今日の臨床サポート

慢性腎臓病に伴う骨・ミネラル代謝異常

著者: 駒場大峰 東海大学 腎内分泌代謝内科

著者: 深川雅史 東海大学 腎内分泌代謝内科

監修: 岡田浩一 埼玉医科大学 腎臓内科

著者校正/監修レビュー済:2020/12/16
参考ガイドライン:
  1. 日本透析医学会慢性腎臓病に伴う骨・ミネラル代謝異常の診療ガイドライン[1]
  1. 日本腎臓学会:[https://cdn.jsn.or.jp/data/CKD2018.pdf エビデンスに基づくCKD診療ガイドライン2018[2]
  1. Kidney Disease: Improving Global Outcomes (KDIGO) :KDIGO 2017 Clinical Practice Guideline Update for the Diagnosis, Evaluation, Prevention, and Treatment of Chronic Kidney Disease–Mineral and Bone Disorder (CKD-MBD)[3]
患者向け説明資料

概要・推奨   

  1. 血清P値、血清Ca値、PTH値などCKD-MBDに関連する検査値の異常は、透析患者において心血管イベントリスクや死亡リスクに関連することが示されている。これらの観察研究のデータに基づき、わが国のガイドラインや国際的なガイドラインでは、CKD-MBDに関連する検査値を一定の範囲に管理することが推奨されている(推奨度2OJG)。
  1. 血管石灰化は透析患者において頻度が高く、心血管イベントの重要な要因である。血管石灰化は単純X線やCT検査により評価可能であり、生命予後の改善を念頭にCKD-MBD管理を行ううえで診療の一助となる(推奨度2OJG)。
  1. Ca非含有リン吸着薬はCa含有リン吸着薬と比較し、高Ca血症や血管石灰化のリスクが低く、メタアナリシスでは生命予後の改善につながる可能性も指摘されている。このため、Ca含有製剤を使用する際は高Ca血症や血管石灰化に注意し、過剰な投与を控えることが望ましい(推奨度2SRsJG)。
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薬剤監修について:
オーダー内の薬剤用量は日本医科大学付属病院 薬剤部 部長 伊勢雄也 以下、林太祐、渡邉裕次、井ノ口岳洋、梅田将光による疑義照会のプロセスを実施、疑義照会の対象については著者の方による再確認を実施しております。
※薬剤中分類、用法、同効薬、診療報酬は、エルゼビアが独自に作成した薬剤情報であり、
著者により作成された情報ではありません。
尚、用法は添付文書より、同効薬は、薬剤師監修のもとで作成しております。
※薬剤情報の(適外/適内/⽤量内/⽤量外/㊜)等の表記は、エルゼビアジャパン編集部によって記載日時にレセプトチェックソフトなどで確認し作成しております。ただし、これらの記載は、実際の保険適用の査定において保険適用及び保険適用外と判断されることを保証するものではありません。また、検査薬、輸液、血液製剤、全身麻酔薬、抗癌剤等の薬剤は保険適用の記載の一部を割愛させていただいています。
(詳細はこちらを参照)
著者のCOI(Conflicts of Interest)開示:
駒場大峰 : 講演料(協和キリン),企業などが提供する寄付講座(協和キリン)[2021年]
深川雅史 : 講演料(協和キリン,アストラゼネカ),奨学(奨励)寄付など(中外製薬,小野薬品,鳥居薬品,協和キリン)[2021年]
監修:岡田浩一 : 講演料(協和キリン,中外製薬,田辺三菱,第一三共),研究費・助成金など(協和キリン),奨学(奨励)寄付など(協和キリン,中外製薬,田辺三菱,第一三共,アステラス,MSD,武田薬品,鳥居薬品,ファイザー,ノバルティス,日本ベーリンガーインゲルハイム,大塚製薬,塩野義,大日本住友)[2021年]

改訂のポイント:
  1. 2017年に改訂されたKDIGOガイドライン、2018年に発表された日本腎臓学会によるエビデンスに基づくCKD診療ガイドラインを中心に、近年のエビデンスに基づき改訂を行った。

病態・疫学・診察

疾患情報  
  1. 腎臓は、副甲状腺ホルモン(parathyroid hormone、PTH)などのホルモンの調節を受けて、カルシウム(Ca)やリン(P)を尿中に排泄する一方、活性型ビタミンD[1,25(OH)2D]を産生することにより、腸管でのCa吸収や骨代謝の維持にも関与している。
  1. 慢性腎臓病(chronic kidney disease、CKD)患者では、腎機能低下の進行とともに、高P血症低Ca血症、活性型ビタミンD低下などのミネラル代謝異常を生じ、これらを代償するためにPTH分泌が刺激され、二次性副甲状腺機能亢進症に至る。
  1. このような病態は従来、主に骨病変に着目して「腎性骨異栄養症(renal osteodystrophy、ROD)」として認識されてきたが、近年、この病態が血管石灰化や生命予後にも深刻な影響を及ぼすことが明らかとなり「慢性腎臓病に伴う骨・ミネラル代謝異常(CKD-mineral and bone disorder、CKD-MBD)」という全身性疾患としての概念が誕生し、その管理も生命予後の改善を目的に行われるようになった[1][3]
問診・診察のポイント  
  1. CKD-MBDを管理するためには、臨床検査値の異常を適切に評価することが基本となる。行うべき臨床項目には血清P値、Ca値、PTH値など日常的に測定されるものが含まれる。これら検査値の管理は介入が可能で、アウトカムを改善するために最も重要な部分といえる。

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文献 

著者: Kidney Disease: Improving Global Outcomes (KDIGO) CKD-MBD Update Work Group
雑誌名: Kidney Int Suppl (2011). 2017 Jul;7(1):1-59. doi: 10.1016/j.kisu.2017.04.001. Epub 2017 Jun 21.
Abstract/Text
PMID 30675420  Kidney Int Suppl (2011). 2017 Jul;7(1):1-59. doi: 10.10・・・
著者: Kidney Disease: Improving Global Outcomes (KDIGO) CKD-MBD Work Group
雑誌名: Kidney Int Suppl. 2009 Aug;(113):S1-130. doi: 10.1038/ki.2009.188.
Abstract/Text The 2009 Kidney Disease: Improving Global Outcomes (KDIGO) clinical practice guideline on the management of chronic kidney disease-mineral and bone disorder (CKD-MBD) is intended to assist the practitioner caring for adults and children with CKD stages 3-5, on chronic dialysis therapy, or with a kidney transplant. The guideline contains recommendations on evaluation and treatment for abnormalities of CKD-MBD. This disease concept of CKD-MBD is based on a prior KDIGO consensus conference. Tests considered are those that relate to the detection and monitoring of laboratory, bone, and cardiovascular abnormalities. Treatments considered are interventions to treat hyperphosphatemia, hyperparathyroidism, and bone disease in patients with CKD stages 3-5D and 1-5T. The guideline development process followed an evidence based approach and treatment recommendations are based on systematic reviews of relevant treatment trials. Recommendations for testing used evidence based on diagnostic accuracy or risk prediction and linked it indirectly with how this would be expected to achieve better outcomes for patients through better detection, evaluation or treatment of disease. Critical appraisal of the quality of the evidence and the strength of recommendations followed the GRADE approach. An ungraded statement was provided when a question did not lend itself to systematic literature review. Limitations of the evidence, especially the lack of definitive clinical outcome trials, are discussed and suggestions are provided for future research.

PMID 19644521  Kidney Int Suppl. 2009 Aug;(113):S1-130. doi: 10.1038/k・・・
著者: Geoffrey A Block, Preston S Klassen, J Michael Lazarus, Norma Ofsthun, Edmund G Lowrie, Glenn M Chertow
雑誌名: J Am Soc Nephrol. 2004 Aug;15(8):2208-18. doi: 10.1097/01.ASN.0000133041.27682.A2.
Abstract/Text Mortality rates in ESRD are unacceptably high. Disorders of mineral metabolism (hyperphosphatemia, hypercalcemia, and secondary hyperparathyroidism) are potentially modifiable. For determining associations among disorders of mineral metabolism, mortality, and morbidity in hemodialysis patients, data on 40,538 hemodialysis patients with at least one determination of serum phosphorus and calcium during the last 3 mo of 1997 were analyzed. Unadjusted, case mix-adjusted, and multivariable-adjusted relative risks of death were calculated for categories of serum phosphorus, calcium, calcium x phosphorus product, and intact parathyroid hormone (PTH) using proportional hazards regression. Also determined was whether disorders of mineral metabolism were associated with all-cause, cardiovascular, infection-related, fracture-related, and vascular access-related hospitalization. After adjustment for case mix and laboratory variables, serum phosphorus concentrations >5.0 mg/dl were associated with an increased relative risk of death (1.07, 1.25, 1.43, 1.67, and 2.02 for serum phosphorus 5.0 to 6.0, 6.0 to 7.0, 7.0 to 8.0, 8.0 to 9.0, and >/=9.0 mg/dl). Higher adjusted serum calcium concentrations were also associated with an increased risk of death, even when examined within narrow ranges of serum phosphorus. Moderate to severe hyperparathyroidism (PTH concentrations >/=600 pg/ml) was associated with an increase in the relative risk of death, whereas more modest increases in PTH were not. When examined collectively, the population attributable risk percentage for disorders of mineral metabolism was 17.5%, owing largely to the high prevalence of hyperphosphatemia. Hyperphosphatemia and hyperparathyroidism were significantly associated with all-cause, cardiovascular, and fracture-related hospitalization. Disorders of mineral metabolism are independently associated with mortality and morbidity associated with cardiovascular disease and fracture in hemodialysis patients.

PMID 15284307  J Am Soc Nephrol. 2004 Aug;15(8):2208-18. doi: 10.1097/・・・
著者: K Kalantar-Zadeh, N Kuwae, D L Regidor, C P Kovesdy, R D Kilpatrick, C S Shinaberger, C J McAllister, M J Budoff, I B Salusky, J D Kopple
雑誌名: Kidney Int. 2006 Aug;70(4):771-80. doi: 10.1038/sj.ki.5001514. Epub 2006 Jul 5.
Abstract/Text Although renal osteodystrophy and vitamin D analogs may be related to survival in maintenance hemodialysis (MHD) patients, most studies have examined associations between baseline values and survival without accounting for variations in clinical and laboratory measures over time. We examined associations between survival and quarterly laboratory values and administered paricalcitol in a 2-year (July 2001-June 2003) cohort of 58,058 MHD patients from all DaVita dialysis clinics in USA using both time-dependent Cox models with repeated measures and fixed-covariate Cox models with only baseline values. Whereas hypercalcemia and hyperphosphatemia were robust predictors of higher death risk in all models, the association between serum calcium and mortality was different in time-varying models. Changes in baseline calcium and phosphorus values beyond the Kidney Disease Outcome Quality Initiative recommended targets were associated with increased mortality. Associations between high serum parathyroid hormone and increased death risk were masked by case-mix characteristics of MHD patients. Time-varying serum alkaline phosphatase had an incremental association with mortality. Administration of any dose of paricalcitol was associated with improved survival in time-varying models. Controlling for nutritional markers may introduce overadjustment bias owing to their strong collinearity with osteodystrophy surrogates. Whereas both time-dependent and fixed-covariate Cox models result in similar associations between osteodystrophy indicators and survival, subtle but potentially clinically relevant differences between the two models exist, probably because fixed models do not account for variations of osteodystrophy indices and changes in medication dose over time.

PMID 16820797  Kidney Int. 2006 Aug;70(4):771-80. doi: 10.1038/sj.ki.5・・・
著者: Francesca Tentori, Margaret J Blayney, Justin M Albert, Brenda W Gillespie, Peter G Kerr, Jürgen Bommer, Eric W Young, Tadao Akizawa, Takashi Akiba, Ronald L Pisoni, Bruce M Robinson, Friedrich K Port
雑誌名: Am J Kidney Dis. 2008 Sep;52(3):519-30. doi: 10.1053/j.ajkd.2008.03.020. Epub 2008 Jun 2.
Abstract/Text BACKGROUND: Abnormalities in serum calcium, phosphorus, and parathyroid hormone (PTH) concentrations are common in patients with chronic kidney disease and have been associated with increased morbidity and mortality. No clinical trials have been conducted to clearly identify categories of calcium, phosphorus, and PTH levels associated with the lowest mortality risk. Current clinical practice guidelines are based largely on expert opinions, and clinically relevant differences exist among guidelines across countries. We sought to describe international trends in calcium, phosphorus, and PTH levels during 10 years and identify mortality risk categories in the Dialysis Outcomes and Practice Patterns Study (DOPPS), an international study of hemodialysis practices and associated outcomes.
STUDY DESIGN: Prospective cohort study.
PARTICIPANTS: 25,588 patients with end-stage renal disease on hemodialysis therapy for longer than 180 days at 925 facilities in DOPPS I (1996-2001), DOPPS II (2002-2004), or DOPPS III (2005-2007).
PREDICTORS: Serum calcium, albumin-corrected calcium (Ca(Alb)), phosphorus, and PTH levels.
OUTCOMES: Adjusted hazard ratios for all-cause and cardiovascular mortality calculated using Cox models.
RESULTS: Distributions of mineral metabolism markers differed across DOPPS countries and phases, with lower calcium and phosphorus levels observed in the most recent phase of DOPPS. Survival models identified categories with the lowest mortality risk for calcium (8.6 to 10.0 mg/dL), Ca(Alb) (7.6 to 9.5 mg/dL), phosphorus (3.6 to 5.0 mg/dL), and PTH (101 to 300 pg/mL). The greatest risk of mortality was found for calcium or Ca(Alb) levels greater than 10.0 mg/dL, phosphorus levels greater than 7.0 mg/dL, and PTH levels greater than 600 pg/mL and in patients with combinations of high-risk categories of calcium, phosphorus, and PTH.
LIMITATIONS: Because of the observational nature of DOPPS, this study can only indicate an association between mineral metabolism categories and mortality.
CONCLUSIONS: Our results provide important information about mineral metabolism trends in hemodialysis patients in 12 countries during a decade. The risk categories identified in the DOPPS cohort may be relevant to efforts at international harmonization of existing clinical guidelines for mineral metabolism.

PMID 18514987  Am J Kidney Dis. 2008 Sep;52(3):519-30. doi: 10.1053/j.・・・
著者: Jürgen Floege, Joseph Kim, Elizabeth Ireland, Charles Chazot, Tilman Drueke, Angel de Francisco, Florian Kronenberg, Daniele Marcelli, Jutta Passlick-Deetjen, Guntram Schernthaner, Bruno Fouqueray, David C Wheeler, ARO Investigators
雑誌名: Nephrol Dial Transplant. 2011 Jun;26(6):1948-55. doi: 10.1093/ndt/gfq219. Epub 2010 Apr 25.
Abstract/Text BACKGROUND: A number of US observational studies reported an increased mortality risk with higher intact parathyroid hormone (iPTH), calcium and/or phosphate. The existence of such a link in a European haemodialysis population was explored as part of the Analysing Data, Recognising Excellence and Optimising Outcomes (ARO) Chronic Kidney Disease (CKD) Research Initiative.
METHODS: The association between the markers of mineral and bone disease and clinical outcomes was examined in 7970 patients treated in European Fresenius Medical Care facilities over a median of 21 months. Baseline and time-dependent (TD) Cox regression were performed using Kidney Disease Outcomes Quality Initiative (KDOQI) target ranges as reference categories, adjusting for demographics, medical history, dialysis parameters, inflammation, medications and laboratory parameters. Fractional polynomial (FP) models were also used.
RESULTS: Hazard ratio (HR) estimates from baseline analysis for iPTH were U-shaped [>600 pg/mL, HR = 2.10, 95% confidence interval (CI) 1.62-2.73; <75 pg/mL, HR = 1.46, 95% CI 1.17-1.83]. TD analysis confirmed the results for iPTH. Baseline analysis showed that calcium >2.75 mmol/L increased risk of death (HR = 1.70, 95% CI 1.19-2.42). TD analysis showed that both low (HR = 1.19, 95% CI 1.04-1.37) and high calcium (HR = 1.74, 95% CI 1.30-2.34) increased risk of death. Baseline analysis for phosphate showed a U-shaped pattern (<1.13 mmol/L, HR = 1.18, 95% CI 1.01-1.37; >1.78 mmol/L, HR = 1.32, 95% CI 1.13-1.55). TD analysis confirmed the results for phosphate <1.13 mmol/L. HR estimates were higher in patients with diabetes versus those without diabetes for baseline analysis only (P-value = 0.014). FP analysis confirmed the results of baseline and TD analyses.
CONCLUSION: Patients with iPTH, calcium and phosphate levels within the KDOQI target ranges have the lowest risk of mortality compared with those outside the target ranges.

