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低りん血症

著者: 小泉賢洋 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: 花房規男 東京女子医科大学 血液浄化療法科

著者校正/監修レビュー済:2021/07/14
患者向け説明資料

概要・推奨   

  1. ①アルコール依存症症例、②ICUにて全身管理を要する症例、③持続的腎代替療法(CRRT)を施行中の症例では低りん血症を呈しやすく、積極的にその可能性を疑い、血清P値を測定する。
  1. 低りん血症の原因として、refeeding症候群は重症かつ頻度が高く、原因不明の乳酸アシドーシスに遭遇した場合は低りん血症の関与を疑い血清P値を測定する。
  1. 低りん血症のまれな原因として、骨細胞より産生されるP利尿因子であるFGF23が関与する腫瘍性骨軟化症(Tumor-induced osteomalacia, TIO)や腎移植後低りん血症が挙げられる。
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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:
小泉賢洋 : 特に申告事項無し[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:花房規男 : 講演料(協和キリン,ノーベルファーマ,キッセイ薬品,バイエル薬品株式会社)[2021年]

改訂のポイント:
  1. 定期レビューを行った(変更なし)。

病態・疫学・診察

疫学情報・病態・注意事項  
  1. 軽度の低りん血症(低リン血症)(<2.5㎎/dl)は一般入院患者では多くとも5%とされているが、アルコール依存症患者や重症の敗血症や外傷患者では30~50%と高頻度に生じるとされている[1][2]。症候性の重度の低りん血症(<1.0㎎/dl)は非常にまれである。
  1. ①細胞外から内へのシフト、②腸管での再吸収低下(経口摂取低下)、③腎での再吸収低下の3つの機序が考えられているが、高度の低りん血症では単独ではなくいくつかの原因が重なって生じていることが多い。
 
  1. 骨由来のP利尿因子であるFGF23は、Pの代謝制御において重要な役割を果たしている(推奨度2)。
  1. FGF23は骨細胞由来の液性因子であり、①近位尿細管の2型Na-P共輸送体(NaPi-2)の発現を低下させ、②ビタミンD1α水酸化酵素の抑制を介して1,25(OH)2Dの産生を抑制することにより、血清P濃度を低下させる作用を有する[3]
  1. これまでの研究により、家族性腫瘍状石灰化症(familial tumoral calcinosis)やX染色体優性低りん血症性クル病(X-linked hypophosphatemic rickets: XLH)などの遺伝子P代謝異常疾患や腫瘍性骨軟化症(tumor-induced osteomalacia: TIO)の原因因子であることが明らかにされている。(表<図表>
  1. 慢性腎臓病(CKD)患者では、早期よりP蓄積を防ぐためにFGF23の産生・分泌が亢進していることが知られている[4]。さらに、P負荷に反応して血清P値よりも早期に上昇することより、血清P値以上にP蓄積を鋭敏に反映するマーカーとなり得る可能性がある。透析導入患者よりなる前向き観察研究において、FGF23値の上昇が血清P値にかかわらず、用量依存的に死亡リスクの増大と関連することが報告されている[5]
 
FGF23が関与する疾患・病態

参考文献:
柴垣有吾:より理解を深める!体液電解質異常と輸液.改訂3版。深川雅史監修.中外医学社 2007;194.

出典

img1:  著者提供
 
 
 
  1. 人工呼吸器にて管理されている患者では、低りん血症の場合、呼吸器からの離脱が困難である(推奨度2)。
  1. 低りん血症はICU症例において10~80%(平均25%)と高率に認められ[9]、予後悪化と関連することが報告されている[10][11]。また、重度の低りん血症では、筋力低下により呼吸不全を生じたり、人工呼吸器からの離脱が困難であると症例レベルで報告されてきた。
  1. 2010年Alsumrainらは横断研究において、離脱不成功の症例では成功症例に比べて血清P値が有意に低く、血清P値が2.4mg/dl以下の場合離脱できないリスクが20%増加することが報告されている[12]。類似したデータが、AKI(急性腎障害)にて持続透析を受けている患者321人を対象とした研究で示されている[13]
 
  1. 腎移植後に高頻度に生じる低りん血症にはFGF23が関与している(推奨度2)。
  1. 腎移植後の患者では、P利尿亢進に起因する低りん血症が非常に高頻度に生じることが知られている[6]。従来、この病態の原因の1つとして、遷延性副甲状腺機能亢進症の関与が考えられてきた。しかし、移植前の二次性副甲状腺機能亢進症が軽度である患者においても移植後低りん血症は観察され、また移植後PTHが基準値範囲内に低下しても、P利尿亢進や低りん血症が遷延する症例が存在することから、PTHによるP利尿作用のみではこれらの現象を説明することはできない[7]。また、腎移植が成功し移植腎における1,25(OH)2D産生が期待される状況においても1,25(OH)2D低下が遷延する理由については明らかではなかった。
  1. このように、腎移植後患者において、低りん血症や1,25(OH)2D低下が遷延する原因は長い間不明であったが、近年の研究によりFGF23が深く関与していることが示されている。2006年Bhanらは、生体腎移植患者を対象とした前向きコホート研究において、移植前に異常高値を示すFGF23は移植後、比較的急速に低下するものの、しばらくは基準値以上で推移し、PTHに独立して、さらにPTHよりも有意にP利尿、低りん血症と相関することを示した[8]
  1. 以上より、腎移植後に低りん血症や1,25(OH)2D低下を来す機序は、次のように考えられている。つまり、CKD末期の状況では、高P血症に反応してFGF23分泌は著明に亢進するものの、その機能が廃絶している腎では尿中にPを排泄することがほとんどできない。ここで腎移植が行われると、異常高値を示すFGF23は、移植腎に作用して高度なP利尿を来すと同時に、腎臓での1α水酸化酵素活性を抑制し、これがPTHによる同酵素活性の亢進よりも有意に作用するために移植腎での1,25(OH)2D産生が抑制される。
問診・診察のポイント  
 
  1. 薬剤歴:腸管からの吸収低下(Al,Mg,Ca含有製剤、P吸着薬)、腎からの排泄増加(利尿剤、ビスホスホネート、エストロゲンなど)、薬剤性ファンコニ症候群(テトラサイクリン、バルプロ酸など)など、薬剤性低りん血症を来す薬剤は多岐にわたることから必ず問診することが重要である[14]
  1. 飲酒歴および栄養状態:アルコール依存症や低栄養患者では高頻度に低りん血症を来すことから、特に重要である。さらに高度の低栄養の患者で高カロリー輸液を開始した際には高度の低りん血症がみられる(refeeding syndrome)。
  1. 家族歴:X染色体優性低りん血症性クル病(X-linked hypophosphatemic rickets、XLH)、常染色体優性低りん血症性クル病(autosomal dominant hypophosphatemic rickets、ADHR)など
  1. 既往歴:糖尿病、悪性腫瘍、慢性下痢症、腎移植後
  1. 治療歴:持続腎代替療法施術中の患者でも高度の低りん血症がしばしばみられる。
  1. 症状:血清P濃度<1.0mg/dlの高度低りん血症で症状を来すことが多く、骨ミネラル代謝異常由来と細胞内ATPレベル低下由来の症状に分けられる。
  1. 骨ミネラル代謝異常由来の症状:クル病、骨軟化症、尿路結石(尿中Ca排泄増加)

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文献 

著者: L Larsson, K Rebel, B Sörbo
雑誌名: Acta Med Scand. 1983;214(3):221-3.
Abstract/Text Eleven patients with a serum phosphate concentration below 0.3 mmol/l were detected in a prospective study of severe hypophosphatemia carried out over 7 weeks on 13 579 adult inpatients. For only one of these patients had a serum phosphate determination been requested by the ward, whereas the remaining cases of severe hypophosphatemia were detected as a result of the study. The most common cause of unexpected severe hypophosphatemia was chronic alcoholism.

