinary albumin levels. Histological and immunohistochemical analysis of the kidney revealed that febuxostat alleviated glomerular, tubulointerstitial, and arteriolar injury in RK + HUA rats. Moreover, in the heart, RK + HUA showed individual myofiber hypertrophy and cardiac fibrosis, which was significantly attenuated by febuxostat. We found that renal injury and the indices of cardiac changes were well correlated, confirming the cardio-renal interaction in this model. Finally, NF-E2-related factor 2 (Nrf2) and the downstream target heme oxygenase-1 (HO-1) protein levels were increased both in the heart and in the kidney in RK + HUA rats, and these changes were alleviated by febuxostat, suggesting that tissue oxidative stress burden was attenuated by the treatment. These data demonstrate that febuxostat protects against cardiac and renal injury in RK + HUA rats, and underscore the pathological importance of XO in the cardio-renal interaction.
    MeSH term(s) Animals ; Cardiotonic Agents/pharmacology ; Disease Models, Animal ; Febuxostat/pharmacology ; Heart/drug effects ; Hyperuricemia/drug therapy ; Hyperuricemia/etiology ; Hyperuricemia/physiopathology ; Kidney Diseases/drug therapy ; Kidney Diseases/etiology ; Kidney Function Tests ; Male ; Myocardium/pathology ; Nephrectomy/adverse effects ; Oxidative Stress/drug effects ; Oxonic Acid/pharmacology ; Protective Agents/pharmacology ; Rats, Sprague-Dawley ; Xanthine Oxidase/antagonists & inhibitors
    Chemical Substances Cardiotonic Agents ; Protective Agents ; Febuxostat (101V0R1N2E) ; Oxonic Acid (5VT6420TIG) ; Xanthine Oxidase (EC 1.17.3.2)
    Language English
    Publishing date 2020-06-09
    Publishing country England
    Document type Journal Article ; Research Support, Non-U.S. Gov't
    ZDB-ID 2615211-3
    ISSN 2045-2322 ; 2045-2322
    ISSN (online) 2045-2322
    ISSN 2045-2322
    DOI 10.1038/s41598-020-65706-6
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  2. Article ; Online: Phosphate binding by sucroferric oxyhydroxide ameliorates renal injury in the remnant kidney model.

    Nemoto, Yoshikazu / Kumagai, Takanori / Ishizawa, Kenichi / Miura, Yutaka / Shiraishi, Takeshi / Morimoto, Chikayuki / Sakai, Kazuhiro / Omizo, Hiroki / Yamazaki, Osamu / Tamura, Yoshifuru / Fujigaki, Yoshihide / Kawachi, Hiroshi / Kuro-O, Makoto / Uchida, Shunya / Shibata, Shigeru

    Scientific reports

    2019  Volume 9, Issue 1, Page(s) 1732

    Abstract: Recent clinical studies indicate that the disturbed phosphate metabolism in chronic kidney disease (CKD) may facilitate kidney injury; nonetheless, the causal role of phosphate in CKD progression remains to be elucidated. Here, we show that intestinal ... ...

    Abstract Recent clinical studies indicate that the disturbed phosphate metabolism in chronic kidney disease (CKD) may facilitate kidney injury; nonetheless, the causal role of phosphate in CKD progression remains to be elucidated. Here, we show that intestinal phosphate binding by sucroferric oxyhydroxide (SF) ameliorates renal injury in the rat remnant kidney model. Sprague-Dawley rats received 5/6 nephrectomy (RK) and had a normal chow or the same diet containing SF (RK + SF). RK rats showed increased plasma FGF23 and phosphate levels, which were suppressed by SF administration. Of note, albuminuria in RK rats was significantly ameliorated by SF at both 4 and 8 weeks. SF also attenuated glomerulosclerosis and tubulointerstitial injury. Moreover, several different approaches confirmed the protective effects on podocytes, explaining the attenuation of glomerulosclerosis and albuminuria observed in this study. As a possible mechanism, we found that SF attenuated renal inflammation and fibrosis in RK rats. Interestingly, von Kossa staining of the kidney revealed calcium phosphate deposition in neither RK nor RK + SF rats; however, plasma levels of calciprotein particles were significantly reduced by SF. These data indicate that latent positive phosphate balance accelerates CKD progression from early stages, even when overt ectopic calcification is absent.
    MeSH term(s) Animals ; Biomarkers ; Biopsy ; Disease Models, Animal ; Disease Susceptibility ; Drug Combinations ; Ferric Compounds/metabolism ; Glomerulosclerosis, Focal Segmental/etiology ; Glomerulosclerosis, Focal Segmental/metabolism ; Glomerulosclerosis, Focal Segmental/pathology ; Immunohistochemistry ; Male ; Phosphates/metabolism ; Podocytes/metabolism ; Podocytes/pathology ; Podocytes/ultrastructure ; Rats ; Renal Insufficiency, Chronic/etiology ; Renal Insufficiency, Chronic/metabolism ; Renal Insufficiency, Chronic/pathology ; Sucrose/metabolism
    Chemical Substances Biomarkers ; Drug Combinations ; Ferric Compounds ; Phosphates ; sucroferric oxyhydroxide ; Sucrose (57-50-1)
    Language English
    Publishing date 2019-02-11
    Publishing country England
    Document type Journal Article ; Research Support, Non-U.S. Gov't
    ZDB-ID 2615211-3
    ISSN 2045-2322 ; 2045-2322
    ISSN (online) 2045-2322
    ISSN 2045-2322
    DOI 10.1038/s41598-018-38389-3
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  3. Article ; Online: The Impact of Normal Range of Serum Phosphorus on the Incidence of End-Stage Renal Disease by A Propensity Score Analysis.