PMID 20466670  Nephrol Dial Transplant. 2011 Jun;26(6):1948-55. doi: 1・・・
著者: Masatomo Taniguchi, Masafumi Fukagawa, Naohiko Fujii, Takayuki Hamano, Tetsuo Shoji, Keitaro Yokoyama, Shigeru Nakai, Takashi Shigematsu, Kunitoshi Iseki, Yoshiharu Tsubakihara, Committee of Renal Data Registry of the Japanese Society for Dialysis Therapy
雑誌名: Ther Apher Dial. 2013 Apr;17(2):221-8. doi: 10.1111/1744-9987.12030.
Abstract/Text Mineral metabolism affects mortality in hemodialysis patients and is identified by imbalances in serum phosphate (P), calcium (Ca), and parathyroid hormone (PTH). We examined associations between annual mineral values (P, Ca, PTH) and mortality in a 3-year cohort (Dec 2006-2009) of 128,125 hemodialysis patients using three models, that is, baseline, time-dependent and time-average Cox models. We also examined associations between achieved Japanese guideline targets (P: 3.5-6.0 mg/dL, corrected Ca 8.4-10.0 mg/dL, intact PTH 60-180 mg/dL) and all-cause survival to elucidate which parameter should be controlled as a priority. High and low serum P (>6.0 or ≤ 3.5 mg/dL), high Ca (>9.5 mg/dL), higher PTH (>300 pg/mL) and lower PTH (≤ 60 pg/mL) were significantly associated with high mortality in all three models (P < 0.01). When we examined the association between combination of mineral targets and mortality, patients who achieved all targets simultaneously (20% of subjects, reference) showed lowest mortality. Those who achieved both P and Ca targets showed the same mortality as the reference group. Those who only met P target had a lower risk of death (hazard ratio = 1.17) compared to those that achieved Ca or PTH target (1.41, 1.47, respectively). As time of achieving P and Ca targets increased, all-cause mortalities diminished incrementally, significantly. Mineral metabolism disorder would lead to high mortality in prevalent hemodialysis patients. Among mineral values, P would be the strongest predictor for high mortality. Consistent achievement of P and Ca targets would lead to good survival.

© 2013 The Authors. Therapeutic Apheresis and Dialysis © 2013 International Society for Apheresis.
PMID 23551679  Ther Apher Dial. 2013 Apr;17(2):221-8. doi: 10.1111/174・・・
著者: Paolo Raggi, Amy Boulay, Scott Chasan-Taber, Naseem Amin, Maureen Dillon, Steven K Burke, Glenn M Chertow
雑誌名: J Am Coll Cardiol. 2002 Feb 20;39(4):695-701.
Abstract/Text OBJECTIVES: We sought to determine clinical and laboratory correlates of calcification of the coronary arteries (CAs), aorta and mitral and aortic valves in adult subjects with end-stage renal disease (ESRD) receiving hemodialysis.
BACKGROUND: Vascular calcification is known to be a risk factor for ischemic heart disease in non-uremic individuals. Patients with ESRD experience accelerated vascular calcification, due at least in part to dysregulation of mineral metabolism. Clinical correlates of the extent of calcification in ESRD have not been identified. Moreover, the clinical relevance of calcification as measured by electron-beam tomography (EBT) has not been determined in the ESRD population.
METHODS: We conducted a cross-sectional analysis of 205 maintenance hemodialysis patients who received baseline EBT for evaluation of vascular and valvular calcification. We compared subjects with and without clinical evidence of atherosclerotic vascular disease and determined correlates of the extent of vascular and valvular calcification using multivariable linear regression and proportional odds logistic regression analyses.
RESULTS: The median coronary artery calcium score was 595 (interquartile range, 76 to 1,600), values consistent with a high risk of obstructive coronary artery disease in the general population. The CA calcium scores were directly related to the prevalence of myocardial infarction (p < 0.0001) and angina (p < 0.0001), and the aortic calcium scores were directly related to the prevalence of claudication (p = 0.001) and aortic aneurysm (p = 0.02). The extent of coronary calcification was more pronounced with older age, male gender, white race, diabetes, longer dialysis vintage and higher serum concentrations of calcium and phosphorus. Total cholesterol (and high-density lipoprotein and low-density lipoprotein subfractions), triglycerides, hemoglobin and albumin were not significantly related to the extent of CA calcification. Only dialysis vintage was significantly associated with the prevalence of valvular calcification.
CONCLUSIONS: Coronary artery calcification is common, severe and significantly associated with ischemic cardiovascular disease in adult ESRD patients. The dysregulation of mineral metabolism in ESRD may influence vascular calcification risk.

PMID 11849871  J Am Coll Cardiol. 2002 Feb 20;39(4):695-701.
著者: Gérard M London, Alain P Guérin, Sylvain J Marchais, Fabien Métivier, Bruno Pannier, Hasan Adda
雑誌名: Nephrol Dial Transplant. 2003 Sep;18(9):1731-40.
Abstract/Text BACKGROUND: Cross-sectional and follow-up studies on end-stage renal disease patients showed that arterial calcifications are associated with cardiovascular (CV) morbidity and are an independent predictor of all-cause and CV mortality. However, these studies did not examine the impact on prognosis according to the type of calcification, i.e. intimal vs medial. Arterial media calcification (AMC), a non-occlusive condition, affects haemodynamics differently from arterial intima calcification (AIC), which occurs in atherosclerotic plaques. The aim of this study was to investigate the prognostic value of AMC in relationship to all-cause or CV mortality for stable haemodialysis (HD) patients.
METHODS: We included 202 such patients in the present study. At baseline, soft-tissue native radiograms of the pelvis and the thigh were analysed for the presence and type (AMC vs AIC) of arterial calcifications. All patients underwent B-mode ultrasonography of the common carotid artery to determine the presence of atherosclerotic calcified plaques, measurement of aortic pulse wave velocity and echocardiography.
RESULTS: AIC was usually observed in older patients with a clinical history of atherosclerosis before starting HD treatment and typical risk factors associated with atherosclerotic disease. AMC was observed in young and middle-aged patients without conventional atherosclerotic risk factors. AMC was closely associated with the duration of HD and calcium-phosphate disorders, including the oral dose of elemental calcium prescribed as phosphate binder (CaCO(3)). Compared to patients with AIC, patients with AMC had a longer survival, but in turn their survival was significantly shorter than that of patients without calcifications.
CONCLUSIONS: AMC is a strong prognostic marker of all-cause and CV mortality in HD patients, independently of classical atherogenic factors. The principal effect of AMC on arterial function is increased arterial stiffness.

PMID 12937218  Nephrol Dial Transplant. 2003 Sep;18(9):1731-40.
著者: Senji Okuno, Eiji Ishimura, Kayoko Kitatani, Yoko Fujino, Kaori Kohno, Yoshifumi Maeno, Kiyoshi Maekawa, Tomoyuki Yamakawa, Yasuo Imanishi, Masaaki Inaba, Yoshiki Nishizawa
雑誌名: Am J Kidney Dis. 2007 Mar;49(3):417-25. doi: 10.1053/j.ajkd.2006.12.017.
Abstract/Text BACKGROUND: Although abdominal aortic calcification (AAC) is reported as a predictor for cardiovascular mortality in the general population, it is unknown whether this is also true in hemodialysis patients in whom vascular calcification and cardiovascular diseases are highly prevalent.
STUDY DESIGN: Cohort study.
SETTINGS & PARTICIPANTS: 515 patients on maintenance hemodialysis therapy at a single center.
PREDICTOR: AAC evaluated in a plain roentgenograph of the lateral abdomen at baseline.
OUTCOMES & MEASUREMENTS: All-cause and cardiovascular death.
RESULTS: Mean age was 60 +/- 12 (SD) years. AAC was present in 291 patients (56.5%). During a mean follow-up period of 51 +/- 17 months, there were 103 all-cause deaths, of which 41 were from cardiovascular diseases. Of patients with and without AAC, 27.8% and 9.8% died, respectively (11.6% and 3.1% of cardiovascular diseases, respectively). Kaplan-Meier analysis showed that all-cause mortality was significantly greater in patients with AAC compared to those without (P < 0.0001, log-rank test). Similarly, cardiovascular mortality was significantly greater in the former than in the latter group (P = 0.0001, log-rank test). Multivariate Cox proportional hazards analysis found that the presence of AAC was significantly associated with increased all-cause mortality (hazard ratio, 2.07; 95% confidence interval, 1.21 to 3.56; P < 0.01) and increased cardiovascular mortality (hazard ratio, 2.39; 95% confidence interval, 1.01 to 5.66; P < 0.05) after adjustment for age, hemodialysis duration, presence of diabetes, serum albumin level, and C-reactive protein level.
LIMITATIONS: Nonquantitative assessment of AAC and the lack of information for medication and history of cardiovascular diseases.
CONCLUSION: The presence of AAC is significantly associated with both all-cause and cardiovascular mortality in hemodialysis patients, suggesting that careful attention should be given to the presence of AAC in a simple radiograph of the lateral abdomen as a prognostic indicator.

PMID 17336703  Am J Kidney Dis. 2007 Mar;49(3):417-25. doi: 10.1053/j.・・・
著者: Kathryn L Adeney, David S Siscovick, Joachim H Ix, Stephen L Seliger, Michael G Shlipak, Nancy S Jenny, Bryan R Kestenbaum
雑誌名: J Am Soc Nephrol. 2009 Feb;20(2):381-7. doi: 10.1681/ASN.2008040349. Epub 2008 Dec 10.
Abstract/Text Within the normal range, higher serum phosphate concentrations are associated with cardiovascular events and mortality in individuals with chronic kidney disease (CKD) and in those with normal kidney function. Experimental models suggest that phosphate has a direct calcifying effect on vascular smooth muscle. We examined associations of serum phosphate concentrations with vascular and valvular calcification in 439 participants from the Multi-Ethnic Study of Atherosclerosis who had moderate CKD and no clinical cardiovascular disease. Serum phosphate concentrations were within the normal range (2.5 to 4.5 mg/dl) in 95% of study participants. The prevalence of calcification in the coronary arteries, descending thoracic aorta, aortic valve, and mitral valve was 67, 49, 25, and 20%, respectively, measured by electron-beam or multi-detector row computed tomography. After adjustment for demographics and estimated GFR, each 1-mg/dl increment in serum phosphate concentration was associated with a 21% (P = 0.002), 33% (P = 0.001), 25% (P = 0.16), and 62% (P = 0.007) greater prevalence of coronary artery, thoracic, aortic valve, and mitral valve calcification, respectively. Adjustment for traditional risk factors for atherosclerosis, parathyroid hormone, or 1,25-dihydroxyvitamin D levels did not alter these associations. In conclusion, higher serum phosphate concentrations, although still within the normal range, are associated with a greater prevalence of vascular and valvular calcification in people with moderate CKD. It remains to be determined whether lowering phosphate concentrations will impact calcification risk in the setting of kidney disease.

PMID 19073826  J Am Soc Nephrol. 2009 Feb;20(2):381-7. doi: 10.1681/AS・・・
著者: Stephan Schwarz, Bhairvi K Trivedi, Kamyar Kalantar-Zadeh, Csaba P Kovesdy
雑誌名: Clin J Am Soc Nephrol. 2006 Jul;1(4):825-31. doi: 10.2215/CJN.02101205. Epub 2006 May 17.
Abstract/Text Abnormalities of mineral metabolism are associated with increased mortality in patients with ESRD, but their effects in predialysis chronic kidney disease (CKD) are less well characterized. In this study, the associations between levels of serum phosphorus, calcium, and calcium-phosphorus product and progression of CKD were examined. Historical data were collected on 985 male US veterans (age 67.4 +/- 10.9; 23.9% black) with CKD stages 1 through 5. Unadjusted and multivariable-adjusted relative risks for progressive CKD (defined as the composite of ESRD or doubling of serum creatinine) were calculated for categories of serum phosphorus, calcium, and calcium-phosphorus product using Cox proportional hazards models. Higher phosphorus was associated with a higher risk for the composite end point (adjusted hazard ratio [HR] [95% confidence interval (CI)] for phosphorus levels 3.3 to 3.8, 3.81 to 4.3, and >4.3 versus <3.3 mg/dl 0.83 [0.54 to 1.27], 1.24 [0.82 to 1.88], and 1.60 [1.06 to 2.41]; P = 0.001 for trend). A 1-mg/dl higher phosphorus level was associated with an adjusted HR (95% CI) of 1.29 (1.12 to 1.48; P < 0.001). Higher calcium-phosphorus product also was associated with higher risk for progressive CKD (adjusted HR [95% CI] for calcium-phosphorus products 30 to 35, 36 to 40, and >40 versus <30 mg2/dl2 0.58 [0.36 to 0.94], 0.87 [0.57 to 1.34], and 1.37 [0.91 to 2.07]; P = 0.002 for trend). A 10-mg2/dl2 higher calcium-phosphorus product was associated with an adjusted HR (95% CI) of 1.29 (1.11 to 1.51; P = 0.001). Lower serum calcium showed a trend toward higher risk for progressive CKD but without statistical significance. Higher serum phosphorus and higher calcium-phosphorus product are associated with progression of CKD.

PMID 17699293  Clin J Am Soc Nephrol. 2006 Jul;1(4):825-31. doi: 10.22・・・
著者: Marcello Tonelli, Frank Sacks, Marc Pfeffer, Zhiwei Gao, Gary Curhan, Cholesterol And Recurrent Events Trial Investigators
雑誌名: Circulation. 2005 Oct 25;112(17):2627-33. doi: 10.1161/CIRCULATIONAHA.105.553198.
Abstract/Text BACKGROUND: Higher levels of serum phosphate are associated with adverse cardiovascular outcomes, especially in the setting of overt hyperphosphatemia. Given the biological importance of phosphorus, it is plausible that higher levels of serum phosphate within the normal range may also be associated with adverse outcomes.
METHODS AND RESULTS: We performed a post hoc analysis of data from the Cholesterol And Recurrent Events (CARE) study. Baseline serum phosphate levels were measured in 4127 fasting participants who were randomized to receive pravastatin 40 mg daily or placebo and followed up for a median of 59.7 months. We used Cox proportional-hazards models to examine the association between serum phosphate and adverse clinical outcomes after adjustment for potential confounders. During nearly 60 months of follow-up, 375 participants died. A significant association was noted between baseline serum phosphate level and the age-, race-, and sex-adjusted risk of all-cause death (hazard ratio per 1 mg/dL, 1.27; 95% confidence interval, 1.02 to 1.58). After categorization based on baseline phosphate level (<2.5, 2.5 to 3.4, 3.5 to 3.9, and > or =4 mg/dL) and further adjustment, a graded independent relation between phosphate and death was observed (P for trend=0.03). For instance, participants with serum phosphate > or =3.5 mg/dL had an adjusted hazard ratio for death of 1.27 (95% confidence interval, 1.02 to 1.59) compared with those with serum phosphate of <3.5 mg/dL. Higher levels of serum phosphate were also associated with increased risk of new heart failure, myocardial infarction, and the composite of coronary death or nonfatal myocardial infarction, but not the risk of stroke.
CONCLUSIONS: We found a graded independent relation between higher levels of serum phosphate and the risk of death and cardiovascular events in people with prior myocardial infarction, most of whom had serum phosphate levels within the normal range. Given the ready availability and low cost of serum phosphate assays, this finding may prove clinically useful.