PMID 6660029  Acta Med Scand. 1983;214(3):221-3.
著者: André Gaasbeek, A Edo Meinders
雑誌名: Am J Med. 2005 Oct;118(10):1094-101. doi: 10.1016/j.amjmed.2005.02.014.
Abstract/Text Phosphate plays a key role in several biological processes. In recent years, new insights have been obtained into the regulation of the phosphate metabolism, including a growing amount of evidence suggesting that factors other than parathyroid hormone (PTH) and vitamin D are involved in maintaining the phosphate balance. A new class of phosphate-regulating factors, the so-called "phosphatonins," have been shown to be important in phosphate-wasting diseases. However, the role of the phosphatonins in the normal human homeostasis remains to be established. The incidence of hypophosphatemia in selected patient series can be more than 20%, with clinical sequelae ranging from mild to life threatening. Only when combined with phosphate depletion does hypophosphatemia become clinically significant. The factors that are involved in the phosphate homeostasis, the pathophysiology, the relevance in patient care, the clinical manifestations, and an appropriate management of phosphate depletion are discussed in this review.

PMID 16194637  Am J Med. 2005 Oct;118(10):1094-101. doi: 10.1016/j.amj・・・
著者: Takashi Shimada, Hisashi Hasegawa, Yuji Yamazaki, Takanori Muto, Rieko Hino, Yasuhiro Takeuchi, Toshiro Fujita, Kazuhiko Nakahara, Seiji Fukumoto, Takeyoshi Yamashita
雑誌名: J Bone Miner Res. 2004 Mar;19(3):429-35. doi: 10.1359/JBMR.0301264. Epub 2003 Dec 29.
Abstract/Text UNLABELLED: We analyzed the effects of an FGF-23 injection in vivo. FGF-23 caused a reduction in serum 1,25-dihydroxyvitamin D by altering the expressions of key enzymes for the vitamin D metabolism followed by hypophosphatemia. This study indicates that FGF-23 is a potent regulator of the vitamin D and phosphate metabolism.
INTRODUCTION: The pathophysiological contribution of FGF-23 in hypophosphatemic diseases was supported by animal studies in which the long-term administration of recombinant fibroblast growth factor-23 reproduced hypophosphatemic rickets with a low serum 1,25-dihydroxyvitamin D [1,25(OH)2D] level. However, there is no clear understanding of how FGF-23 causes these changes.
MATERIALS AND METHODS: To elucidate the molecular mechanisms of the FGF-23 function, we investigated the short-term effects of a single administration of recombinant FGF-23 in normal and parathyroidectmized animals.
RESULTS: An injection of recombinant FGF-23 caused a reduction in serum phosphate and 1,25(OH)2D levels. A decrease in serum phosphate was first observed 9 h after the injection and was accompanied with a reduction in renal mRNA and protein levels for the type IIa sodium-phosphate cotransporter (NaPi-2a). There was no increase in the parathyroid hormone (PTH) level throughout the experiment, and hypophosphatemia was reproduced by FGF-23 in parathyroidectomized rats. Before this hypophosphatemic effect, the serum 1,25(OH)2D level had already descended at 3 h and reached the nadir 9 h after the administration. FGF-23 reduced renal mRNA for 25-hydroxyvitamin D-1alpha-hydroxylase and increased that for 25-hydroxyvitamin D-24-hydroxylase starting at 1 h. In addition, an injection of calcitriol into normal mice increased the serum FGF-23 level within 4 h.
CONCLUSIONS: FGF-23 regulates NaPi-2a independently of PTH and the serum 1,25(OH)2D level by controlling renal expressions of key enzymes of the vitamin D metabolism. In conclusion, FGF-23 is a potent regulator of phosphate and vitamin D homeostasis.

PMID 15040831  J Bone Miner Res. 2004 Mar;19(3):429-35. doi: 10.1359/J・・・
著者: Orlando Gutierrez, Tamara Isakova, Eugene Rhee, Anand Shah, Julie Holmes, Gina Collerone, Harald Jüppner, Myles Wolf
雑誌名: J Am Soc Nephrol. 2005 Jul;16(7):2205-15. doi: 10.1681/ASN.2005010052. Epub 2005 May 25.
Abstract/Text Hyperphosphatemia, calcitriol deficiency, and secondary hyperparathyroidism (SHPT) are common complications of chronic kidney disease (CKD). Fibroblast growth factor-23 (FGF-23) is a novel phosphaturic hormone that also inhibits renal 1alpha-hydroxylase activity and thus may be involved in the pathogenesis of SHPT. Several hypotheses were tested: that FGF-23 increases as renal function declines; is linearly associated with serum phosphate levels; is associated with increased phosphaturia independent of parathyroid hormone (PTH); and is associated with decreased calcitriol levels independent of renal function, hyperphosphatemia, and vitamin D stores. FGF-23, PTH, 25(OH)D3, calcitriol, calcium, phosphate, and urinary fractional excretion of phosphate (Fe(PO4)) were measured in 80 CKD patients. Multiple linear regression was used to test the hypotheses. FGF-23 and PTH were inversely associated with estimated GFR (eGFR), whereas calcitriol levels were linearly associated with eGFR. Hyperphosphatemia and hypocalcemia were present in only 12 and 6% of patients, respectively, all of whose eGFR was <30. Increased Fe(PO4) was associated with decreased eGFR, and both increased FGF-23 and PTH were independently associated with increased Fe(PO4). Increased FGF-23 and decreased 25(OH)D3 were independent predictors of decreased calcitriol, but the effects on calcitriol levels of renal function itself and hyperphosphatemia were completely extinguished by adjusting for FGF-23. It is concluded that FGF-23 levels increase early in CKD before the development of serum mineral abnormalities and are independently associated with serum phosphate, Fe(PO4), and calcitriol deficiency. Increased FGF-23 may contribute to maintaining normal serum phosphate levels in the face of advancing CKD but may worsen calcitriol deficiency and thus may be a central factor in the early pathogenesis of SHPT.