    Chang, Wen Xiu / Xu, Ning / Kumagai, Takanori / Shiraishi, Takeshi / Kikuyama, Takahiro / Omizo, Hiroki / Sakai, Kazuhiro / Arai, Shigeyuki / Tamura, Yoshifuru / Ota, Tatsuru / Shibata, Shigeru / Fujigaki, Yoshihide / Shen, Zhong Yang / Uchida, Shunya

    PloS one

    2016  Volume 11, Issue 4, Page(s) e0154469

    Abstract: Background: Although hyperphosphatemia is deemed a risk factor of the progression of chronic kidney disease (CKD), it remains unclear whether the normal range of serum phosphorus likewise deteriorates CKD. A propensity score analysis was applied to ... ...

    Abstract Background: Although hyperphosphatemia is deemed a risk factor of the progression of chronic kidney disease (CKD), it remains unclear whether the normal range of serum phosphorus likewise deteriorates CKD. A propensity score analysis was applied to examine the causal effect of the normal range of serum phosphorus on the incidence of end-stage renal disease (ESRD).
    Methods: A retrospective CKD cohort of 803 participants in a single institution was analyzed. Propensity score was estimated using 22 baseline covariates by multivariate binary logistic regression for the different thresholds of time-averaged phosphorus (TA-P) in the normal range of serum phosphorus incremented by 0.1 mg/dL from 3.3 to 4.5 mg/dL.
    Results: The incidence rate of ESRD was 33.9 per 1,000 person-years over median follow-up of 4.3 years. Total patients showed the mean baseline phosphorus of 3.37 mg/dL and were divided to quartile. The higher quartile was associated with the parameters consistent with the advancement of CKD. A stratified Cox regression showed the highest hazard ratio (HR) at TA-P 3.4 mg/dL (HR 17.60, 95% CI 3.92-78.98) adjusted for baseline covariates such as sex, age, diabetic nephropathy, estimated GFR, serum albumin, Na-Cl, phosphorus, LDL-C and proteinuria. Adjusted HRs remained high up to TA-P 4.2 mg/dL (HR 2.22, 95% CI 1.33-3.71). After propensity score matching conducted at the thresholds of TA-P 3.4, 3.6, 3.8 and 4.0 mg/dL, the higher levels of TA-P showed the higher HRs by Kaplan-Meier analysis (p < 0.05 by stratified log-rank test). The numbers needed to treat were calculated as 3.9 to 5.3 over 5 years.
    Conclusions: The propensity score analysis shows that even the normal range of serum phosphorus clearly accelerates CKD progression to ESRD. Our results encourage clinicians to target serum phosphorus to inhibit CKD progression in the manner of 'the lower the better.'
    MeSH term(s) Aged ; Female ; Humans ; Incidence ; Kidney Failure, Chronic/blood ; Kidney Failure, Chronic/epidemiology ; Kidney Failure, Chronic/metabolism ; Logistic Models ; Male ; Middle Aged ; Phosphorus/blood ; Propensity Score ; Retrospective Studies ; Risk Factors
    Chemical Substances Phosphorus (27YLU75U4W)
    Language English
    Publishing date 2016
    Publishing country United States
    Document type Journal Article ; Research Support, Non-U.S. Gov't
    ISSN 1932-6203
    ISSN (online) 1932-6203
    DOI 10.1371/journal.pone.0154469
    Database MEDical Literature Analysis and Retrieval System OnLINE

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