PMID 16246962  Circulation. 2005 Oct 25;112(17):2627-33. doi: 10.1161/・・・
著者: Bryan Kestenbaum, Joshua N Sampson, Kyle D Rudser, Donald J Patterson, Stephen L Seliger, Bessie Young, Donald J Sherrard, Dennis L Andress
雑誌名: J Am Soc Nephrol. 2005 Feb;16(2):520-8. doi: 10.1681/ASN.2004070602. Epub 2004 Dec 22.
Abstract/Text Elevated serum phosphate levels have been linked with vascular calcification and mortality among dialysis patients. The relationship between phosphate and mortality has not been explored among patients with chronic kidney disease (CKD). A retrospective cohort study was conducted from eight Veterans Affairs' Medical Centers located in the Pacific Northwest. CKD was defined by two continuously abnormal outpatient serum creatinine measurements at least 6 mo apart between 1999 and 2002. Patients who received chronic dialysis, those with a present or previous renal transplant, and those without a recent phosphate measurement were excluded. The primary end point was all-cause mortality. Secondary end points were acute myocardial infarction and the combined end point of myocardial infarction plus death. A total of 95,619 veterans with at least one primary care or internal medicine clinic contact from a Northwest VA facility and two or more outpatient measurements of serum creatinine, at least 6 mo apart, between January 1, 1999, and December 31, 2002, were identified. From this eligible population, 7021 patients met our definition of CKD. After exclusions, 6730 CKD patients were available for analysis, and 3490 had a serum phosphate measurement during the previous 18 mo. After adjustment, serum phosphate levels >3.5 mg/dl were associated with a significantly increased risk for death. Mortality risk increased linearly with each subsequent 0.5-mg/dl increase in serum phosphate levels. Elevated serum phosphate levels were independently associated with increased mortality risk among this population of patients with CKD.

PMID 15615819  J Am Soc Nephrol. 2005 Feb;16(2):520-8. doi: 10.1681/AS・・・
著者: Vandana Menon, Tom Greene, Arema A Pereira, Xuelei Wang, Gerald J Beck, John W Kusek, Alan J Collins, Andrew S Levey, Mark J Sarnak
雑誌名: Am J Kidney Dis. 2005 Sep;46(3):455-63. doi: 10.1053/j.ajkd.2005.05.025.
Abstract/Text BACKGROUND: Abnormalities of mineral metabolism are prevalent in patients with kidney failure and are associated with increased risk for cardiovascular events. There are limited data investigating relationships of phosphorus and calcium-phosphorus product with outcomes in patients with chronic kidney disease (CKD) stages 3 to 4.
METHODS: Serum phosphorus and calcium were measured at baseline in 840 participants from the randomized cohort of the Modification of Diet in Renal Disease Study. Survival status until December 31, 2000, was obtained from the National Death Index. Cox models were performed to assess the relationship of serum phosphorus level and calcium-phosphorus product with all-cause and cardiovascular disease (CVD) mortality.
RESULTS: Mean serum phosphorus level was 3.8 +/- 0.7 mg/dL (1.23 +/- 0.23 mmol/L), calcium-phosphorus product was 34.7 +/- 6.3 mg2/dL2, and glomerular filtration rate (GFR) was 33 +/- 12 mL/min/1.73 m2 (0.55 +/- 0.20 mL/s/1.73 m2). All-cause and CVD mortality rates were 25% and 15%. Serum phosphorus level was not related to all-cause mortality in multivariable models (P = 0.46). In unadjusted analysis, serum phosphorus level was associated with (hazard ratio [HR] per 1 mg/dL increase, 1.34; 95% confidence interval [CI], 1.05 to 1.71; P = 0.02) increased risk for CVD mortality, but this association was partly attenuated and not statistically significant after adjustment for GFR and other confounders (HR, 1.27; 95% CI, 0.94 to 1.73; P = 0.12). Calcium-phosphorus product was not associated with all-cause mortality in unadjusted (P = 0.23) or multivariate analysis (P = 0.35). Calcium-phosphorus product was related to CVD mortality in unadjusted (HR per 10 mg2/dL2 increase, 1.30; 95% CI, 1.01 to 1.69; P = 0.04) analysis, but this association was not statistically significant after adjustment for GFR and other confounders (HR, 1.22; 95% CI, 0.89 to 1.66; P = 0.23).
CONCLUSION: In the Modification of Diet in Renal Disease Study cohort, serum phosphorus level and calcium-phosphorus product were not statistically associated with all-cause or CVD mortality after adjustment for GFR; however larger studies with additional statistical power are needed to evaluate these relationships, especially in the context of current practice patterns in patients with CKD.

PMID 16129207  Am J Kidney Dis. 2005 Sep;46(3):455-63. doi: 10.1053/j.・・・
著者: Helen Eddington, Richard Hoefield, Smeeta Sinha, Constantina Chrysochou, Beverley Lane, Robert N Foley, Janet Hegarty, John New, Donal J O'Donoghue, Rachel J Middleton, Philip A Kalra
雑誌名: Clin J Am Soc Nephrol. 2010 Dec;5(12):2251-7. doi: 10.2215/CJN.00810110. Epub 2010 Aug 5.
Abstract/Text BACKGROUND AND OBJECTIVES: Higher phosphate is associated with mortality in dialysis patients but few prospective studies assess this in nondialysis patients managed in an outpatient nephrology clinic. This prospective longitudinal study examined whether phosphate level was associated with death in a referred population.
DESIGN, SETTING, PARTICIPANTS & MEASUREMENTS: Patients (1203) of nondialysis chronic kidney disease (CKD) in the Chronic Renal Insufficiency Standards Implementation Study were assessed. Survival analyses were performed for quartiles of baseline phosphate relative to GFR, 12-month time-averaged phosphate, and baseline phosphate according to published phosphate targets.
RESULTS: Mean (SD) eGFR was 32 (15) ml/min per 1.73 m(2), age 64 (14) years, and phosphate 1.2 (0.30) mmol/L. Cox multivariate adjusted regression in CKD stages 3 to 4 patients showed an increased risk of all-cause and cardiovascular mortality in the highest quartile compared with that in the lowest quartile of phosphate. No association was found in CKD stage 5 patients. Patients who had values above recommended targets for phosphate control had increased risk of all-cause and cardiovascular death compared with patients below target. The highest quartile compared with the lowest quartile of 12-month time-averaged phosphate was associated with an increased risk of mortality.
CONCLUSIONS: In CKD stages 3 to 4 patients, higher phosphate was associated with a stepwise increase in mortality. As phosphate levels below published targets (as opposed to within them) are associated with better survival, guidelines for phosphate in nondialysis CKD patients should be re-examined. Intervention trials are required to determine whether lowering phosphate will improve survival.

PMID 20688884  Clin J Am Soc Nephrol. 2010 Dec;5(12):2251-7. doi: 10.2・・・
著者: Csaba P Kovesdy, Olga Kuchmak, Jun Ling Lu, Kamyar Kalantar-Zadeh
雑誌名: Am J Kidney Dis. 2010 Nov;56(5):842-51. doi: 10.1053/j.ajkd.2010.06.011. Epub 2010 Aug 21.
Abstract/Text BACKGROUND: Phosphorus binders are used to treat hyperphosphatemia in maintenance dialysis patients, in whom the use of these medications has been associated with lower mortality in some observational studies. It is not clear whether similar benefits can be seen in patients with non-dialysis-dependent chronic kidney disease (CKD).
STUDY DESIGN: Historical cohort.
SETTING & PARTICIPANTS: 1,188 men with moderate and advanced non-dialysis-dependent CKD at a single medical center.
PREDICTOR: Administration of any phosphorus binder.
OUTCOMES & MEASUREMENTS: We examined associations of any phosphorus-binder administration with all-cause mortality and the slopes of estimated glomerular filtration rate using time-varying Cox models and mixed-effects models. Associations also were examined in intention-to-treat analyses and in 133 patient-pairs matched according to propensity scores.
RESULTS: 344 patients were treated with a phosphorus binder; 658 patients died (mortality rate, 141 deaths/1,000 patient-years; 95% CI, 131-153) during a median follow-up of 3.1 years. Treatment with phosphorus binders was associated with significantly lower mortality (adjusted HR, 0.61; 95% CI, 0.45-0.81; P < 0.001). Results were similar when exposure was modeled in intention-to-treat analyses and examining propensity-matched patients. Phosphorus-binder use was not associated with significant changes in kidney function loss.
LIMITATIONS: Results may not apply to all patients with non-dialysis-dependent CKD.
CONCLUSIONS: Administration of phosphorus binders is associated with lower mortality in men with moderate and advanced non-dialysis-dependent CKD. Clinical trials are needed to determine the risks and benefits of phosphorus-binder use in this patient population.

Published by Elsevier Inc.
PMID 20728255  Am J Kidney Dis. 2010 Nov;56(5):842-51. doi: 10.1053/j.・・・
著者: Geoffrey A Block, David C Wheeler, Martha S Persky, Bryan Kestenbaum, Markus Ketteler, David M Spiegel, Matthew A Allison, John Asplin, Gerard Smits, Andrew N Hoofnagle, Laura Kooienga, Ravi Thadhani, Michael Mannstadt, Myles Wolf, Glenn M Chertow
雑誌名: J Am Soc Nephrol. 2012 Aug;23(8):1407-15. doi: 10.1681/ASN.2012030223. Epub 2012 Jul 19.
Abstract/Text Some propose using phosphate binders in the CKD population given the association between higher levels of phosphorus and mortality, but their safety and efficacy in this population are not well understood. Here, we aimed to determine the effects of phosphate binders on parameters of mineral metabolism and vascular calcification among patients with moderate to advanced CKD. We randomly assigned 148 patients with estimated GFR=20-45 ml/min per 1.73 m(2) to calcium acetate, lanthanum carbonate, sevelamer carbonate, or placebo. The primary endpoint was change in mean serum phosphorus from baseline to the average of months 3, 6, and 9. Serum phosphorus decreased from a baseline mean of 4.2 mg/dl in both active and placebo arms to 3.9 mg/dl with active therapy and 4.1 mg/dl with placebo (P=0.03). Phosphate binders, but not placebo, decreased mean 24-hour urine phosphorus by 22%. Median serum intact parathyroid hormone remained stable with active therapy and increased with placebo (P=0.002). Active therapy did not significantly affect plasma C-terminal fibroblast growth factor 23 levels. Active therapy did, however, significantly increase calcification of the coronary arteries and abdominal aorta (coronary: median increases of 18.1% versus 0.6%, P=0.05; abdominal aorta: median increases of 15.4% versus 3.4%, P=0.03). In conclusion, phosphate binders significantly lower serum and urinary phosphorus and attenuate progression of secondary hyperparathyroidism among patients with CKD who have normal or near-normal levels of serum phosphorus; however, they also promote the progression of vascular calcification. The safety and efficacy of phosphate binders in CKD remain uncertain.

PMID 22822075  J Am Soc Nephrol. 2012 Aug;23(8):1407-15. doi: 10.1681/・・・
著者: Ravi Thadhani, Evan Appelbaum, Yili Pritchett, Yuchiao Chang, Julia Wenger, Hector Tamez, Ishir Bhan, Rajiv Agarwal, Carmine Zoccali, Christoph Wanner, Donald Lloyd-Jones, Jorge Cannata, B Taylor Thompson, Dennis Andress, Wuyan Zhang, David Packham, Bhupinder Singh, Daniel Zehnder, Amil Shah, Ajay Pachika, Warren J Manning, Scott D Solomon
雑誌名: JAMA. 2012 Feb 15;307(7):674-84. doi: 10.1001/jama.2012.120.
Abstract/Text CONTEXT: Vitamin D is associated with decreased cardiovascular-related morbidity and mortality, possibly by modifying cardiac structure and function, yet firm evidence for either remains lacking.
OBJECTIVE: To determine the effects of an active vitamin D compound, paricalcitol, on left ventricular mass over 48 weeks in patients with an estimated glomerular filtration rate of 15 to 60 mL/min/1.73 m(2).
DESIGN, SETTING, AND PARTICIPANTS: Multinational, double-blind, randomized placebo-controlled trial among 227 patients with chronic kidney disease, mild to moderate left ventricular hypertrophy, and preserved left ventricular ejection fraction, conducted in 11 countries from July 2008 through September 2010.
INTERVENTION: Participants were randomly assigned to receive oral paricalcitol, 2 μg/d (n =115), or matching placebo (n = 112).
MAIN OUTCOME MEASURES: Change in left ventricular mass index over 48 weeks by cardiovascular magnetic resonance imaging. Secondary end points included echocardiographic changes in left ventricular diastolic function.
RESULTS: Treatment with paricalcitol reduced parathyroid hormone levels within 4 weeks and maintained levels within the normal range throughout the study duration. At 48 weeks, the change in left ventricular mass index did not differ between treatment groups (paricalcitol group, 0.34 g/m(2.7) [95% CI, -0.14 to 0.83 g/m(2.7)] vs placebo group, -0.07 g/m(2.7) [95% CI, -0.55 to 0.42 g/m(2.7)]). Doppler measures of diastolic function including peak early diastolic lateral mitral annular tissue velocity (paricalcitol group, -0.01 cm/s [95% CI, -0.63 to 0.60 cm/s] vs placebo group, -0.30 cm/s [95% CI, -0.93 to 0.34 cm/s]) also did not differ. Episodes of hypercalcemia were more frequent in the paricalcitol group compared with the placebo group.
CONCLUSION: Forty-eight week therapy with paricalcitol did not alter left ventricular mass index or improve certain measures of diastolic dysfunction in patients with chronic kidney disease.
TRIAL REGISTRATION: clinicaltrials.gov Identifier: NCT00497146.