PMID 15917335  J Am Soc Nephrol. 2005 Jul;16(7):2205-15. doi: 10.1681/・・・
著者: Orlando M Gutiérrez, Michael Mannstadt, Tamara Isakova, Jose Alejandro Rauh-Hain, Hector Tamez, Anand Shah, Kelsey Smith, Hang Lee, Ravi Thadhani, Harald Jüppner, Myles Wolf
雑誌名: N Engl J Med. 2008 Aug 7;359(6):584-92. doi: 10.1056/NEJMoa0706130.
Abstract/Text BACKGROUND: Fibroblast growth factor 23 (FGF-23) is a hormone that increases the rate of urinary excretion of phosphate and inhibits renal production of 1,25-dihydroxyvitamin D, thus helping to mitigate hyperphosphatemia in patients with kidney disease. Hyperphosphatemia and low 1,25-dihydroxyvitamin D levels are associated with mortality among patients with chronic kidney disease, but the effect of the level of FGF-23 on mortality is unknown.
METHODS: We examined mortality according to serum phosphate levels in a prospective cohort of 10,044 patients who were beginning hemodialysis treatment and then analyzed FGF-23 levels and mortality in a nested case-control sample of 200 subjects who died and 200 who survived during the first year of hemodialysis treatment. We hypothesized that increased FGF-23 levels at the initiation of hemodialysis would be associated with increased mortality.
RESULTS: Serum phosphate levels in the highest quartile (>5.5 mg per deciliter [1.8 mmol per liter]) were associated with a 20% increase in the multivariable adjusted risk of death, as compared with normal levels (3.5 to 4.5 mg per deciliter [1.1 to 1.4 mmol per liter]) (hazard ratio, 1.2; 95% confidence interval [CI], 1.1 to 1.4). Median C-terminal FGF-23 (cFGF-23) levels were significantly higher in case subjects than in controls (2260 vs. 1406 reference units per milliliter, P<0.001). Multivariable adjusted analyses showed that increasing FGF-23 levels were associated with a monotonically increasing risk of death when examined either on a continuous scale (odds ratio per unit increase in log-transformed cFGF-23 values, 1.8; 95% CI, 1.4 to 2.4) or in quartiles, with quartile 1 as the reference category (odds ratio for quartile 2, 1.6 [95% CI, 0.8 to 3.3]; for quartile 3, 4.5 [95% CI, 2.2 to 9.4]; and for quartile 4, 5.7 [95% CI, 2.6 to 12.6]).
CONCLUSIONS: Increased FGF-23 levels appear to be independently associated with mortality among patients who are beginning hemodialysis treatment. Future studies might investigate whether FGF-23 is a potential biomarker that can be used to guide strategies for the management of phosphorus balance in patients with chronic kidney disease.

2008 Massachusetts Medical Society
PMID 18687639  N Engl J Med. 2008 Aug 7;359(6):584-92. doi: 10.1056/NE・・・
著者: P M Ambühl, D Meier, B Wolf, U Dydak, P Boesiger, U Binswanger
雑誌名: Am J Kidney Dis. 1999 Nov;34(5):875-83. doi: 10.1016/S0272-6386(99)70045-4.
Abstract/Text Hypophosphatemia caused by renal phosphate loss occurs frequently after kidney transplantation. In assumption of systemic phosphorus depletion, the presumed deficit commonly is replaced by oral phosphate supplements. However, such treatment is debatable, because intracellular phosphorus stores have not been assessed in this setting and may not be accurately reflected by serum phosphate concentrations. Moreover, disturbances in mineral metabolism from chronic renal failure, such as hypocalcemia and hyperparathyroidism, may be prolonged with oral phosphate supplements. Conversely, a neutral phosphate salt might improve renal acid excretion and systemic acid/base homeostasis for its properties as a urinary buffer and a poorly reabsorbable anion. Twenty-eight patients with mild early posttransplantation hypophosphatemia (0.3-0.75 mmol/L) were randomly assigned to receive either neutral sodium phosphate (Na(2)HPO(4)) or sodium chloride (NaCl) for 12 weeks and examined with regard to (1) correction of serum phosphate concentration and urinary phosphate handling; (2) muscular phosphate content; (3) serum calcium and parathyroid hormone (PTH); and, (4) renal acid handling and systemic acid/base homeostasis. Mean serum phosphate concentrations were similar and normal in both groups after 12 weeks of treatment; however, more patients in the NaCl group remained hypophosphatemic (93% versus 67%). Total muscular phosphorus content did not correlate with serum phosphate concentrations and was 25% below normophosphatemic controls but was completely restored after 12 weeks with and without phosphate supplementation. However, the percentage of the energy-rich phosphorus compound adenosine triphosphate (ATP) was significantly higher in the Na(2)HPO(4) group, as was the relative content of phosphodiesters. Also, compensated metabolic acidosis (hypobicarbonatemia with respiratory stimulation) was detected in most patients, which was significantly improved by neutral phosphate supplements through increased urinary titratable acidity. These benefits of added phosphate intake were not associated with any adverse effects on serum calcium and PTH concentrations. In conclusion, oral supplementation with a neutral phosphate salt effectively corrects posttransplantation hypophosphatemia, increases muscular ATP and phosphodiester content without affecting mineral metabolism, and improves renal acid excretion and systemic acid/base status.

PMID 10561144  Am J Kidney Dis. 1999 Nov;34(5):875-83. doi: 10.1016/S0・・・
著者: J Green, H Debby, E Lederer, M Levi, H K Zajicek, T Bick
雑誌名: Kidney Int. 2001 Sep;60(3):1182-96. doi: 10.1046/j.1523-1755.2001.0600031182.x.
Abstract/Text BACKGROUND: Patients undergoing successful kidney transplantation often manifest overt hypophosphatemia associated with exaggerated phosphaturia during the early post-transplant period (2 weeks to 3 months). The mechanism for this phenomenon has not been fully elucidated. We tested the hypothesis that a circulating serum factor [non-parathyroid hormone (non-PTH)], which operates during chronic renal failure (CRF) to maintain phosphate (Pi) homeostasis, can increase fractional excretion of Pi (FE(PO4)) in normal functioning kidney grafts during the early post-transplant period, thereby causing phosphaturia and hypophosphatemia.
METHODS: Five groups of patients were studied: control subjects (group 1, N = 16), "early" (2 weeks to 1 month) post-transplant patients (group 2, N = 22), "late" (9 to 12 months) post-transplant patients (group 3, N = 14), patients with advanced CRF (glomerular filtration rate = 30 to 40 mL/min; group 4, N = 8), and patients who suffered from end-stage renal failure and were treated by chronic hemodialysis (group 5, N = 14). Group 2 manifested significant hypophosphatemia and phosphaturia when compared with groups 1 and 3 (Pi = 0.9 +/- 0.003 mg/dL, FE(PO4) = 68+/- 5%, P < 0.0005 vs. groups 1 and 3). Sera were taken from each of the five subject groups and applied to the proximal tubular opossum kidney (OK) cells. The activity of Na/Pi-type 4 (that is, OK-specific type II transporter) was evaluated by measuring Na(+)-dependent (32)Pi flux. The expression of Na/Pi type II mRNA and the abundance of Na/Pi protein were determined by Northern and Western blot assays, respectively.
RESULTS: When compared with sera from groups 1 and 3, 10% sera taken from groups 2, 4, and 5 (incubated overnight with OK cells) inhibited (32)Pi flux by 25 to 30% (P < 0.0003). Both Na/Pi mRNA and the expression of Na/Pi protein were markedly augmented under the same conditions (P < 0.05 groups 2, 4, and 5 vs. groups 1 and 3). Time-course analysis revealed that the up-regulation of Na/Pi protein by sera from groups 2, 4, and 5 was observed as early as four hours of incubation, whereas augmented abundance of Na/Pi mRNA was only seen after eight hours of incubation. The addition of PTH (1-34) to sera from groups 2, 4, and 5 abolished the augmented expression of NaPi protein. We labeled OK cell surface membrane proteins with N-hydroxysuccinimide bound to biotin (NHS-SS-biotin). Biotinylated transporters incubated with the different sera were precipitated by strepavidin and identified by Western blot analysis. Cells incubated in sera from group 2 showed increased membrane bound transporter when compared with control sera, whereas the intracellular pool of the transporter was comparable between the two groups.
CONCLUSION: A non-PTH circulating serum factor (possibly phosphatonin) that increases FE(PO4) during CRF is also responsible for phosphaturia and hypophosphatemia in the early period following successful kidney transplantation. The putative factor inactivates Na/Pi activity along with inhibition of the transporter trafficking from the cell membrane into the cytosol.