PMID 22337679  JAMA. 2012 Feb 15;307(7):674-84. doi: 10.1001/jama.2012・・・
著者: Angela Yee-Moon Wang, Fang Fang, John Chan, Yue-Yi Wen, Shang Qing, Iris Hiu-Shuen Chan, Gladys Lo, Kar-Neng Lai, Wai-Kei Lo, Christopher Wai-Kei Lam, Cheuk-Man Yu
雑誌名: J Am Soc Nephrol. 2014 Jan;25(1):175-86. doi: 10.1681/ASN.2013010103. Epub 2013 Sep 19.
Abstract/Text Vitamin D seems to protect against cardiovascular disease, but the reported effects of vitamin D on patient outcomes in CKD are controversial. We conducted a prospective, double blind, randomized, placebo-controlled trial to determine whether oral activated vitamin D reduces left ventricular (LV) mass in patients with stages 3-5 CKD with LV hypertrophy. Subjects with echocardiographic criteria of LV hypertrophy were randomly assigned to receive either oral paricalcitol (1 μg) one time daily (n=30) or matching placebo (n=30) for 52 weeks. The primary end point was change in LV mass index over 52 weeks, which was measured by cardiac magnetic resonance imaging. Secondary end points included changes in LV volume, echocardiographic measures of systolic and diastolic function, biochemical parameters of mineral bone disease, and measures of renal function. Change in LV mass index did not differ significantly between groups (median [interquartile range], -2.59 [-6.13 to 0.32] g/m(2) with paricalcitol versus -4.85 [-9.89 to 1.10] g/m(2) with placebo). Changes in LV volume, ejection fraction, tissue Doppler-derived measures of early diastolic and systolic mitral annular velocities, and ratio of early mitral inflow velocity to early diastolic mitral annular velocity did not differ between the groups. However, paricalcitol treatment significantly reduced intact parathyroid hormone (P<0.001) and alkaline phosphatase (P=0.001) levels as well as the number of cardiovascular-related hospitalizations compared with placebo. In conclusion, 52 weeks of treatment with oral paricalcitol (1 μg one time daily) significantly improved secondary hyperparathyroidism but did not alter measures of LV structure and function in patients with severe CKD.

PMID 24052631  J Am Soc Nephrol. 2014 Jan;25(1):175-86. doi: 10.1681/A・・・
著者: W N Suki, R Zabaneh, J L Cangiano, J Reed, D Fischer, L Garrett, B N Ling, S Chasan-Taber, M A Dillon, A T Blair, S K Burke
雑誌名: Kidney Int. 2007 Nov;72(9):1130-7. doi: 10.1038/sj.ki.5002466. Epub 2007 Aug 29.
Abstract/Text Elevated serum phosphorus and calcium are associated with arterial calcification and mortality in dialysis patients. Unlike calcium-based binders, sevelamer attenuates arterial calcification but it is unknown whether sevelamer affects mortality or morbidity. In a multicenter, randomized, open-label, parallel design trial we compared sevelamer and calcium-based binders on all-cause and cause-specific mortality (cardiovascular, infection, and other) in prevalent hemodialysis patients. A total of 2103 patients were initially randomized to treatment and 1068 patients completed the study. All-cause mortality rates and cause-specific mortality rates were not significantly different. There was a significant age interaction on the treatment effect. Only in patients over 65 years of age was there a significant effect of sevelamer in lowering the mortality rate. There was a suggestion that sevelamer was associated with lower overall, but not cardiovascular-linked, mortality in older patients. We suggest that further research is needed to confirm these findings.

PMID 17728707  Kidney Int. 2007 Nov;72(9):1130-7. doi: 10.1038/sj.ki.5・・・
著者: G A Block, P Raggi, A Bellasi, L Kooienga, D M Spiegel
雑誌名: Kidney Int. 2007 Mar;71(5):438-41. doi: 10.1038/sj.ki.5002059. Epub 2007 Jan 3.
Abstract/Text The risk of death in hemodialysis patients treated with calcium-containing phosphate binders or sevelamer is not known. We assessed all-cause mortality in 127 patients new to hemodialysis assigned to calcium-containing binders or sevelamer after a median follow-up of 44 months from randomization. This was a predetermined secondary end point of a randomized clinical trial designed to assess progression of coronary artery calcium (CAC) scores in the two treatment arms. Thirty-four deaths occurred during the follow-up period: 23 in subjects randomized to calcium-containing phosphate binders and 11 in subjects randomized to sevelamer. Baseline CAC score was a significant predictor of mortality after adjustment for age, race, gender, and diabetes with increased mortality proportional to baseline score (P=0.002). Mortality was borderline significantly lower in subjects randomized to sevelamer (5.3/100 patient years, confidence interval (CI) (2.2-8.5) compared to those randomized to calcium-containing binders (10.6/100 patient years, CI 6.3-14.9) (P=0.05). The greater risk of death for patients treated with calcium-containing phosphate binders persisted after full multivariable adjustment (P=0.016, hazard ratio 3.1, CI 1.23-7.61). In subjects new to hemodialysis baseline CAC score was a significant predictor of all-cause mortality. Treatment with sevelamer was associated with a significant survival benefit as compared to the use of calcium-containing phosphate binders.

PMID 17200680  Kidney Int. 2007 Mar;71(5):438-41. doi: 10.1038/sj.ki.5・・・
著者: Geoffrey A Block, David M Spiegel, James Ehrlich, Ravindra Mehta, Jill Lindbergh, Albert Dreisbach, Paolo Raggi
雑誌名: Kidney Int. 2005 Oct;68(4):1815-24. doi: 10.1111/j.1523-1755.2005.00600.x.
Abstract/Text BACKGROUND: Hemodialysis patients are at increased risk for progressive coronary artery calcification; however, the development and progression of this disease process in patients new to hemodialysis is unknown.
METHOD: One hundred and twenty-nine patients new to hemodialysis were randomized to receive calcium containing phosphate binders or the noncalcium phosphate binder sevelamer hydrochloride. Subjects underwent electron beam computed tomography scanning (EBCT) at entry into the study and again at 6, 12, and 18 months.
RESULTS: One hundred and nine patients underwent baseline and at least one additional assessment of coronary calcification. At baseline, 37% of sevelamer treated and 31% of calcium treated patients had no evidence of coronary calcification. No subject with a zero coronary artery calcium score (CACS) at baseline progressed to a CACS >30 over 18 months. Subjects with a CACS > 30 at baseline showed progressive increases in CACS in both treatment arms (P < 0.05 for each time point in both groups). Subjects treated with calcium containing phosphate binders showed more rapid and more severe increases in CACS when compared with those receiving sevelamer hydrochloride (P= 0.056 at 12 months, P= 0.01 at 18 months).
CONCLUSION: New hemodialysis patients with no evidence of coronary calcification showed little evidence of disease development over 18 months independent of phosphate binder therapy. However, subjects with evidence of at least mild coronary calcification had significant progression at 6, 12, and 18 months. Use of calcium containing phosphate binders resulted in more rapid progression of coronary calcification than did use of sevelamer hydrochloride.

PMID 16164659  Kidney Int. 2005 Oct;68(4):1815-24. doi: 10.1111/j.1523・・・
著者: Glenn M Chertow, Steven K Burke, Paolo Raggi, Treat to Goal Working Group
雑誌名: Kidney Int. 2002 Jul;62(1):245-52. doi: 10.1046/j.1523-1755.2002.00434.x.
Abstract/Text BACKGROUND: Cardiovascular disease is frequent and severe in patients with end-stage renal disease. Disorders of mineral metabolism may contribute by promoting cardiovascular calcification.
METHODS: We conducted a randomized clinical trial comparing sevelamer, a non-absorbed polymer, with calcium-based phosphate binders in 200 hemodialysis patients. Study outcomes included the targeted concentrations of serum phosphorus, calcium, and intact parathyroid hormone (PTH), and calcification of the coronary arteries and thoracic aorta using a calcification score derived from electron beam tomography.
RESULTS: Sevelamer and calcium provided equivalent control of serum phosphorus (end-of-study values 5.1 +/- 1.2 and 5.1 +/- 1.4 mg/dL, respectively, P = 0.33). Serum calcium concentration was significantly higher in the calcium-treated group (P = 0.002), and hypercalcemia was more common (16% vs. 5% with sevelamer, P = 0.04). More subjects in the calcium group had end-of-study intact PTH below the target of 150 to 300 pg/mL (57% vs. 30%, P = 0.001). At study completion, the median absolute calcium score in the coronary arteries and aorta increased significantly in the calcium treated subjects but not in the sevelamer-treated subjects (coronary arteries 36.6 vs. 0, P = 0.03 and aorta 75.1 vs. 0, P = 0.01, respectively). The median percent change in coronary artery (25% vs. 6%, P = 0.02) and aortic (28% vs. 5%, P = 0.02) calcium score also was significantly greater with calcium than with sevelamer.
CONCLUSIONS: Compared with calcium-based phosphate binders, sevelamer is less likely to cause hypercalcemia, low levels of PTH, and progressive coronary and aortic calcification in hemodialysis patients.

PMID 12081584  Kidney Int. 2002 Jul;62(1):245-52. doi: 10.1046/j.1523-・・・
著者: Sophie A Jamal, Ben Vandermeer, Paolo Raggi, David C Mendelssohn, Trish Chatterley, Marlene Dorgan, Charmaine E Lok, David Fitchett, Ross T Tsuyuki
雑誌名: Lancet. 2013 Oct 12;382(9900):1268-77. doi: 10.1016/S0140-6736(13)60897-1. Epub 2013 Jul 19.
Abstract/Text BACKGROUND: Phosphate binders (calcium-based and calcium-free) are recommended to lower serum phosphate and prevent hyperphosphataemia in patients with chronic kidney disease, but their effects on mortality and cardiovascular outcomes are unknown. We aimed to update our meta-analysis on the effect of calcium-based versus non-calcium-based phosphate binders on mortality in patients with chronic kidney disease.
METHODS: We did a systematic review of articles published in any language after Aug 1, 2008, up until Oct 22, 2012, by searching Medline, Embase, International Pharmaceutical Abstracts, Cochrane Central Register of Controlled Trials, and Cumulative Index to Nursing and Allied Health Literature. We included all randomised and non-randomised trials that compared outcomes between patients with chronic kidney disease taking calcium-based phosphate binders with those taking non-calcium-based binders. Eligible studies, determined by consensus with predefined criteria, were reviewed, and data were extracted onto a standard form. We combined data from randomised trials to assess the primary outcome of all-cause mortality using the DerSimonian and Laird random effects model.
FINDINGS: Our search identified 847 reports, of which eight new studies (five randomised trials) met our inclusion criteria and were added to the ten (nine randomised trials) included in our previous meta-analysis. Analysis of the 11 randomised trials (4622 patients) that reported an outcome of mortality showed that patients assigned to non-calcium-based binders had a 22% reduction in all-cause mortality compared with those assigned to calcium-based phosphate binders (risk ratio 0·78, 95% CI 0·61-0·98).
INTERPRETATION: Non-calcium-based phosphate binders are associated with a decreased risk of all-cause mortality compared with calcium-based phosphate binders in patients with chronic kidney disease. Further studies are needed to identify causes of mortality and to assess whether mortality differs by type of non-calcium-based phosphate binder.
FUNDING: None.

Copyright © 2013 Elsevier Ltd. All rights reserved.
PMID 23870817  Lancet. 2013 Oct 12;382(9900):1268-77. doi: 10.1016/S01・・・
著者: Nigel D Toussaint, Kenneth K Lau, Kevan R Polkinghorne, Peter G Kerr
雑誌名: Nephrology (Carlton). 2011 Mar;16(3):290-8. doi: 10.1111/j.1440-1797.2010.01412.x.
Abstract/Text BACKGROUND: Vascular calcification (VC) contributes to cardiovascular disease in haemodialysis (HD) patients. Few controlled studies have addressed interventions to reduce VC but non-calcium-based phosphate binders may be beneficial. No published randomized study to date has assessed the effect of lanthanum carbonate (LC) on VC progression.
METHODS: We conducted a pilot randomized controlled trial to determine the effect of LC on VC. Forty-five HD patients were randomized to either LC or calcium carbonate (CC). Primary outcome was change in aortic VC after 18 months. Secondary outcomes included superficial femoral artery (SFA) VC, bone mineral density (BMD) of lumbar spine and serum markers of mineral metabolism. At baseline, 6 and 18 month computed tomography was performed to measure VC and BMD. A random effect linear regression model was performed to assess differences.
RESULTS: Thirty patients completed the study (17 LC, 13 CC); baseline median age 58 years, 38% diabetic, 64% male. Ninety-three per cent had aortic VC at commencement and 87% showed progression. At 18 months, there was significantly less aortic VC progression with LC than CC (adjusted difference -98.1 (-149.4, -46.8) Hounsfield units (HU), P < 0.001). There was also a non-significant reduction with LC in left SFA VC (-25.8 (-67.7, 16.1) HU, P = 0.2) and right SFA VC (-35.9 (-77.8, 5.9) HU, P = 0.09). There was no difference in lumbar spine BMD and serum phosphate, calcium and parathyroid hormone levels between groups. Limitations to the study include small sample size and loss to follow up.
CONCLUSIONS: Lanthanum carbonate was associated with reduced progression of aortic calcification compared with CC in HD patients over 18 months.

© 2011 The Authors. Nephrology © 2011 Asian Pacific Society of Nephrology.
PMID 21342323  Nephrology (Carlton). 2011 Mar;16(3):290-8. doi: 10.111・・・
著者: Hirotaka Komaba, Takatoshi Kakuta, Takehiko Wada, Miho Hida, Takao Suga, Masafumi Fukagawa
雑誌名: Nephrol Dial Transplant. 2019 Feb 1;34(2):318-325. doi: 10.1093/ndt/gfy090.
Abstract/Text Background: Hyperphosphatemia and poor nutritional status are associated with increased mortality. Lanthanum carbonate is an effective, calcium-free phosphate binder, but little is known about the long-term impact on mineral metabolism, nutritional status and survival.
Methods: We extended the follow-up period of a historical cohort of 2292 maintenance hemodialysis patients that was formed in late 2008. We examined 7-year all-cause mortality according to the serum phosphate levels and nutritional indicators in the entire cohort and then compared the mortality rate of the 562 patients who initiated lanthanum with that of the 562 propensity score-matched patients who were not treated with lanthanum.
Results: During a mean ± SD follow-up of 4.9 ± 2.3 years, 679 patients died in the entire cohort. Higher serum phosphorus levels and lower nutritional indicators (body mass index, albumin and creatinine) were each independently associated with an increased risk of death. In the propensity score-matched analysis, patients who initiated lanthanum had a 23% lower risk for mortality compared with the matched controls. During the follow-up period, the serum phosphorus levels tended to decrease comparably in both groups, but the lanthanum group maintained a better nutritional status than the control group. The survival benefit associated with lanthanum was unchanged after adjustment for time-varying phosphorus or other mineral metabolism parameters, but was attenuated by adjustments for time-varying indicators of nutritional status.
Conclusions: Treatment with lanthanum is associated with improved survival in hemodialysis patients. This effect may be partially mediated by relaxation of dietary phosphate restriction and improved nutritional status.

PMID 29672760  Nephrol Dial Transplant. 2019 Feb 1;34(2):318-325. doi:・・・
著者: Giovanni F M Strippoli, Suetonia Palmer, Allison Tong, Grahame Elder, Piergiorgio Messa, Jonathan C Craig
雑誌名: Am J Kidney Dis. 2006 May;47(5):715-26. doi: 10.1053/j.ajkd.2006.01.015.
Abstract/Text BACKGROUND: Many randomized trials have now evaluated the effects of calcimimetics in patients with chronic kidney disease and secondary hyperparathyroidism (SHPT) on standard therapy with vitamin D and/or phosphate binders. We conducted a meta-analysis to evaluate outcomes of therapy with these novel agents.
METHODS: MEDLINE, EMBASE, the Cochrane Controlled Trials Register, and conference proceedings were searched for randomized controlled trials evaluating any calcimimetic against placebo or another agent in predialysis or dialysis patients with chronic kidney disease. Data were extracted for all relevant patient-centered and surrogate outcomes. Analysis was by means of a random-effects model, and results are expressed as relative risk or weighted mean difference (WMD) with 95% confidence intervals (CIs).
RESULTS: Eight trials (1,429 patients) were identified that compared a calcimimetic agent plus standard therapy with placebo plus standard therapy. End-of-treatment values for parathyroid hormone (4 trials; 1,278 patients; WMD, -290.49 pg/mL; 95% CI, -359.91 to -221.07), serum calcium (3 trials; 1,201 patients; WMD, -0.85 mg/dL; 95% CI, -1.14 to -0.56), serum phosphorus (3 trials; 1,195 patients; WMD, -0.29 mg/dL; 95% CI, -0.50 to -0.08), and calcium x phosphorus product (3 trials; 1,194 patients; WMD, -7.90 mg2/dL2; 95% CI, -10.25 to -5.54) were significantly lower with calcimimetic therapy compared with placebo. No significant effects on patient-based end points were shown.
CONCLUSION: Calcimimetic treatment of patients with SHPT leads to significant improvements in biochemical parameters that observational studies have associated with increased mortality, cardiovascular risk, and osteitis fibrosa, but patient-based benefits have not yet been shown. For patients with SHPT, the benefits of calcimimetics over standard therapy remain uncertain until additional randomized trials become available.

PMID 16632010  Am J Kidney Dis. 2006 May;47(5):715-26. doi: 10.1053/j.・・・
著者: Hirotaka Komaba, Shohei Nakanishi, Akira Fujimori, Motoko Tanaka, Jeongsoo Shin, Koji Shibuya, Masato Nishioka, Hirohito Hasegawa, Takeshi Kurosawa, Masafumi Fukagawa
雑誌名: Clin J Am Soc Nephrol. 2010 Dec;5(12):2305-14. doi: 10.2215/CJN.02110310. Epub 2010 Aug 26.
Abstract/Text BACKGROUND AND OBJECTIVES: Cinacalcet is effective in reducing serum parathyroid hormone (PTH) in patients with secondary hyperparathyroidism. However, it has not been proven whether parathyroid gland size predicts response to therapy and whether cinacalcet is capable of inducing a reduction in parathyroid volume.
DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: This 52-week, multicenter, open-label study enrolled hemodialysis patients with moderate to severe secondary hyperparathyroidism (intact PTH >300 pg/ml). Doses of cinacalcet were adjusted between 25 and 100 mg to achieve intact PTH <180 pg/ml. Ultrasonography was performed to measure the parathyroid gland size at baseline, week 26, and week 52. Findings were also compared with those of historical controls.
RESULTS: Of the 81 subjects enrolled, 56 had parathyroid glands smaller than 500 mm(3) (group S) and 25 had at least one enlarged gland larger than 500 mm(3) (group L). Treatment with cinacalcet effectively decreased intact PTH by 55% from baseline in group S and by 58% in group L. A slightly greater proportion of patients in group S versus group L achieved an intact PTH <180 pg/ml (46 versus 32%) and a >30% reduction from baseline (88 versus 78%), but this was not statistically significant. Cinacalcet therapy also resulted in a significant reduction in parathyroid gland volume regardless of pretreatment size, which was in sharp contrast to historical controls (n = 87) where parathyroid gland volume progressively increased with traditional therapy alone.
CONCLUSIONS: Cinacalcet effectively decreases serum PTH levels and concomitantly reduces parathyroid gland volume, even in patients with marked parathyroid hyperplasia.

PMID 20798251  Clin J Am Soc Nephrol. 2010 Dec;5(12):2305-14. doi: 10.・・・
著者: Geoffrey A Block, David Zaun, Gerard Smits, Martha Persky, Stephanie Brillhart, Kimberly Nieman, Jiannong Liu, Wendy L St Peter
雑誌名: Kidney Int. 2010 Sep;78(6):578-89. doi: 10.1038/ki.2010.167. Epub 2010 Jun 16.
Abstract/Text Secondary hyperparathyroidism (SHPT) affects a significant number of hemodialysis patients, and metabolic disturbances associated with it may contribute to their high mortality rate. As patients with lower serum calcium, phosphorus, and parathyroid hormone are reported to have improved survival, we tested whether prescription of the calcimimetic cinacalcet to hemodialysis patients with SHPT improved their survival. We prospectively collected data on hemodialysis patients from a large provider beginning in 2004, a time coincident with the commercial availability of cinacalcet hydrochloride. This information was merged with data in the United States Renal Data System to determine all-cause and cardiovascular mortality. Patients included in the study received intravenous (i.v.) vitamin D therapy (a surrogate for the diagnosis of SHPT). Of 19,186 patients, 5976 received cinacalcet and all were followed from November 2004 for up to 26 months. Unadjusted and adjusted time-dependent Cox proportional hazards modeling found that all-cause and cardiovascular mortality rates were significantly lower for those treated with cinacalcet than for those without calcimimetic. Hence, this observational study found a significant survival benefit associated with cinacalcet prescription in patients receiving i.v. vitamin D. Definitive proof, however, of a survival advantage awaits the performance of randomized clinical trials.

PMID 20555319  Kidney Int. 2010 Sep;78(6):578-89. doi: 10.1038/ki.2010・・・
著者: EVOLVE Trial Investigators, Glenn M Chertow, Geoffrey A Block, Ricardo Correa-Rotter, Tilman B Drüeke, Jürgen Floege, William G Goodman, Charles A Herzog, Yumi Kubo, Gerard M London, Kenneth W Mahaffey, T Christian H Mix, Sharon M Moe, Marie-Louise Trotman, David C Wheeler, Patrick S Parfrey
雑誌名: N Engl J Med. 2012 Dec 27;367(26):2482-94. doi: 10.1056/NEJMoa1205624. Epub 2012 Nov 3.
Abstract/Text BACKGROUND: Disorders of mineral metabolism, including secondary hyperparathyroidism, are thought to contribute to extraskeletal (including vascular) calcification among patients with chronic kidney disease. It has been hypothesized that treatment with the calcimimetic agent cinacalcet might reduce the risk of death or nonfatal cardiovascular events in such patients.
METHODS: In this clinical trial, we randomly assigned 3883 patients with moderate-to-severe secondary hyperparathyroidism (median level of intact parathyroid hormone, 693 pg per milliliter [10th to 90th percentile, 363 to 1694]) who were undergoing hemodialysis to receive either cinacalcet or placebo. All patients were eligible to receive conventional therapy, including phosphate binders, vitamin D sterols, or both. The patients were followed for up to 64 months. The primary composite end point was the time until death, myocardial infarction, hospitalization for unstable angina, heart failure, or a peripheral vascular event. The primary analysis was performed on the basis of the intention-to-treat principle.
RESULTS: The median duration of study-drug exposure was 21.2 months in the cinacalcet group, versus 17.5 months in the placebo group. The primary composite end point was reached in 938 of 1948 patients (48.2%) in the cinacalcet group and 952 of 1935 patients (49.2%) in the placebo group (relative hazard in the cinacalcet group vs. the placebo group, 0.93; 95% confidence interval, 0.85 to 1.02; P=0.11). Hypocalcemia and gastrointestinal adverse events were significantly more frequent in patients receiving cinacalcet.
CONCLUSIONS: In an unadjusted intention-to-treat analysis, cinacalcet did not significantly reduce the risk of death or major cardiovascular events in patients with moderate-to-severe secondary hyperparathyroidism who were undergoing dialysis. (Funded by Amgen; EVOLVE ClinicalTrials.gov number, NCT00345839.).

PMID 23121374  N Engl J Med. 2012 Dec 27;367(26):2482-94. doi: 10.1056・・・
著者: Paul D Miller, Christian Roux, Steven Boonen, Ian P Barton, Lisa E Dunlap, David E Burgio
雑誌名: J Bone Miner Res. 2005 Dec;20(12):2105-15. doi: 10.1359/JBMR.050817. Epub 2005 Aug 22.
Abstract/Text UNLABELLED: The incidences of osteoporosis and renal insufficiency increase with age. We studied the influence of renal function on the safety and efficacy of risedronate 5 mg daily in osteoporotic women. Risedronate was safe and effective in osteoporotic women with mild, moderate, or severe age-related renal impairment.
INTRODUCTION: The incidences of both osteoporosis and renal insufficiency increase with age; thus, the effect of renal impairment on the safety and efficacy of osteoporosis treatments is a clinical concern. Risedronate is a pyridinyl bisphosphonate well established as safe and effective in the treatment and prevention of osteoporosis. Currently, there is little available information about the effect of bisphosphonate treatment in patients with renal insufficiency. This retrospective analysis was conducted to study the influence of renal function on the safety and efficacy of risedronate in a population of osteoporotic women.
MATERIALS AND METHODS: Combined data from nine randomized, double-blind, placebo-controlled phase III risedronate trials were analyzed. The patients in these studies had no markedly abnormal laboratory parameters that were considered clinically significant and no evidence of significant disease. This analysis included patients who received placebo (n = 4,500) or risedronate 5 mg (n = 4,496) for up to 3 years (average duration of exposure, 2 years) and who had renal impairment (creatinine clearance [CrCl] < 80 ml/min). CrCl was estimated by the Cockcroft and Gault method, based on age, weight, and serum creatinine. Patients were categorized as having mild (CrCl >or=50 to <80 ml/min), moderate (CrCl >or=30 to <50 ml/min), or severe (CrCl < 30 ml/min) renal impairment.
RESULTS: Of the patients studied, renal impairment at baseline was mild in 48% (mean [range] serum creatinine, 0.9 [0.4-1.6] mg/dl), moderate in 45% (1.1 [0.6-1.9] mg/dl), and severe in 7% (1.3 [0.7-2.7] mg/dl). In both the placebo and risedronate treatment groups, the patients with the most severe renal impairment were older and had more severe osteoporosis. The incidences of overall adverse events and of renal function-related adverse events were similar in the placebo and risedronate 5 mg groups regardless of renal function. Furthermore, evaluation of changes from baseline in serum creatinine revealed no difference in renal function between the placebo and risedronate 5 mg groups in any of the renal impairment subgroups at any time-point. In all three subgroups, risedronate effectively preserved BMD and reduced the incidence of vertebral fractures.
CONCLUSIONS: These findings show that risedronate is safe and effective in osteoporotic women with age-related mild, moderate, or severe renal impairment.

PMID 16294264  J Bone Miner Res. 2005 Dec;20(12):2105-15. doi: 10.1359・・・
著者: Sophie A Jamal, Douglas C Bauer, Kristine E Ensrud, Jane A Cauley, Marc Hochberg, Areef Ishani, Steven R Cummings
雑誌名: J Bone Miner Res. 2007 Apr;22(4):503-8. doi: 10.1359/jbmr.070112.
Abstract/Text UNLABELLED: To determine if alendronate had differential effects on BMD and fracture by renal function, we performed a secondary data analysis of women participating in the FIT. Alendronate increased BMD and decreased fractures to a similar degree among women with and without reduced renal function. There was no increase in adverse events among women with impaired renal function treated with alendronate. Alendronate is safe and effective among this group of women with reduced renal function.
INTRODUCTION: Alendronate is cleared by the kidney and may have sustained effects on bone in subjects with impaired renal function. We hypothesized that, with decreasing renal function, alendronate treatment would result in greater increases in BMD and greater decreases in fractures and that the frequency of adverse events would be increased.
MATERIALS AND METHODS: We studied women participating in the Fracture Intervention Trial (FIT), a randomized controlled trial of alendronate or placebo (n = 6458). We estimated baseline creatinine clearance (eGFR) using the Cockcroft Gault Formula.
RESULTS: Five hundred eighty-one (9.9%) participants had a severely reduced eGFR (<45 ml/minute). Alendronate increased BMD regardless of eGFR, but women with reduced eGFR had a 5.6% (95% CI: 4.8-6.5) increase in total hip BMD compared with 4.8% (95% CI: 4.6-5.0) among women with normal to moderate renal dysfunction (interaction: p = 0.04). Compared with placebo, alendronate increased spine BMD by 6.6 +/- 5.8%, but there was no significant interaction for the increase in spine BMD (interaction: p = 0.75). Treatment with alendronate reduced the risk of clinical fractures to a similar degree in those with (OR: 0.78; 95% CI: 0.51-1.21) and without reduced renal function (OR: 0.80; 95% CI; 0.70-0.93; p for interaction = 0.89). Treatment with alendronate reduced the risk of spine fractures to a similar degree in those with (OR: 0.72; 95% CI: 0.31-1.7) and without reduced renal function (OR: 0.50; 95% CI: 0.32-0.76; p for interaction = 0.44). There were no differences in adverse events by renal function.
CONCLUSIONS: Alendronate is safe and effective at increasing BMD and decreasing fractures among this group of women with reduced renal function.

PMID 17243862  J Bone Miner Res. 2007 Apr;22(4):503-8. doi: 10.1359/jb・・・
著者: Areef Ishani, Terri Blackwell, Sophie A Jamal, Steven R Cummings, Kristine E Ensrud, MORE Investigators
雑誌名: J Am Soc Nephrol. 2008 Jul;19(7):1430-8. doi: 10.1681/ASN.2007050555. Epub 2008 Apr 9.
Abstract/Text It is unknown whether treatment for osteoporosis with raloxifene is safe or effective in those with chronic kidney disease (CKD). With data from a multicenter, randomized, placebo-controlled trial of 7705 postmenopausal women with osteoporosis, the effect of raloxifene on rate of change of bone mineral density (BMD), incidence of fractures, and adverse events by stage of CKD was examined over 3 yr. Baseline serum creatinine values were available for 7316 women, and these values were used to assign a category of creatinine clearance (CrCl) using the Cockcroft-Gault formula (CrCl < 45, 45 to 59, and > or = 60 ml/min). BMD was measured at baseline and annually by dual x-ray absorptiometry. Within the placebo group, lower baseline CrCl was associated with a trend for higher annual losses of BMD at the femoral neck; however, within the raloxifene group, lower baseline CrCl was associated with greater increases in femoral neck BMD. This interaction between category of CrCl and treatment assignment was significant for rate of change of BMD at the hip. Irrespective of kidney function, raloxifene treatment was associated with a greater increase in spine BMD, a reduction in vertebral fractures, and no effect on nonvertebral fractures compared with placebo. Within each category of kidney function, adverse events were similar between the raloxifene and placebo groups. In conclusion, raloxifene increases BMD at both the hip and the spine and reduces the risk for vertebral fractures among individuals with CKD. The effect ofraloxifene on hip BMD is greater among those with mild to moderate CKD.