PMID 11532115  Kidney Int. 2001 Sep;60(3):1182-96. doi: 10.1046/j.1523・・・
著者: I Bhan, A Shah, J Holmes, T Isakova, O Gutierrez, S M Burnett, H Jüppner, M Wolf
雑誌名: Kidney Int. 2006 Oct;70(8):1486-94. doi: 10.1038/sj.ki.5001788. Epub 2006 Aug 30.
Abstract/Text Hypophosphatemia is a common complication of kidney transplantation. Tertiary hyperparathyroidism has long been thought to be the etiology, but hypophosphatemia can occur despite low parathyroid hormone (PTH) levels and can persist after high PTH levels normalize. Furthermore, even in the setting of normal allograft function, hypophosphatemia, and hyperparathyroidism, calcitriol levels remain inappropriately low following transplantation, suggesting that mechanisms other than PTH contribute. Fibroblast growth factor-23 (FGF-23) induces phosphaturia, inhibits calcitriol synthesis, and accumulates in chronic kidney disease. We performed a prospective, longitudinal study of 27 living donor transplant recipients to test the hypotheses that excessive FGF-23 accounts for hypophosphatemia and decreased calcitriol levels following kidney transplantation. Hypophosphatemia <2.5 mg/dl developed in 85% of subjects, including one who had previously undergone parathyroidectomy; 37% developed phosphate < or =1.5 mg/dl. The mean pre-transplant FGF-23 level was 1,218+/-542 RU/ml. Within the first week following transplantation, mean levels decreased to 557+/-579 RU/ml, which were still above normal. FGF-23 was independently associated with serum phosphate (P < 0.01), urinary excretion of phosphate (P < 0.01), and calcitriol levels (P < 0.01); PTH was not independently associated with any of these parameters. We calculated area under the curve for FGF-23 and PTH between the pre- and first post-transplant levels as a summary measure of early exposure to these phosphaturic hormones. An area under the FGF-23 curve greater than the median was associated with a relative risk of developing hypophosphatemia < or =1.5 mg/dl of 5.3 (P = 0.02) compared with lower levels. Increased area under the PTH curve was not associated with greater risk of hypophosphatemia. Excessive FGF-23 exposure in the early post-transplant period appears to be more strongly associated with post-transplant hypophosphatemia than PTH.

PMID 16941023  Kidney Int. 2006 Oct;70(8):1486-94. doi: 10.1038/sj.ki.・・・
著者: Daniël A Geerse, Alexander J Bindels, Michael A Kuiper, Arnout N Roos, Peter E Spronk, Marcus J Schultz
雑誌名: Crit Care. 2010;14(4):R147. doi: 10.1186/cc9215. Epub 2010 Aug 3.
Abstract/Text INTRODUCTION: Currently no evidence-based guideline exists for the approach to hypophosphatemia in critically ill patients.
METHODS: We performed a narrative review of the medical literature to identify the incidence, symptoms, and treatment of hypophosphatemia in critically ill patients. Specifically, we searched for answers to the questions whether correction of hypophosphatemia is associated with improved outcome, and whether a certain treatment strategy is superior.
RESULTS: Incidence: hypophosphatemia is frequently encountered in the intensive care unit; and critically ill patients are at increased risk for developing hypophosphatemia due to the presence of multiple causal factors.
SYMPTOMS: hypophosphatemia may lead to a multitude of symptoms, including cardiac and respiratory failure.
TREATMENT: hypophosphatemia is generally corrected when it is symptomatic or severe. However, although multiple studies confirm the efficacy and safety of intravenous phosphate administration, it remains uncertain when and how to correct hypophosphatemia.
OUTCOME: in some studies, hypophosphatemia was associated with higher mortality; a paucity of randomized controlled evidence exists for whether correction of hypophosphatemia improves the outcome in critically ill patients.
CONCLUSIONS: Additional studies addressing the current approach to hypophosphatemia in critically ill patients are required. Studies should focus on the association between hypophosphatemia and morbidity and/or mortality, as well as the effect of correction of this electrolyte disorder.

PMID 20682049  Crit Care. 2010;14(4):R147. doi: 10.1186/cc9215. Epub 2・・・
著者: Satoshi Suzuki, Moritoki Egi, Antoine G Schneider, Rinaldo Bellomo, Graeme K Hart, Colin Hegarty
雑誌名: J Crit Care. 2013 Aug;28(4):536.e9-19. doi: 10.1016/j.jcrc.2012.10.011. Epub 2012 Dec 21.
Abstract/Text PURPOSE: The aim of this study was to assess the association of phosphate concentration with key clinical outcomes in a heterogeneous cohort of critically ill patients.
MATERIALS AND METHODS: This was a retrospective observational study at a general intensive care unit (ICU) of an Australian university teaching hospital enrolling 2730 adult critically ill patients.
RESULTS: We studied 10504 phosphate measurements with a mean value of 1.17 mmol/L (measurements every 28.8 hours on average). Hyperphosphatemia (inorganic phosphate [iP] concentration > 1.4 mmol/L) occurred in 45% and hypophosphatemia (iP ≤ 0.6 mmol/L) in 20%. Among patients without any episodes of hyperphosphatemia, patients with at least 1 episode of hypophosphatemia had a higher ICU mortality than those without hypophosphatemia (P = .004). In addition, ICU nonsurvivors had lower minimum phosphate concentrations than did survivors (P = .009). Similar results were seen for hospital mortality. However, on multivariable logistic regression analysis, hypophosphatemia was not independently associated with ICU mortality (adjusted odds ratio, 0.86 [95% confidence interval, 0.66-1.10]; P = .24) and hospital mortality (odds ratio, 0.89 [0.73-1.07]; P = .21). Even when different cutoff points were used for hypophosphatemia (iP ≤ 0.5, 0.4, 0.3, or 0.2 mmol/L), hypophosphatemia was not an independent risk factor for ICU and hospital morality. In addition, timing of onset and duration of hypophosphatemia were not independent risk factor for ICU and hospital mortality.
CONCLUSIONS: Hypophosphatemia behaves like a general marker of illness severity and not as an independent predictor of ICU or in-hospital mortality in critically ill patients.

Copyright © 2013 Elsevier Inc. All rights reserved.
PMID 23265292  J Crit Care. 2013 Aug;28(4):536.e9-19. doi: 10.1016/j.j・・・
著者: Lichun Wang, Chaoxing Xiao, Lei Chen, Xiaofei Zhang, Qiuye Kou
雑誌名: BMC Anesthesiol. 2019 May 24;19(1):86. doi: 10.1186/s12871-019-0746-2. Epub 2019 May 24.
Abstract/Text BACKGROUND: Hypophosphatemia generally occurs in Intensive Care Units (ICUs), but its impact is often ignored. The aim of this study was to investigate whether hypophosphatemia can be a risk factor for ICU 28-day mortality.
METHODS: A single-center retrospective cohort study was conducted by collecting data from 1073 patients admitted to general ICU and then presented to the Sixth Affiliated Hospital, Sun Yat-sen University (Guangzhou City, Guangdong Province, China) from 1 January 2016 to 31 December 2017. The patients were divided into a normal control group (serum phosphate levels 0.80-1.60 mmol/L) and a hypophosphatemia group (serum phosphate levels < 0.80 mmol/L), based on the concentration of phosphorus at the time of ICU admission. The association between phosphate levels and ICU 28-day mortality was evaluated by binary logistic regression analysis. Multivariate logistic regression was employed to predict the ICU 28-day mortality.
RESULTS: The cohort included 946 patients with a median phosphate concentration of 0.77 mmol/L (interquartile range 0.55-1.03 mmol/L). Patients with hypophosphatemia had a higher ICU 28-day mortality than the normal control group (33.3% vs 24.0%, P < 0.05). Patients with hypophosphatemia had a longer ICU and hospital stays, and prolonged duration of mechanical ventilation (all P < 0.05). Hypophosphatemia was an independent risk factor for ICU 28-day mortality (adjusted OR = 1.5, 95% CI = 1.1-2.1, P = 0.01) in the multivariate logistic regression analysis.
CONCLUSIONS: Hypophosphatemia at admission is an independent risk factor for 28-day mortality in general ICU patients.
TRIAL REGISTRATION: The medical study was approved by the Institutional Ethics Committee of the Six Affiliated Hospital, Sun Yat-sen University (Approval number: 2017ZSLYEC-110). No consent was given as the data were analyzed anonymously.