PMID 18400939  J Am Soc Nephrol. 2008 Jul;19(7):1430-8. doi: 10.1681/A・・・
著者: P D Miller, E N Schwartz, P Chen, D A Misurski, J H Krege
雑誌名: Osteoporos Int. 2007 Jan;18(1):59-68. doi: 10.1007/s00198-006-0189-8. Epub 2006 Sep 30.
Abstract/Text INTRODUCTION: The prevalence of both osteoporosis and renal impairment increases with age.
METHODS: Using data from the Fracture Prevention Trial, the safety and efficacy of teriparatide [rhPTH(1-34)] in postmenopausal women with osteoporosis and renal impairment were explored. Patients were required to have serum creatinine concentrations < or =2.0 mg/dl and normal serum parathyroid hormone (PTH) concentrations and were randomized to receive daily subcutaneous injections of placebo or teriparatide 20 or 40 mcg/day. Glomerular filtration rate (GFR) was estimated using the Cockcroft-Gault equation. Patients were defined from baseline assessments to have normal (GFR > or =80 ml/min), mildly impaired (GFR 50-79 ml/min), or moderately impaired (GFR 30-49 ml/min) renal function for bone mineral density (BMD) and amino-terminal extension peptide of procollagen type 1 (PINP) analyses, and normal (GFR > or =80 ml/min) or impaired (GFR <80 ml/min) renal function for fracture analyses.
RESULTS AND CONCLUSIONS: Compared with patients with normal renal function, patients with renal impairment were older, shorter, weighed less, had been postmenopausal longer, and had lower baseline lumbar spine and femoral neck BMD. Compared with placebo, teriparatide significantly increased PINP and lumbar spine and femoral neck BMD within each renal function subgroup, and there was no evidence that these increases were altered by renal insufficiency (each treatment-by-subgroup interaction p>0.05). Similarly, teriparatide-mediated vertebral and nonvertebral fracture risk reductions were similar and did not differ significantly between patients with normal or impaired renal function (treatment-by-subgroup interactions p>0.05). The incidences of treatment-emergent and renal-related adverse events were consistent across treatment assignment in the normal, mildly impaired, and moderately impaired renal function subgroups. Teriparatide induced changes in mean GFR were unaffected by baseline renal function (treatment-by-renal function interaction p>0.05 for normal, mildly impaired, or moderately impaired subgroups). Patients in all renal function categories treated with teriparatide 20 or 40 mcg had an increased incidence of 4-6-h postdose serum calcium >10.6 mg/dl (the upper limit of normal) versus placebo; however, teriparatide 20 mcg/day was not associated with significantly increased incidence of 4-6-h postdose serum calcium >11 mg/dl in any renal function category. Teriparatide therapy was associated with increased incidence of elevated uric acid, with the incidences being highest in patients with moderately impaired renal function and in those receiving teriparatide 40 mcg/day. Even so, adverse event data did not suggest an increased incidence of gout or arthralgia or of nephrolithiasis events in teriparatide-treated patients with normal, mild, or moderate renal impairment.

PMID 17013567  Osteoporos Int. 2007 Jan;18(1):59-68. doi: 10.1007/s001・・・
著者: Sophie A Jamal, Osten Ljunggren, Catherine Stehman-Breen, Steven Ron Cummings, Michael R McClung, Stefan Goemaere, Peter R Ebeling, Edward Franek, Yu-Ching Yang, Ogo I Egbuna, Steven Boonen, Paul D Miller
雑誌名: J Bone Miner Res. 2011 Aug;26(8):1829-35. doi: 10.1002/jbmr.403.
Abstract/Text The incidences of osteoporosis and chronic kidney disease (CKD) both increase with increasing age, yet there is a paucity of data on treatments for osteoporosis in the setting of impaired kidney function. We examined the efficacy and safety of denosumab (DMAb) among subjects participating in the Fracture Reduction Evaluation of Denosumab in Osteoporosis Every 6 Months (FREEDOM) Study. We estimated creatinine clearance (eGFR) using Cockcroft-Gault and classified levels of kidney function using the modified National Kidney Foundation classification of CKD. We examined incident fracture rates; changes in bone mineral density (BMD), serum calcium, and creatinine; and the incidence of adverse events after 36 months of follow-up in subjects receiving DMAb or placebo, stratified by level of kidney function. We used a subgroup interaction term to determine if there were differences in treatment effect by eGFR. Most (93%) women were white, and the mean age was 72.3 ± 5.2 years; 73 women had an eGFR of 15 to 29 mL/min; 2817, between 30 to 59 mL/min; 4069, between 60 to 89 mL/min, and 842 had an eGFR of 90 mL/min or greater. None had stage 5 CKD. Fracture risk reduction and changes in BMD at all sites were in favor of DMAb. The test for treatment by subgroup interaction was not statistically significant, indicating that treatment efficacy did not differ by kidney function. Changes in creatinine and calcium and the incidence of adverse events were similar between groups and did not differ by level of kidney function. It is concluded that DMAb is effective at reducing fracture risk and is not associated with an increase in adverse events among patients with impaired kidney function.

Copyright © 2011 American Society for Bone and Mineral Research.
PMID 21491487  J Bone Miner Res. 2011 Aug;26(8):1829-35. doi: 10.1002/・・・
著者: Ercan Ok, Gulay Asci, Selen Bayraktaroglu, Huseyin Toz, Mehmet Ozkahya, Mumtaz Yilmaz, Fatih Kircelli, Ebru Sevinc Ok, Naim Ceylan, Soner Duman, Mustafa Cirit, Marie-Claude Monier-Faugere, Hartmut H Malluche
雑誌名: J Am Soc Nephrol. 2016 Aug;27(8):2475-86. doi: 10.1681/ASN.2015030268. Epub 2015 Dec 23.
Abstract/Text Exposure to high Ca concentrations may influence the development of low-turnover bone disease and coronary artery calcification (CAC) in patients on hemodialysis (HD). In this randomized, controlled study, we investigated the effects of lowering dialysate Ca level on progression of CAC and histologic bone abnormalities in patients on HD. Patients on HD with intact parathyroid hormone levels ≤300 pg/ml receiving dialysate containing 1.75 or 1.50 mmol/L Ca (n=425) were randomized to the 1.25-mmol/L Ca (1.25 Ca; n=212) or the 1.75-mmol/L Ca (1.75 Ca; n=213) dialysate arm. Primary outcome was a change in CAC score measured by multislice computerized tomography; main secondary outcome was a change in bone histomorphometric parameters determined by analysis of bone biopsy specimens. CAC scores increased from 452±869 (mean±SD) in the 1.25 Ca group and 500±909 in the 1.75 Ca group (P=0.68) at baseline to 616±1086 and 803±1412, respectively, at 24 months (P=0.25). Progression rate was significantly lower in the 1.25 Ca group than in the 1.75 Ca group (P=0.03). The prevalence of histologically diagnosed low bone turnover decreased from 85.0% to 41.8% in the 1.25 Ca group (P=0.001) and did not change in the 1.75 Ca group. At 24 months, bone formation rate, trabecular thickness, and bone volume were higher in the 1.25 Ca group than in the 1.75 Ca group. Thus, lowering dialysate Ca levels slowed the progression of CAC and improved bone turnover in patients on HD with baseline intact parathyroid hormone levels ≤300 pg/ml.

Copyright © 2016 by the American Society of Nephrology.
PMID 26701977  J Am Soc Nephrol. 2016 Aug;27(8):2475-86. doi: 10.1681/・・・
著者: Masafumi Fukagawa, Hirotaka Komaba, Yoshihiro Onishi, Shunichi Fukuhara, Tadao Akizawa, Kiyoshi Kurokawa, MBD-5D Study Group
雑誌名: Am J Nephrol. 2011;33(5):427-37. doi: 10.1159/000327654. Epub 2011 Apr 21.
Abstract/Text BACKGROUND/AIMS: The Mineral and Bone Disorder Outcomes Study for Japanese CKD Stage 5D Patients (MBD-5D) is a multicenter, prospective observational study of hemodialysis patients with secondary hyperparathyroidism (SHPT) in Japan, where the national guideline recommends targets for serum calcium (8.4-10.0 mg/dl), phosphorus (3.5-6.0 mg/dl), and intact parathyroid hormone (PTH) (60-180 pg/ml).
METHODS: The MBD-5D involved patients who were receiving hemodialysis for more than 3 months and met at least one of the following conditions: having intact PTH levels >180 pg/ml, or receiving intravenous vitamin D receptor activators (VDRAs) or oral VDRA analog. This report describes the baseline characteristics of the study participants and examines factors associated with mineral metabolism controllability.
RESULTS: A total of 8,229 patients were registered from 86 facilities as the whole cohort, and 3,276 patients were randomly selected as the subcohort. The severity of SHPT was associated with a lower likelihood of achieving the targets for calcium and phosphorus, whereas patients with a history of parathyroidectomy were more likely to achieve these targets as compared with those who had not undergone surgery despite high PTH levels. The use of 2.5 mEq/l calcium dialysate was also associated with a higher likelihood of achieving the targets compared with the use of 3.0 mEq/l calcium dialysate.
CONCLUSION: The severity of SHPT and the use of dialysate with higher calcium concentration are associated with practical difficulty in managing mineral metabolism in dialysis patients. Further prospective follow-up is needed to confirm our findings and to examine their impact on patient-level outcomes.

Copyright © 2011 S. Karger AG, Basel.
PMID 21508631  Am J Nephrol. 2011;33(5):427-37. doi: 10.1159/000327654・・・
著者: Roman Fiedler, Heinz J Deuber, Thomas Langer, Bernd Osten, Subburaman Mohan, Peter M Jehle
雑誌名: Nephron Clin Pract. 2004;96(1):c3-9. doi: 10.1159/000075565.
Abstract/Text BACKGROUND: The safety of using reduced calcium dialysate (RDC) in hemodialysis (HD) patients is controversial due to related changes in bone metabolism. In the present study we investigated whether an 18-month treatment period with RDC may induce significant changes in calcium-phosphorus product (CaxP), bone metabolism, and components of the insulin-like growth factor (IGF) system in HD patients.
STUDY DESIGN: In this prospective study, 13 HD patients with biochemical signs of diminished or low-normal bone turnover and high CaxP due to high serum calcium level were treated by lowering dialysate calcium from 3.5 to 2.5 mEq/l for 18 months. By specific immunometric assays, serum levels of intact parathyroid hormone (PTH), bone alkaline phosphatase (B-ALP), pyridinoline (PYR), desoxypyridinoline (D-PYR), 25-OH-vitamin D(3) (25-vit D(3)), 1,25-(OH)(2)-vitamin D(3) (1,25-vit D(3)), free IGF-I, IGF-II, and IGF-binding protein (IGFBP)-1 to -6 were measured.
RESULTS: CaxP decreased significantly from 5.62 (baseline) to 3.95 mmol(2)/l(2) (at 18 months), whereas PTH increased from 81 +/- 57 pg/ml at baseline to 236 +/- 188 at 12 months (p < 0.01), remaining in this range thereafter. Parameters of bone resorption (PYR) as well as formation (B-ALP) significantly increased during RDC, with peak levels after 12 months. Despite increasing doses of oral alfacalcidol, levels of 25-vit D(3) and 1,25-vit D(3) subsequently declined during RDC. In parallel with the changes in bone markers, free IGF-I levels decreased (baseline: 1.9 +/- 0.9 ng/ml, after 18 months: 1.1 +/- 0.7; p < 0.01). The decline of free IGF-I correlated with decreasing levels of IGFBP-3 and increasing levels of IGFBP-1/-4.
CONCLUSION: The treatment with RDC effectively lowered CaxP and stimulated bone formation and resorption. The different changes in bone markers and IGF system components mirror the complex effects on bone metabolism.

Copyright 2004 S. Karger AG, Basel
PMID 14752247  Nephron Clin Pract. 2004;96(1):c3-9. doi: 10.1159/00007・・・
著者: Naoki Kimata, Justin M Albert, Takashi Akiba, Shin Yamazaki, Takehiko Kawaguchi, Yoshindo Kawaguchi, Shunichi Fukuhara, Tadao Akizawa, Akira Saito, Yasushi Asano, Kiyoshi Kurokawa, Ronald L Pisoni, Friedrich K Port
雑誌名: Hemodial Int. 2007 Jul;11(3):340-8. doi: 10.1111/j.1542-4758.2007.00190.x.
Abstract/Text Abnormalities in mineral metabolism have been linked to mortality in hemodialysis (HD) patients. We postulated that these abnormalities would have a particularly large deleterious impact on deaths due to cardiovascular causes in Japan. This study describes the recent status of abnormal mineral metabolism, significant predictors, and potential consequences in the Dialysis Outcomes and Practice Patterns Study (DOPPS), Phases 1 and 2, in Japan. Major predictor variables were patient demographics, comorbidities, and laboratory markers of mineral metabolism such as albumin-adjusted serum calcium (calciumAlb), phosphorus, and intact PTH (iPTH). In a cross section of 3973 Japanese HD patients in DOPPS I and II, a large faction had laboratory values outside of the recommended Kidney Disease Outcomes Quality Initiative (K/DOQI) guideline range for serum concentrations of phosphorus (51% of patients above upper target range), calciumAlb (43.7% above), calcium-phosphorus (Ca x P) product (41.1% above), and iPTH (18.6% above). All-cause mortality was significantly and independently associated with calciumAlb (relative risk [RR]=1.22 per 1 mg/dL, p=0.0005) and iPTH (RR=1.04 per 100 pg/mL, p=0.04). Cardiovascular mortality was significantly associated with calciumAlb (RR=1.28, p=0.02), phosphorus (RR=1.13 per 1 mg/dL, p=0.008), Ca x P product (RR=1.07 per 2 mg(2)/dL(2), p=0.002), and PTH (RR=1.08, p=0.0001). This study expands our understanding of the relationship between altered mineral metabolism and mortality outcomes, showing slightly stronger associations with cardiovascular causes than observed for all-cause mortality. These findings have important therapeutic implications for Japanese HD patients.

PMID 17576300  Hemodial Int. 2007 Jul;11(3):340-8. doi: 10.1111/j.1542・・・
著者: T Shigematsu, Lanthanum Carbonate Group
雑誌名: Clin Nephrol. 2008 Nov;70(5):404-10.
Abstract/Text BACKGROUND: The efficacy of lanthanum carbonate as a phosphate binder for the treatment of hyperphosphatemia has been reported, but not from a double-blind, comparator-controlled comparative study.
METHODS: The safety and efficacy of lanthanum carbonate and calcium carbonate on serum phosphate and calcium levels in Japanese hemodialysis patients were assessed by a randomized, double-blind, comparator-controlled, parallel group, multicenter study. This study is the first study using a randomized, double-blind method to compare lanthanum carbonate and calcium carbonate as phosphate binders.
RESULTS: In the double-blind phase, the changes in the serum phosphate level were similar in the lanthanum carbonate and calcium carbonate groups. The differences in the corrected serum calcium level or the calcium x phosphate products between the 2 groups were not statistically significant. However, the mean change in the corrected serum calcium level from baseline to the last outpatient visit was significantly lower in the lanthanum carbonate group than in the calcium carbonate group. The incidence of hypercalcemia in the lanthanum carbonate group was also significantly lower than in the calcium carbonate group.
CONCLUSION: Both compounds show similar efficacy on the serum phosphate level in patients undergoing hemodialysis when the dose is managed in a dose-variable and double-blind manner. However, lanthanum carbonate is superior in terms of lowering the incidence of hypercalcemia.

PMID 19000540  Clin Nephrol. 2008 Nov;70(5):404-10.
著者: R Wilson, P Zhang, M Smyth, R Pratt
雑誌名: Curr Med Res Opin. 2009 Dec;25(12):3021-8. doi: 10.1185/03007990903399398.
Abstract/Text OBJECTIVE: Epidemiological data link elevated levels of serum phosphorus with increased mortality among patients with chronic kidney disease. Recent data also suggest improved survival with the use of dietary phosphate binders in patients on dialysis. However, few studies have comprehensively evaluated the survival benefit associated with different phosphate binders. A post-hoc survival analysis was undertaken of lanthanum carbonate (Fosrenol *) versus standard therapy.
RESEARCH DESIGN AND METHODS: Patients on dialysis enrolled in a phase 3, 2-year, comparative safety study were randomized 1:1 to lanthanum carbonate or standard therapy to treat serum phosphorus to a target of < or =5.9 mg/dL (1.90 mmol/L). Patients (N = 1354) were followed up for survival status during, or after completion of or discontinuation from the study.
MAIN OUTCOME MEASURES: Survival was measured by time from first dose of study medication to all-cause mortality or last contact.
RESULTS: The distribution of follow-up time was similar in the lanthanum carbonate and standard therapy groups (mean 23.7 versus 23.9 months [median 27.0 versus 26.0 months], respectively). Serum phosphorus levels were similar across treatment groups, as patients were treated to target. At follow-up, 19.9% (135/680) of patients treated with lanthanum carbonate had died versus 23.3% (157/674) on standard therapy (log-rank p = 0.18). In the subgroup of patients aged >65 years (n = 336), 27.0% (44/163) of lanthanum-carbonate-treated patients had died compared with 39.3% (68/173) on standard therapy (log-rank p = 0.04).
CONCLUSION: In these survival analyses, overall mortality was similar in the lanthanum carbonate and standard therapy groups, but results suggest that there was a survival benefit associated with lanthanum carbonate treatment for patients aged >65 years, who are likely to carry the greatest burden of vascular calcification. These results were similar to those observed in the Dialysis Clinical Outcomes Revisited study, a prospective trial of sevelamer hydrochloride designed to assess survival.