PMID 31122196  BMC Anesthesiol. 2019 May 24;19(1):86. doi: 10.1186/s12・・・
著者: Mohammad H Alsumrain, Sami Abdul Jawad, Nashat B Imran, Sandeep Riar, Vincent A DeBari, Marc Adelman
雑誌名: Ann Clin Lab Sci. 2010 Spring;40(2):144-8.
Abstract/Text Severe hypophosphatemia is known to be associated with respiratory failure, but there are few studies that specifically examine the relationship between serum phosphorus concentration and failure to wean patients from mechanical ventilation. This study investigated the association between hypophosphatemia and weaning failure in patients in two medical intensive care units (ICU). The study was conducted in a prospectively developed cohort of 66 patients being treated with ventilatory support and in whom 193 weaning trials were attempted. Ultimately, all 66 subjects were successfully weaned. A cross-sectional analysis was conducted on serum phosphorus levels and success or failure to wean the patients from ventilators. At the time of the successful weaning attempts (n = 66), the subjects' serum phosphorus concentrations (mean +/- SD) were 1.18 +/- 0.27 mmol/L, whereas at all failed weaning attempts (n = 127) serum phosphorus concentrations averaged 1.06 +/- 0.31 mmol/L (p = 0.008). Subjects with phosphorus concentrations below the reference interval (RI) in our laboratory (<0.80 mmol/L) had greater risk for weaning failure compared to subjects with phosphorus concentrations at or above the RI (relative risk = 1.18; 95% confidence interval = 1.06 to 1.32; p = 0.01). Serum calcium concentrations were not significantly different at the time of successful weaning compared to those at failed weaning attempts. This study indicates that there is an association between hypophosphatemia and failure-to-wean from mechanical ventilation in ICU patients on ventilatory support.

PMID 20421625  Ann Clin Lab Sci. 2010 Spring;40(2):144-8.
著者: Sevag Demirjian, Boon Wee Teo, Jorge A Guzman, Robert J Heyka, Emil P Paganini, William H Fissell, Jesse D Schold, Martin J Schreiber
雑誌名: Nephrol Dial Transplant. 2011 Nov;26(11):3508-14. doi: 10.1093/ndt/gfr075. Epub 2011 Mar 7.
Abstract/Text BACKGROUND: Hypophosphatemia is common in critically ill patients and has been associated with generalized muscle weakness, ventilatory failure and myocardial dysfunction. Continuous renal replacement therapy causes phosphate depletion, particularly with prolonged and intensive therapy. In a prospective observational cohort of critically ill patients with acute kidney injury (AKI), we examined the incidence of hypophosphatemia during dialysis, associated risk factors and its relationship with prolonged respiratory failure and 28-day mortality.
METHODS: This is a single-center prospective observational study. Included in the study were 321 patients with AKI on continuous dialysis as initial treatment modality.
RESULTS: Four per cent of the patients had a phosphate level <2 mg/dL at initiation and 27% during dialysis. Low baseline phosphate was associated with older age, female gender, parenteral nutrition, vasopressor support, low calcium, and high urea, bilirubin and creatinine, whereas hypophosphatemia during dialysis correlated with the ischemic acute tubular necrosis etiology of renal failure, intensive dose and longer therapy. Serum phosphate decline during dialysis was associated with higher incidence of prolonged respiratory failure requiring tracheostomy [odds ratio (OR) = 1.81; 95% confidence interval (CI) = 1.07-3.08], but not 28-day mortality (OR = 1.16; 95% CI = 0.76-1.77) in multivariable analysis.
CONCLUSIONS: Hypophosphatemia occurs frequently during dialysis, particularly with long and intensive treatment. Decline in serum phosphate levels during dialysis is associated with higher incidence of prolonged respiratory failure requiring tracheostomy, but not 28-day mortality.

PMID 21382993  Nephrol Dial Transplant. 2011 Nov;26(11):3508-14. doi: ・・・
著者: G Liamis, H J Milionis, M Elisaf
雑誌名: QJM. 2010 Jul;103(7):449-59. doi: 10.1093/qjmed/hcq039. Epub 2010 Mar 30.
Abstract/Text Hypophosphatemia (serum phosphorus concentration <2.5 mg/dl, 0.8 mmol/l), although rare in the general population, is commonly observed in hospitalized patients and may be associated with drug therapy. In fact, hypophosphatemia frequently develops in the course of treatment with drugs used in every-day clinical practice including diuretics and bisphosphonates. Proper diagnostic approach of patients with low serum phosphorus concentrations should involve a detailed medical history with special attention to the recent use of medications. The clinical manifestations of drug-induced hypophosphatemia are usually mild but might also be severe and potentially life-threatening. This review aims at a thorough understanding of the underlying pathophysiological mechanisms and risk factors of drug therapy-related hypophosphatemia thus allowing prevention and effective intervention strategies.

PMID 20356849  QJM. 2010 Jul;103(7):449-59. doi: 10.1093/qjmed/hcq039.・・・
著者: R J Walton, R G Russell, R Smith
雑誌名: Clin Sci Mol Med. 1975 Jul;49(1):45-56. doi: 10.1042/cs0490045.
Abstract/Text 1. The diphosphonate, disodium etidronate (disodium ethane-1-hydroxy-1, 1-diphosphonate; (EHDP), is known to increase plasma inorganic phosphate in man. The present study examines the mechanism of this effect. 2. When EHDP was given by mouth at a dose of 80 mumol (20 mg) kg-minus 1day-minus 1, plasma phosphate was significantly increased 24 h after the first dose but did not reach its maximum value for 2-3 weeks. When the drug was stopped, plasma phosphate returned to pretreatment values within 3 weeks. 3. Urinary excretion rate of phosphate was not greatly changed during treatment with EHDP despite the large increase in plasma phosphate, suggesting an alteration in renal handling. This was examined directly by infusing phosphate and inulin in six patients off and on EDPH. 4. EHDP had no effect on glomerular filtration rate (GFR) but produced a large increase in the maximum rate of renal tubular reabsorption of phosphate (TmP). The ratio Tm,P/GFR increased from a mean value of 1.15 mmol/1 to 2.10 mmol/1 on EHDP. This increase accounted for the hyperphosphataemia. 5. The same amount of phosphate infused at the same rate produced a greater rise in plasma phosphate when patients were on EHDP than when they were not, indicating a reduced net rate of entry of phosphate into tissues other than kidney. 6. Fasting total plasma calcium concentration and urine calcium excretion rate were not significantly altered by EHDP but the ability of infused phosphate to decrease plasma calcium was diminished. 7. It is suggested that EHDP alters phosphate transport in kidney and other tissues by a mechanism which is probably independent of the known hormonal influences on phosphate metabolism.