PMID 19845495  Curr Med Res Opin. 2009 Dec;25(12):3021-8. doi: 10.1185・・・
著者: Tetsuo Shoji, Kayo Shinohara, Eiji Kimoto, Masanori Emoto, Hideki Tahara, Hidenori Koyama, Masaaki Inaba, Shinya Fukumoto, Eiji Ishimura, Takami Miki, Tsutomu Tabata, Yoshiki Nishizawa
雑誌名: Nephrol Dial Transplant. 2004 Jan;19(1):179-84.
Abstract/Text BACKGROUND: Renal failure results in deficiency of active vitamin D3 that has diverse effects on metabolism and organ functions. Treatment with active forms of vitamin D(3) ameliorates abnormalities in bone and mineral metabolism, cardiac function, immune response and others. We hypothesized that treatment with vitamin D(3) may be beneficial for survival in patients with end-stage renal disease (ESRD).
METHODS: We compared the risk of death between regular users (n = 162) and non-users (n = 80) of oral 1alpha-hydroxyvitamin D3 (alfacalcidol) in a cohort of ESRD patients undergoing haemodialysis for a follow-up of 61 +/- 23 months. The daily dose of alfacalcidol ranged from 0.25 to 1.5 microg, with a median of 0.5 microg.
RESULTS: The alfacalcidol users showed a lower risk of death from cardiovascular disease than the non-users in a univariate Cox model [hazards ratio (HR) 0.287, 95% confidence interval (CI) 0.127-0.649, P = 0.003], whereas the risk for death from non-cardiovascular disease was not different between the two groups. Stepwise multivariate Cox analysis showed that cardiovascular mortality was significantly associated with age, presence of diabetes mellitus and treatment with alfacalcidol (HR 0.377, 95% CI 0.246-0.578, P = 0.022).
CONCLUSIONS: These results indicate that use of oral alfacalcidol was associated with reduced risk for cardiovascular death in this cohort of ESRD patients. The result of this observational study warrants further randomized controlled trials with 1alpha-hydroxy vitamin D3 to confirm the possibility that such medication improves survival of ESRD patients.

PMID 14671054  Nephrol Dial Transplant. 2004 Jan;19(1):179-84.
著者: Ming Teng, Myles Wolf, M Norma Ofsthun, J Michael Lazarus, Miguel A Hernán, Carlos A Camargo, Ravi Thadhani
雑誌名: J Am Soc Nephrol. 2005 Apr;16(4):1115-25. doi: 10.1681/ASN.2004070573. Epub 2005 Feb 23.
Abstract/Text Patients with ESRD commonly experience secondary hyperparathyroidism, a condition primarily managed with activated injectable vitamin D. The biologic effects of vitamin D, however, are widespread, and it is possible that activated injectable vitamin D alters survival in ESRD. This hypothesis was tested in a historical cohort study of incident hemodialysis patients who lived throughout the United States between January 1996 and December 1999. The primary outcome was 2-yr survival among those who survived for at least 90 d after initiation of chronic hemodialysis. During this period, 51,037 chronic hemodialysis patients survived for at least 90 d from the initiation of hemodialysis, and in the ensuing 2 yr, 37,173 received activated injectable vitamin D and 13,864 did not. At 2 yr, mortality rates were 13.8/100 person-years in the group that received injectable vitamin D compared with 28.6/100 person-years in the group that did not (P < 0.001). Cox proportional hazards analyses adjusting for several potential confounders and examining injectable vitamin D therapy as a time-dependent exposure suggested that compared with patients who did not receive injectable vitamin D, the 2-yr survival advantage associated with the group that did receive injectable vitamin D was 20% (hazard ratio, 0.80; 95% confidence interval, 0.76 to 0.83). The incidence of cardiovascular-related mortality was 7.6/100 person-years in the injectable vitamin D group, compared with 14.6/100 person-years in the non-vitamin D group (P < 0.001). The benefit of injectable vitamin D was evident in 48 of 49 strata examined, including those with low serum levels of intact parathyroid hormone and elevated levels of serum calcium and phosphorus, situations in which injectable vitamin D is often withheld. Repeating the entire analysis using marginal structural models to adjust for time-dependent confounding by indication yielded a survival advantage of 26% (hazard ratio, 0.74; 95% confidence interval, 0.71 to 0.79) associated with the injectable vitamin D group. In this historical cohort study, chronic hemodialysis patients in the group that received injectable vitamin D had a significant survival advantage over patients who did not. Randomized clinical trials would permit definitive conclusions.

PMID 15728786  J Am Soc Nephrol. 2005 Apr;16(4):1115-25. doi: 10.1681/・・・
著者: F Tentori, W C Hunt, C A Stidley, M R Rohrscheib, E J Bedrick, K B Meyer, H K Johnson, P G Zager, Medical Directors of Dialysis Clinic Inc
雑誌名: Kidney Int. 2006 Nov;70(10):1858-65. doi: 10.1038/sj.ki.5001868. Epub 2006 Oct 4.
Abstract/Text Intravenous vitamin D is standard therapy for secondary hyperparathyroidism in hemodialysis (HD) patients. In for-profit dialysis clinics, mortality was higher for patients on calcitriol compared to paricalcitol. Doxercalciferol, a second vitamin D2 analog, is currently available. We assessed mortality associated with each vitamin D analog and with lack of vitamin D therapy in patients who began HD at Dialysis Clinic Inc. (DCI), a not-for-profit dialysis provider. During the 1999-2004 study period we studied 7731 patients (calcitriol: n=3212; paricalcitol: n=2087; doxercalciferol: n=2432). Median follow-up was 37 weeks. Mortality rates (deaths/100 patient-years) were identical in patients on doxercalciferol (15.4, 95% confidence interval (13.6-17.1)) and paricalcitol (15.3 (13.6-16.9)) and higher in patients on calcitriol (19.6 (18.2-21.1)) (P<0.0001). In all models mortality was similar for paricalcitol versus doxercalciferol (hazard ratios=1.0). In unadjusted models, mortality was lower in patients on doxercalciferol (0.80 (0.66, 0.96)) and paricalcitol (0.79 (0.68, 0.92)) versus calcitriol (P<0.05). In adjusted models, this difference was not statistically significant. In all models mortality was higher for patients who did not receive vitamin D versus those who did (1.2 (1.1-1.3)). Mortality in doxercalciferol- and paricalcitol-treated patients was virtually identical. Differences in survival between vitamin D2 and D3 may be smaller than previously reported.

PMID 17021609  Kidney Int. 2006 Nov;70(10):1858-65. doi: 10.1038/sj.ki・・・
著者: J-DAVID Investigators, Tetsuo Shoji, Masaaki Inaba, Masafumi Fukagawa, Ryoichi Ando, Masanori Emoto, Hisako Fujii, Akira Fujimori, Mitsuru Fukui, Hiroki Hase, Tetsuya Hashimoto, Hideki Hirakata, Hirokazu Honda, Tatsuo Hosoya, Yuji Ikari, Daijo Inaguma, Toru Inoue, Yoshitaka Isaka, Kunitoshi Iseki, Eiji Ishimura, Noritomo Itami, Chiharu Ito, Toshitaka Kakuta, Toru Kawai, Hideki Kawanishi, Shuzo Kobayashi, Junko Kumagai, Kiyoshi Maekawa, Ikuto Masakane, Jun Minakuchi, Koji Mitsuiki, Takashi Mizuguchi, Satoshi Morimoto, Toyoaki Murohara, Tatsuya Nakatani, Shigeo Negi, Shinichi Nishi, Mitsushige Nishikawa, Tetsuya Ogawa, Kazumichi Ohta, Takayasu Ohtake, Mikio Okamura, Senji Okuno, Takashi Shigematsu, Toshitsugu Sugimoto, Masashi Suzuki, Hideki Tahara, Yoshiaki Takemoto, Kenji Tanaka, Yoshihiro Tominaga, Yoshiharu Tsubakihara, Yoshihiro Tsujimoto, Kazuhiko Tsuruya, Shinichiro Ueda, Yuzo Watanabe, Kunihiro Yamagata, Tomoyuki Yamakawa, Shozo Yano, Keitaro Yokoyama, Noriaki Yorioka, Minoru Yoshiyama, Yoshiki Nishizawa
雑誌名: JAMA. 2018 Dec 11;320(22):2325-2334. doi: 10.1001/jama.2018.17749.
Abstract/Text Importance: Patients with chronic kidney disease have impaired vitamin D activation and elevated cardiovascular risk. Observational studies in patients treated with hemodialysis showed that the use of active vitamin D sterols was associated with lower risk of all-cause mortality, regardless of parathyroid hormone levels.
Objective: To determine whether vitamin D receptor activators reduce cardiovascular events and mortality in patients without secondary hyperparathyroidism undergoing hemodialysis.
Design, Setting, and Participants: Randomized, open-label, blinded end point multicenter study of 1289 patients in 207 dialysis centers in Japan. The study included 976 patients receiving maintenance hemodialysis with serum intact parathyroid hormone levels less than or equal to 180 pg/mL. The first and last participants were enrolled on August 18, 2008, and January 26, 2011, respectively. The final date of follow-up was April 4, 2015.
Interventions: Treatment with 0.5 μg of oral alfacalcidol per day (intervention group; n = 495) vs treatment without vitamin D receptor activators (control group; n = 481).
Main Outcomes and Measures: The primary outcome was a composite measure of fatal and nonfatal cardiovascular events, including myocardial infarctions, hospitalizations for congestive heart failure, stroke, aortic dissection/rupture, amputation of lower limb due to ischemia, and cardiac sudden death; coronary revascularization; and leg artery revascularization during 48 months of follow-up. The secondary outcome was all-cause death.
Results: Among 976 patients who were randomized from 108 dialysis centers, 964 patients were included in the intention-to-treat analysis (median age, 65 years; 386 women [40.0%]), and 944 (97.9%) completed the trial. During follow-up (median, 4.0 years), the primary composite outcome of cardiovascular events occurred in 103 of 488 patients (21.1%) in the intervention group and 85 of 476 patients (17.9%) in the control group (absolute difference, 3.25% [95% CI, -1.75% to 8.24%]; hazard ratio, 1.25 [95% CI, 0.94-1.67]; P = .13). There was no significant difference in the secondary outcome of all-cause mortality between the groups (18.2% vs 16.8%, respectively; hazard ratio, 1.12 [95% CI, 0.83-1.52]; P = .46). Of the 488 participants in the intervention group, 199 (40.8%) experienced serious adverse events that were classified as cardiovascular, 64 (13.1%) experienced adverse events classified as infection, and 22 (4.5%) experienced malignancy-related serious adverse events. Of 476 participants in the control group, 191 (40.1%) experienced cardiovascular-related serious adverse events, 63 (13.2%) experienced infection-related serious adverse events, and 21 (4.4%) experienced malignancy-related adverse events.
Conclusions and Relevance: Among patients without secondary hyperparathyroidism undergoing maintenance hemodialysis, oral alfacalcidol compared with usual care did not reduce the risk of a composite measure of select cardiovascular events. These findings do not support the use of vitamin D receptor activators for patients such as these.
Trial Registration: UMIN-CTR Identifier: UMIN000001194.

PMID 30535217  JAMA. 2018 Dec 11;320(22):2325-2334. doi: 10.1001/jama.・・・
著者: M Gallieni, D Brancaccio, P Padovese, D Rolla, P Bedani, G Colantonio, C Bronzieri, B Bagni, G Tarolo
雑誌名: Kidney Int. 1992 Nov;42(5):1191-8. doi: 10.1038/ki.1992.404.
Abstract/Text Intravenous calcitriol is known to directly suppress PTH secretion and release. We evaluated the effect of four months of treatment with low-dose intravenous calcitriol on PTH levels in 83 hemodialysis patients. The criteria for including patients in the study were a serum PTH levels at least four times the normal limit, a serum total calcium less than 10 mg/dl and good control of the serum phosphorus level. All patients underwent standard bicarbonate or acetate dialysis; dialysate calcium level was maintained at the usual 3.5 mEq/liter concentration. Initial calcitriol dose was 0.87 +/- 0.02 (SEM) micrograms (0.015 micrograms/kg body wt) thrice weekly at the end of dialysis, and it was reduced in case of hypercalcemia or elevated calcium-phosphate product. Seven out of 83 patients dropped out during treatment. Among the 76 patients who completed the study, 58 (76%) showed a highly significant decrease of intact PTH levels (average reduction 48%) and of alkaline phosphatase levels after four months of therapy. Total serum calcium increased slightly but significantly in the responder group but remained unchanged in the non-responders. No significant changes in ionized calcium levels could be detected, even in responders. Treatment was well tolerated by patients, but 60% of them had transient episodes of hyperphosphatemia. Mean serum phosphate was 4.95 mg/dl at the beginning of the study. It increased significantly after four months of treatment in patients who showed a decrease of PTH levels, although it remained within acceptable limits, below 5.5 mg/dl. Twenty-eight of 76 patients (37%) reduced the dose of calcitriol because their calcium-phosphate products exceeded 60.(ABSTRACT TRUNCATED AT 250 WORDS)

PMID 1453603  Kidney Int. 1992 Nov;42(5):1191-8. doi: 10.1038/ki.1992・・・
著者: Stuart M Sprague, Francisco Llach, Michael Amdahl, Carol Taccetta, Daniel Batlle
雑誌名: Kidney Int. 2003 Apr;63(4):1483-90. doi: 10.1046/j.1523-1755.2003.00878.x.
Abstract/Text BACKGROUND: Management of secondary hyperparathyroidism has included the use of active vitamin D or vitamin D analogs for the suppression of parathyroid hormone (PTH) secretion. Although, these agents are effective, therapy is frequently limited by hypercalcemia, hyperphosphatemia, and/or elevations in the calcium-phosphorus (Ca x P) product. In clinical studies, paricalcitol was shown to be effective at reducing PTH concentrations without causing significant hypercalcemia or hyperphosphatemia as compared to placebo. A comparative study was undertaken in order to determine whether paricalcitol provides a therapeutic advantage to calcitriol.
METHODS: A double-blind, randomized, multicenter study comparing the safety and effectiveness of intravenous paricalcitol and calcitriol in suppressing PTH concentrations in hemodialysis patients was performed. A total of 263 randomized patients were enrolled at domestic and international sites. Following the baseline period, patients with serum Ca x P < 75, and a PTH level > or =300 pg/mL were randomly assigned to receive either paricalcitol or calcitriol in a dose-escalating fashion for up to 32 weeks. Dose adjustments were based on laboratory results for PTH, calcium, and Ca x P. The primary end point was the greater than 50% reduction in baseline PTH. Secondary end points were the occurrence of hypercalcemia and elevated Ca x P product.
RESULTS: Paricalcitol-treated patients achieved a > or =50% reduction from baseline PTH significantly faster than did the calcitriol-treated patients (P = 0.025) and achieved a mean reduction of PTH into a desired therapeutic range (100 to 300 pg/mL) at approximately week 18, whereas the calcitriol-treated patients, as a group, were unable to achieve this range. Moreover, paricalcitol-treated patients had significantly fewer sustained episodes of hypercalcemia and/or increased Ca x P product than calcitriol patients (P = 0.008).
CONCLUSION: Paricalcitol treatment reduced PTH concentrations more rapidly with fewer sustained episodes of hypercalcemia and increased Ca x P product than calcitriol therapy.

PMID 12631365  Kidney Int. 2003 Apr;63(4):1483-90. doi: 10.1046/j.1523・・・
著者: L D Quarles, D A Yohay, B A Carroll, C E Spritzer, S A Minda, D Bartholomay, B A Lobaugh
雑誌名: Kidney Int. 1994 Jun;45(6):1710-21.
Abstract/Text To examine the most effective route (intravenous vs. "pulse" oral), dose (physiologic vs. pharmacologic) and long-term efficacy of calcitriol therapy for secondary hyperparathyroidism in patients with end-stage renal disease (ESRD), we randomized 19 hemodialysis patients with severe hyperparathyroidism to receive over a 36-week study period either pulse orally administered calcitriol and intravenous placebo (pulse oral group; N = 9) or intravenous calcitriol and oral placebo (intravenous group; N = 10). Calcitriol was given intermittently in a double-blinded fashion at an initial dose of 2 micrograms thrice weekly and increased as tolerated up to a maximum dose of 4 micrograms per treatment. All patients received similar daily calcium supplementation (2.5 g of elemental calcium) and low dialysate calcium (1.25 mmol/liter) throughout the study period. At the maximum tolerated calcitriol dose, serum 1,25-dihydroxyvitamin D levels were significantly greater 60 minutes following intravenous (389 pmol/liter) compared to oral administration (128 pmol/liter). In spite of the different pharmacologic profiles, intravenous and oral administered calcitriol resulted in similar reductions of serum PTH over the 36 week period of observation (P = 0.300), achieving an overall maximum average PTH reduction of 43% (P = 0.016). Long-term intensive calcitriol therapy (independent of administration route), however, failed to decrease parathyroid gland size as assessed by high resolution ultrasound and/or magnetic resonance imaging. Calcitriol therapy also failed to alter the calcium sensitivity as assessed by serial PTH measurements in response to calcium loading. Increases in serum calcium, but not calcitriol dose or parathyroid gland size, predicted decrements in serum PTH, whereas hyperphosphatemia and the level of PTH suppression derived from the PTH/ionized calcium response curves predicted refractoriness to calcitriol therapy. Episodes of hypercalcemia and hyperphosphatemia were similar in both treatment groups and limited the dose of calcitriol that could be administered. These data indicate that intermittent intensive calcitriol therapy, regardless of administration route, is poorly tolerated, fails to correct parathyroid gland size and functional abnormalities, and has a limited ability to achieve sustained serum PTH reductions in end-stage renal failure patients with severe hyperparathyroidism.

PMID 7933819  Kidney Int. 1994 Jun;45(6):1710-21.
著者: Geoffrey A Block, David A Bushinsky, Sunfa Cheng, John Cunningham, Bastian Dehmel, Tilman B Drueke, Markus Ketteler, Reshma Kewalramani, Kevin J Martin, Sharon M Moe, Uptal D Patel, Justin Silver, Yan Sun, Hao Wang, Glenn M Chertow
雑誌名: JAMA. 2017 Jan 10;317(2):156-164. doi: 10.1001/jama.2016.19468.
Abstract/Text Importance: Secondary hyperparathyroidism contributes to extraskeletal calcification and is associated with all-cause and cardiovascular mortality. Control is suboptimal in the majority of patients receiving hemodialysis. An intravenously (IV) administered calcimimetic could improve adherence and reduce adverse gastrointestinal effects.
Objective: To evaluate the relative efficacy and safety of the IV calcimimetic etelcalcetide and the oral calcimimetic cinacalcet.
Design, Setting, and Participants: A randomized, double-blind, double-dummy active clinical trial was conducted comparing IV etelcalcetide vs oral placebo and oral cinacalcet vs IV placebo in 683 patients receiving hemodialysis with serum parathyroid hormone (PTH) concentrations higher than 500 pg/mL on active therapy at 164 sites in the United States, Canada, Europe, Russia, and New Zealand. Patients were enrolled from August 2013 to May 2014, with end of follow-up in January 2015.
Interventions: Etelcalcetide intravenously and oral placebo (n = 340) or oral cinacalcet and IV placebo (n = 343) for 26 weeks. The IV study drug was administered 3 times weekly with hemodialysis; the oral study drug was administered daily.
Main Outcomes and Measures: The primary efficacy end point was noninferiority of etelcalcetide at achieving more than a 30% reduction from baseline in mean predialysis PTH concentrations during weeks 20-27 (noninferiority margin, 12.0%). Secondary end points included superiority in achieving biochemical end points (>50% and >30% reduction in PTH) and self-reported nausea or vomiting.
Results: The mean (SD) age of the trial participants was 54.7 (14.1) years and 56.2% were men. Etelcalcetide was noninferior to cinacalcet on the primary end point. The estimated difference in proportions of patients achieving reduction in PTH concentrations of more than 30% between the 198 of 343 patients (57.7%) randomized to receive cinacalcet and the 232 of 340 patients (68.2%) randomized to receive etelcalcetide was -10.5% (95% CI, -17.5% to -3.5%, P for noninferiority, <.001; P for superiority, .004). One hundred seventy-eight patients (52.4%) randomized to etelcalcetide achieved more than 50% reduction in PTH concentrations compared with 138 patients (40.2%) randomized to cinacalcet (P = .001; difference in proportions, 12.2%; 95% CI, 4.7% to 19.5%). The most common adverse effect was decreased blood calcium (68.9% vs 59.8%).
Conclusions and Relevance: Among patients receiving hemodialysis with moderate to severe secondary hyperparathyroidism, the use of etelcalcetide was not inferior to cinacalcet in reducing serum PTH concentrations over 26 weeks; it also met superiority criteria. Further studies are needed to assess clinical outcomes as well as longer-term efficacy and safety.
Trial Registration: clinicaltrials.gov Identifier: NCT1896232.

PMID 28097356  JAMA. 2017 Jan 10;317(2):156-164. doi: 10.1001/jama.201・・・
著者: Masafumi Fukagawa, Ryutaro Shimazaki, Tadao Akizawa, Evocalcet study group
雑誌名: Kidney Int. 2018 Oct;94(4):818-825. doi: 10.1016/j.kint.2018.05.013. Epub 2018 Jul 24.
Abstract/Text Secondary hyperparathyroidism (SHPT) leads to cardiovascular calcification, which affects survival and quality of life in patients with chronic kidney disease. Cinacalcet is used to control SHPT, but it may induce gastrointestinal symptoms, resulting in lower adherence and insufficient dosages. Therefore, a need exists to develop new calcimimetics that cause fewer gastrointestinal symptoms. Here we conducted a phase 3, randomized, double-blind, double-dummy trial for a head-to-head comparison of the efficacy and safety of evocalcet, a new oral calcimimetic, to the established cinacalcet. Japanese patients with SHPT on hemodialysis were randomized to receive evocalcet or cinacalcet (317 patients each) for 30 weeks. The primary efficacy endpoint was non-inferiority of evocalcet to cinacalcet in the proportion of patients achieving a mean intact parathyroid hormone level of 60 to 240 pg/mL from week 28 to 30 (non-inferiority margin, -15%, per protocol set analyses). In the evocalcet and cinacalcet groups, 72.7% and 76.7%, respectively, achieved the target intact parathyroid hormone level (between-group difference: -4.0% [95% confidence interval -11.4%, 3.5%], for non-inferiority). The incidence of gastrointestinal-related adverse events was 18.6% and 32.8%, respectively (between-group difference: -14.2% [-20.9%, -7.5%], significant for superiority). Thus, the non-inferiority of evocalcet to cinacalcet in suppressing intact parathyroid hormone with fewer gastrointestinal-related adverse events was demonstrated. Hence, evocalcet may be a favorable alternative to existing calcimimetics for management of SHPT.

Copyright © 2018 International Society of Nephrology. Published by Elsevier Inc. All rights reserved.
PMID 30049473  Kidney Int. 2018 Oct;94(4):818-825. doi: 10.1016/j.kint・・・
著者: Bryan Kestenbaum, Dennis L Andress, Stephen M Schwartz, Daniel L Gillen, Stephen L Seliger, Paresh R Jadav, Donald J Sherrard, Catherine Stehman-Breen
雑誌名: Kidney Int. 2004 Nov;66(5):2010-6. doi: 10.1111/j.1523-1755.2004.00972.x.
Abstract/Text BACKGROUND: Secondary hyperparathyroidism (SHPTH) is highly prevalent among persons with end-stage renal disease (ESRD). SHPTH has been linked to uremic bone disease, vascular calcification, and a higher risk of death. Parathyroidectomy (PTX) can dramatically reduce parathyroid hormone (PTH) and phosphate levels; however, the relationship between PTX and survival is not known.
METHODS: We conducted an observational matched cohort study utilizing data from the United States Renal Database System (USRDS) in which 4558 patients undergoing a first PTX while on hemodialysis or peritoneal dialysis were individually matched by age, race, gender, cause of ESRD, dialysis duration, prior transplantation status, and dialysis modality to 4558 control patients who did not undergo PTX. Patients were followed from the date of PTX until they died or were lost to follow-up.
RESULTS: The 30-day postoperative mortality rate following PTX was 3.1%. Long-term relative risks of death among patients undergoing PTX were estimated to be 10% to 15% lower than those of matched control patients not undergoing surgery. Survival curves between the 2 groups crossed 587 days following PTX. Median survival was 53.4 months (95% CI: 51.2-56.4) in the PTX group, and 46.8 months (95% CI: 44.7-48.9) in the control group.
CONCLUSION: PTX was associated with higher short-term, and lower long-term, mortality rates among U.S. patients receiving chronic dialysis. Measures to attenuate SHPTH may play an important role in reducing mortality among patients with end-stage renal disease.

PMID 15496173  Kidney Int. 2004 Nov;66(5):2010-6. doi: 10.1111/j.1523-・・・
著者: Valeria Costa-Hong, Vanda Jorgetti, Luis Henrique W Gowdak, Rosa Maria A Moyses, Eduardo M Krieger, Jose Jayme G De Lima
雑誌名: Surgery. 2007 Nov;142(5):699-703. doi: 10.1016/j.surg.2007.06.015.
Abstract/Text BACKGROUND: Secondary hyperparathyroidism (SHPT) and its associated abnormalities in mineral metabolism increase the risk of cardiovascular morbidity and death in chronic renal failure (CRF). The effect of parathyroidectomy (PTX) on the incidence of major cardiovascular events in CRF patients with SHPT is unknown. We tested the hypothesis that PTX reduces the incidence of cardiovascular complications and death in CRF patients with severe SHPT scheduled for PTX, comparing the outcome of patients treated or not treated by PTX.
METHODS: The study comprised 118 CRF patients with SHPT on maintenance hemodialysis, unresponsive to medical treatment and scheduled for PTX. Patients underwent comprehensive cardiovascular evaluations at baseline. They were followed up until death, occurrence of major cardiovascular events, or kidney transplantation.
RESULTS: No deaths related to PTX occurred. After a median follow-up of 30 months, 50 patients (42%) had undergone PTX whereas 68 (58%) had not. The groups were comparable in terms of age, sex, race, serum parathyroid hormone, calcium or phosphate, calcium x phosphate product, and all major cardiovascular variables, except diastolic blood pressure. PTX was associated with a reduced incidence of major cardiovascular events (P = .02) and overall mortality (P CONCLUSION: PTX confers protection against future major cardiovascular events and death in select CRF patients with severe refractory SHPT.

PMID 17981190  Surgery. 2007 Nov;142(5):699-703. doi: 10.1016/j.surg.2・・・
著者: Hirotaka Komaba, Masatomo Taniguchi, Atsushi Wada, Kunitoshi Iseki, Yoshiharu Tsubakihara, Masafumi Fukagawa
雑誌名: Kidney Int. 2015 Mar 18;. doi: 10.1038/ki.2015.72. Epub 2015 Mar 18.
Abstract/Text Parathyroidectomy (PTx) drastically improves biochemical parameters and clinical symptoms related to severe secondary hyperparathyroidism (SHPT) but the effect of PTx on survival has not been adequately investigated. Here we analyzed data on 114,064 maintenance hemodialysis patients from a nationwide registry of the Japanese Society for Dialysis Therapy to evaluate the associations of severity of SHPT and history of PTx with 1-year all-cause and cardiovascular mortality. We then compared the mortality rate between 4428 patients who had undergone PTx and 4428 propensity score-matched patients who had not despite severe SHPT. During a 1-year follow-up, 7926 patients of the entire study population died, of whom 3607 died from cardiovascular disease. Among patients without a history of PTx, severe SHPT was associated with an increased risk for all-cause and cardiovascular mortality. However, such an increased risk of mortality was not observed among patients with a history of PTx. In the propensity score-matched analysis, patients who had undergone PTx had a 34% and 41% lower risk for all-cause and cardiovascular mortality, respectively, compared to the matched controls. The survival benefit associated with PTx was robust in several sensitivity analyses and consistent across subgroups, except for those who had persistent postoperative SHPT. Thus, successful PTx may reduce the risk for all-cause and cardiovascular mortality in hemodialysis patients with severe, uncontrolled SHPT.Kidney International advance online publication, 18 March 2015; doi:10.1038/ki.2015.72.

PMID 25786097  Kidney Int. 2015 Mar 18;. doi: 10.1038/ki.2015.72. Epub・・・
著者: Kyle D Rudser, Ian H de Boer, Annemarie Dooley, Bessie Young, Bryan Kestenbaum
雑誌名: J Am Soc Nephrol. 2007 Aug;18(8):2401-7. doi: 10.1681/ASN.2007010022. Epub 2007 Jul 18.
Abstract/Text The impact of parathyroidectomy (PTX) on the long-term risks for hip and other fractures is unknown. Uncontrolled case series have reported an increase in bone mineral density after PTX. However, very low serum parathyroid hormone levels have been associated with decreased bone mineral density, adynamic bone disease, and fractures. This study compared long-term fracture rates among hemodialysis patients who underwent PTX with a matched control group. Data were obtained from the US Renal Data System. Patients who underwent a first PTX while receiving hemodialysis were matched with up to three control patients by age, race, gender, year of dialysis initiation, primary cause of renal failure, and the dosage of intravenous vitamin D used before PTX. Patients with a history of fracture or renal transplantation were excluded. Study outcomes were incident hip, vertebral, and distal radius-wrist fractures identified using hospitalization codes. Incident hip fracture rates in the PTX and matched control groups were 6.0 and 9.3 fractures per 1000 person-years, respectively. After adjustment, PTX was associated with a significant 32% lower risk for hip fracture (95% confidence interval 0.54 to 0.86; P = 0.001) and a 31% lower risk for any analyzed fracture (95% confidence interval 0.57 to 0.83; P < 0.001) compared with matched control subjects. Fracture risks were lower among hemodialysis patients who underwent PTX compared with matched control subjects. Surgical amelioration of secondary hyperparathyroidism may outweigh the risk of parathyroid hormone oversuppression in terms of bone health.

PMID 17634437  J Am Soc Nephrol. 2007 Aug;18(8):2401-7. doi: 10.1681/A・・・

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