PMID 807449  Clin Sci Mol Med. 1975 Jul;49(1):45-56. doi: 10.1042/cs・・・
著者: J J Body, A Lortholary, G Romieu, A M Vigneron, J Ford
雑誌名: J Bone Miner Res. 1999 Sep;14(9):1557-61. doi: 10.1359/jbmr.1999.14.9.1557.
Abstract/Text Zoledronate is a new heterocyclic imidazole bisphosphonate that is the most potent bisphosphonate administered in humans because it is 100-850 times more potent than pamidronate, according to in vitro or animal models of bone resorption. We conducted an open-label, dose-finding, single-dose phase I study in tumor-induced hypercalcemia (TIH), which has been similarly used as a model to determine the active doses of other bisphosphonates. The primary objective was to determine, with a dose escalation schedule, two nontoxic dose levels of zoledronate able to induce normocalcemia in at least 80% of patients with TIH after rehydration (corrected Ca for albumin levels >/=2.75 mmol/l). Based on estimates of potency, the starting dose was 0.002 mg/kg, and further tested doses were 0. 005, 0.01, 0.02, and 0.04 mg/kg. To obtain a more precise estimate of the response rate, we treated 10 more patients at the highest of the two effective dose levels. The median infusion time of zoledronate was 30 minutes. Thirty out of the 33 treated patients were evaluable for efficacy. Thirty percent of the patients had breast cancer and 54% had metastatic bone involvement. For all groups combined, mean Ca levels at baseline was 3.0 mmol/l. The two effective dose levels were 0.02 mg/kg and 0.04 mg/kg. Five out of five patients became normocalcemic after 0.02 mg of zoledronate/kg and 14 out of 15 after 0.04 mg of zoledronate/kg. The success rate of the latter dose was thus 93% (95% confidence interval [CI] 68-100%). At this dose, the first day of normocalcemia was day 2 or 3 for all but one patient. The duration of normocalcemia for the two effective doses could be assessed in nine patients; seven patients remained normocalcemic throughout the trial (32-39 days). The fall in serum Ca was accompanied by a marked fall in fasting urinary Ca excretion. Zoledronate was well tolerated: 7 out of 33 patients developed transient hypophosphatemia, and 3 developed transient hypocalcemia. The only clinically detectable side effect was an increase in body temperature occurring in 10 (30%) patients. In summary, very low doses of zoledronate (0.02 mg/kg and 0.04 mg/kg, i. e., 1.2 mg and 2.4 mg for a 60-kg individual, respectively) administered by a short-time infusion effectively treated patients with TIH. The fall in serum Ca was rapid, and normocalcemia was often maintained for several weeks. Zoledronate was well tolerated. Future trials will determine whether prolonged treatment with this potent compound can have greater effects on the skeletal morbidity rate in patients with tumor bone disease than can be achieved with currently available bisphosphonates.

PMID 10469284  J Bone Miner Res. 1999 Sep;14(9):1557-61. doi: 10.1359/・・・
著者: Suzanne M Jan De Beur, Richard B Finnegan, John Vassiliadis, Brian Cook, Dana Barberio, Scott Estes, Partha Manavalan, Joseph Petroziello, Stephen L Madden, Justin Y Cho, Rajiv Kumar, Michael A Levine, Susan C Schiavi
雑誌名: J Bone Miner Res. 2002 Jun;17(6):1102-10. doi: 10.1359/jbmr.2002.17.6.1102.
Abstract/Text Oncogenic osteomalacia (OOM) is associated with primitive mesenchymal tumors that secrete phosphaturic factors resulting in low serum concentrations of phosphate and calcitriol, phosphaturia, and defective bone mineralization. To identify overexpressed genes in these tumors, we compared gene expression profiles of tumors resected from patients with OOM and histologically similar control tumors using serial analysis of gene expression (SAGE). Three hundred and sixty-four genes were expressed at least twofold greater in OOM tumors compared with control tumors. A subset of 67 highly expressed genes underwent validation with an extended set of OOM and control tumors using array analysis or reverse-transcription polymerase chain reaction (RT-PCR). Ten of these validated genes were consistently overexpressed in all OOM tumors relative to control tumors. Strikingly, genes with roles in bone matrix formation, mineral ion transport, and bone mineralization were highly expressed in the OOM tumors.

PMID 12054166  J Bone Miner Res. 2002 Jun;17(6):1102-10. doi: 10.1359/・・・
著者: Yan Jiang, Wei-bo Xia, Xiao-ping Xing, Barbara C Silva, Mei Li, Ou Wang, Hua-bing Zhang, Fang Li, Hong-li Jing, Ding-romg Zhong, Jin Jin, Peng Gao, Lian Zhou, Fang Qi, Wei Yu, John P Bilezikian, Xun-wu Meng
雑誌名: J Bone Miner Res. 2012 Sep;27(9):1967-75. doi: 10.1002/jbmr.1642.
Abstract/Text Tumor-induced osteomalacia (TIO) is an acquired form of hypophosphatemia. Tumor resection leads to cure. We investigated the clinical characteristics of TIO, diagnostic methods, and course after tumor resection in Beijing, China, and compared them with 269 previous published reports of TIO. A total of 94 patients with adult-onset hypophosphatemic osteomalacia were seen over a 6-year period (January, 2004 to May, 2010) in Peking Union Medical College Hospital. After physical examination (PE), all patients underwent technetium-99m octreotide scintigraphy ((99) Tc(m) -OCT). Tumors were removed after localization. The results demonstrated that 46 of 94 hypophosphatemic osteomalacia patients had high uptake in (99) Tc(m) -OCT imaging. Forty of them underwent tumor resection with the TIO diagnosis established in 37 patients. In 2 patients, the tumor was discovered on PE but not by (99) Tc(m) -OCT. The gender distribution was equal (M/F = 19/20). Average age was 42 ± 14 years. In 35 patients (90%), the serum phosphorus concentration returned to normal in 5.5 ± 3.0 days after tumor resection. Most of the tumors (85%) were classified as phosphaturic mesenchymal tumor (PMT) or mixed connective tissue variant (PMTMCT). Recurrence of disease was suggested in 3 patients (9%). When combined with the 269 cases reported in the literature, the mean age and sex distribution were similar. The tumors were of bone (40%) and soft tissue (55%) origins, with 42% of the tumors being found in the lower extremities. In summary, TIO is an important cause of adult-onset hypophosphatemia in China. (99) Tc(m) -OCT imaging successfully localized the tumor in the overwhelming majority of patients. Successful removal of tumors leads to cure in most cases, but recurrence should be sought by long-term follow-up.

Copyright © 2012 American Society for Bone and Mineral Research.
PMID 22532501  J Bone Miner Res. 2012 Sep;27(9):1967-75. doi: 10.1002/・・・
著者: Hisham M Mehanna, Jamil Moledina, Jane Travis
雑誌名: BMJ. 2008 Jun 28;336(7659):1495-8. doi: 10.1136/bmj.a301.
Abstract/Text
PMID 18583681  BMJ. 2008 Jun 28;336(7659):1495-8. doi: 10.1136/bmj.a30・・・
著者: M A Crook, V Hally, J V Panteli
雑誌名: Nutrition. 2001 Jul-Aug;17(7-8):632-7.
Abstract/Text In this review we discuss the refeeding syndrome. This potentially lethal condition can be defined as severe electrolyte and fluid shifts associated with metabolic abnormalities in malnourished patients undergoing refeeding, whether orally, enterally, or parenterally. It can be associated with significant morbidity and mortality. Clinical features are fluid-balance abnormalities, abnormal glucose metabolism, hypophosphatemia, hypomagnesemia, and hypokalemia. In addition, thiamine deficiency can occur. We describe which patient groups are more at risk for this syndrome and the clinical management of the condition.

PMID 11448586  Nutrition. 2001 Jul-Aug;17(7-8):632-7.
著者: Thomas O Carpenter, Michael P Whyte, Erik A Imel, Annemieke M Boot, Wolfgang Högler, Agnès Linglart, Raja Padidela, William Van't Hoff, Meng Mao, Chao-Yin Chen, Alison Skrinar, Emil Kakkis, Javier San Martin, Anthony A Portale
雑誌名: N Engl J Med. 2018 May 24;378(21):1987-1998. doi: 10.1056/NEJMoa1714641.
Abstract/Text BACKGROUND: X-linked hypophosphatemia is characterized by increased secretion of fibroblast growth factor 23 (FGF-23), which leads to hypophosphatemia and consequently rickets, osteomalacia, and skeletal deformities. We investigated burosumab, a monoclonal antibody that targets FGF-23, in patients with X-linked hypophosphatemia.
METHODS: In an open-label, phase 2 trial, we randomly assigned 52 children with X-linked hypophosphatemia, in a 1:1 ratio, to receive subcutaneous burosumab either every 2 weeks or every 4 weeks; the dose was adjusted to achieve a serum phosphorus level at the low end of the normal range. The primary end point was the change from baseline to weeks 40 and 64 in the Thacher rickets severity total score (ranging from 0 to 10, with higher scores indicating greater disease severity). In addition, the Radiographic Global Impression of Change was used to evaluate rachitic changes from baseline to week 40 and to week 64. Additional end points were changes in pharmacodynamic markers, linear growth, physical ability, and patient-reported outcomes and the incidence of adverse events.
RESULTS: The mean Thacher rickets severity total score decreased from 1.9 at baseline to 0.8 at week 40 with every-2-week dosing and from 1.7 at baseline to 1.1 at week 40 with every-4-week dosing (P<0.001 for both comparisons); these improvements persisted at week 64. The mean serum phosphorus level increased after the first dose in both groups, and more than half the patients in both groups had levels within the normal range (3.2 to 6.1 mg per deciliter [1.0 to 2.0 mmol per liter]) by week 6. Stable serum phosphorus levels were maintained through week 64 with every-2-week dosing. Renal tubular phosphate reabsorption increased from baseline in both groups, with an overall mean increase of 0.98 mg per deciliter (0.32 mmol per liter). The mean dose of burosumab at week 40 was 0.98 mg per kilogram of body weight with every-2-week dosing and 1.50 mg per kilogram with every-4-week dosing. Across both groups, the mean serum alkaline phosphatase level decreased from 459 U per liter at baseline to 369 U per liter at week 64. The mean standing-height z score increased in both groups, with greater improvement seen at all time points with every-2-week dosing (an increase from baseline of 0.19 at week 64) than with every-4-week dosing (an increase from baseline of 0.12 at week 64). Physical ability improved and pain decreased. Nearly all the adverse events were mild or moderate in severity.
CONCLUSIONS: In children with X-linked hypophosphatemia, treatment with burosumab improved renal tubular phosphate reabsorption, serum phosphorus levels, linear growth, and physical function and reduced pain and the severity of rickets. (Funded by Ultragenyx Pharmaceutical and Kyowa Hakko Kirin; ClinicalTrials.gov number, NCT02163577 ; EudraCT number, 2014-000406-35 ).

PMID 29791829  N Engl J Med. 2018 May 24;378(21):1987-1998. doi: 10.10・・・
著者: Karl L Insogna, Karine Briot, Erik A Imel, Peter Kamenický, Mary D Ruppe, Anthony A Portale, Thomas Weber, Pisit Pitukcheewanont, Hae Il Cheong, Suzanne Jan de Beur, Yasuo Imanishi, Nobuaki Ito, Robin H Lachmann, Hiroyuki Tanaka, Farzana Perwad, Lin Zhang, Chao-Yin Chen, Christina Theodore-Oklota, Matt Mealiffe, Javier San Martin, Thomas O Carpenter, AXLES 1 Investigators
雑誌名: J Bone Miner Res. 2018 Aug;33(8):1383-1393. doi: 10.1002/jbmr.3475. Epub 2018 Jun 26.
Abstract/Text In X-linked hypophosphatemia (XLH), inherited loss-of-function mutations in the PHEX gene cause excess circulating levels of fibroblast growth factor 23 (FGF23), leading to lifelong renal phosphate wasting and hypophosphatemia. Adults with XLH present with chronic musculoskeletal pain and stiffness, short stature, lower limb deformities, fractures, and pseudofractures due to osteomalacia, accelerated osteoarthritis, dental abscesses, and enthesopathy. Burosumab, a fully human monoclonal antibody, binds and inhibits FGF23 to correct hypophosphatemia. This report summarizes results from a double-blind, placebo-controlled, phase 3 trial of burosumab in symptomatic adults with XLH. Participants with hypophosphatemia and pain were assigned 1:1 to burosumab 1 mg/kg (n = 68) or placebo (n = 66) subcutaneously every 4 weeks (Q4W) and were comparable at baseline. Across midpoints of dosing intervals, 94.1% of burosumab-treated participants attained mean serum phosphate concentration above the lower limit of normal compared with 7.6% of those receiving placebo (p < 0.001). Burosumab significantly reduced the Western Ontario and the McMaster Universities Osteoarthritis Index (WOMAC) stiffness subscale compared with placebo (least squares [LS] mean ± standard error [SE] difference, -8.1 ± 3.24; p = 0.012). Reductions in WOMAC physical function subscale (-4.9 ± 2.48; p = 0.048) and Brief Pain Inventory worst pain (-0.5 ± 0.28; p = 0.092) did not achieve statistical significance after Hochberg multiplicity adjustment. At week 24, 43.1% (burosumab) and 7.7% (placebo) of baseline active fractures were fully healed; the odds of healed fracture in the burosumab group was 16.8-fold greater than that in the placebo group (p < 0.001). Biochemical markers of bone formation and resorption increased significantly from baseline with burosumab treatment compared with placebo. The safety profile of burosumab was similar to placebo. There were no treatment-related serious adverse events or meaningful changes from baseline in serum or urine calcium, intact parathyroid hormone, or nephrocalcinosis. These data support the conclusion that burosumab is a novel therapeutic addressing an important medical need in adults with XLH.© 2018 The Authors. Journal of Bone and Mineral Research Published by Wiley Periodicals, Inc.

© 2018 The Authors. Journal of Bone and Mineral Research Published by Wiley Periodicals, Inc.
PMID 29947083  J Bone Miner Res. 2018 Aug;33(8):1383-1393. doi: 10.100・・・
著者: Karl L Insogna, Frank Rauch, Peter Kamenický, Nobuaki Ito, Takuo Kubota, Akie Nakamura, Lin Zhang, Matt Mealiffe, Javier San Martin, Anthony A Portale
雑誌名: J Bone Miner Res. 2019 Dec;34(12):2183-2191. doi: 10.1002/jbmr.3843. Epub 2019 Oct 1.
Abstract/Text In adults with X-linked hypophosphatemia (XLH), excess FGF23 impairs renal phosphate reabsorption and suppresses production of 1,25-dihydroxyvitamin D, resulting in chronic hypophosphatemia and persistent osteomalacia. Osteomalacia is associated with poor bone quality causing atraumatic fractures, pseudofractures, delayed fracture healing, and bone pain. Burosumab is a fully human monoclonal antibody against FGF23. UX023-CL304 is an ongoing, open-label, single-arm, phase 3 study investigating the efficacy of subcutaneous burosumab, 1.0 mg/kg administered every 4 weeks, in improving osteomalacia in adults with XLH who have not been treated for at least 2 years before enrollment. The primary endpoint was improvement in osteoid volume/bone volume assessed by transiliac bone biopsies obtained at baseline and week 48. Additional assessments included serum phosphorus, markers of bone turnover, fracture/pseudofracture healing, and safety. Fourteen subjects enrolled, 13 completed 48 weeks, and 11 completed paired biopsies. All osteomalacia-related histomorphometric measures improved significantly at week 48 (mean percent change: osteoid volume/bone volume, -54%, osteoid thickness, -32%, osteoid surface/bone surface, -26%, [median] mineralization lag time, -83%). Mean serum phosphorus concentration averaged across the mid-point of the dose cycle between weeks 0 and 24 was 3.3 mg/dL, a 50% increase from 2.2 mg/dL at baseline. Markers of bone formation and resorption increased at week 48 (least squares [LS] mean increase: P1NP, +77%; CTx, +36%; both p < 0.0001). All subjects had one or more treatment-emergent adverse event (AE). Most AEs were mild to moderate in severity. Two subjects experienced serious AEs (migraine; paresthesia) that were unrelated to treatment and resolved. Eleven subjects had 18 biopsy procedure-related AEs: 14 for pain, two for itch, and one each for headache and bandage irritation. No deaths or incidents of hyperphosphatemia occurred. In conclusion, by normalizing phosphate homeostasis, burosumab significantly improved osteomalacia in adults with XLH, which likely explains the improved fracture healing and amelioration of skeletal complications. © 2019 The Authors. Journal of Bone and Mineral Research published by American Society for Bone and Mineral Research.

© 2019 The Authors. Journal of Bone and Mineral Research published by American Society for Bone and Mineral Research.
PMID 31369697  J Bone Miner Res. 2019 Dec;34(12):2183-2191. doi: 10.10・・・
著者: D Prié, F B Blanchet, M Essig, J P Jourdain, G Friedlander
雑誌名: J Am Soc Nephrol. 1998 Jul;9(7):1264-9.
Abstract/Text It has been shown that an acute infusion of dipyridamole increased renal phosphate reabsorption in rats and humans. A prospective study was performed to determine whether chronic treatment by dipyridamole given orally could decrease renal phosphate leak and increase serum phosphorus in patients with idiopathic low renal phosphate threshold (TmPO4/GFR < 0.77 mM). Sixty-four patients with low TmPO4/GFR were included and treated with dipyridamole (75 mg, 4 times daily) for more than 12 mo. Serum phosphorus, TmPO4/GFR, parathyroid hormone, serum calcium, and 1,25-dihydroxyvitamin D were measured sequentially before treatment, and after 3, 6 to 9, and 12 mo of treatment. Under chronic treatment with dipyridamole, TmPO4/GFR and serum phosphorus significantly increased in 80% of patients within 3 mo, with maximal values reached within 9 mo. This improvement persisted after 12 mo of treatment. In 28 patients, 1,25-dihydroxyvitamin D concentrations were above the normal range (> 42 pg/ml) and normalized in parallel with the increase of serum phosphorus. The 24-h calcium excretion (which was initially increased in patients with high vitamin D concentrations) and urolithiasis decreased under treatment. Ionized serum calcium and parathyroid hormone remained unchanged. After 2 yr, treatment was discontinued in three patients; serum phosphorus and TmPO4/GFR decreased within 1 mo after discontinuation. Dipyridamole at a dose of 75 mg 4 times daily increases low TmPO4/GFR and improves hypophosphatemia in patients with renal phosphate losses and can be used to treat these patients.

PMID 9644637  J Am Soc Nephrol. 1998 Jul;9(7):1264-9.
著者: M G Seikaly, R Quigley, M Baum
雑誌名: Pediatr Nephrol. 2000 Nov;15(1-2):57-9.
Abstract/Text X-linked hypophosphatemia (XLH) is characterized clinically by rickets, hypophosphatemia and hyperphosphaturia. Conventional treatment of XLH with oral phosphate and vitamin D is associated with hypercalcuria and nephrocalcinosis. Recently, intravenous and oral dipyridamole has been reported to decrease fractional excretion of phosphate in adults with idiopathic hyperphosphaturia. Our objective was to determine whether oral dipyridamole therapy reduces urinary phosphate excretion and increases serum phosphate concentration in children with XLH. A prospective study was performed in six children with XLH. The average age of the patients at the start of the study was 12.5+/-1.0 years. The effects of 12 weeks of oral dipyridamole therapy, at 4.4+/-0.4 mg/kg body weight per day, on serum phosphorous, parathyroid hormone (PTH), 1,25 (OH)2 vitamin D, osteocalcin, tubular maximum for phosphate reabsorption (TmP/GFR), urinary calcium excretion, and cyclic adenosine 3',5'-monophosphate (cAMP) excretion, were compared to baseline levels. Our results show that there was no change in serum phosphorous concentration or TmP/GFR after 12 weeks of dipyridamole therapy. Dipyridamole therapy also had no effect on serum PTH, serum 1,25 (OH)2 vitamin D, alkaline phosphatase, osteocalcin levels, urinary calcium or cAMP excretion. We therefore concluded that in children with XLH, a 12-week course of dipyridamole had no effect on serum phosphorous or its urinary excretion. Dipyridamole therapy is unlikely to improve the bone disease in children with XLH.

PMID 11095012  Pediatr Nephrol. 2000 Nov;15(1-2):57-9.
著者: M Balal, S Paydas, N Seyrek, Y Sertdemir, I Karayaylali
雑誌名: Clin Nephrol. 2005 Feb;63(2):87-91.
Abstract/Text AIM AND BACKGROUND: Hyphosphatemia can be seen in renal transplant recipients. Hyperparathyroidism, glucocorticoid treatment, renal denervation and impairment of renal tubular phosphate reabsorption are the most common causes of hyphosphatemia in these patients. It is well-known that dipyridamole enhances renal tubular phosphate reabsorption in some clinical conditions. We did not find any information about the effect of dipyridamole in renal transplant recipients (RTRs) with hypophosphatemia. For this reason, we decided to give dipyridamole 11 RTRs with hypophosphatemia.
PATIENTS AND METHODS: Eleven RTRs whose serum phosphate and creatinine levels were below 2.5 mg/dl and 2 mg/dl, respectively, were included in this study. None of the patients received drugs altering phosphate metabolism and they did not change their routine diets. Urinary phosphate excretion and tubular phosphate reabsorption (TPR) were calculated before and 3 weeks after dipyridamole treatment.
RESULTS: The mean levels of serum-urine (daily) phosphate and TPR before dipyridamole treatment were 1.94 +/- 0.46 mg/dl, 7,187.5 +/- 1,833.49 mg/day and -2.78 +/- 0.62, respectively. After treatment, the mean levels of serum-urine phosphate and TPR were 2.73 +/- 0.46 mg/dl, 4,845.27 +/- 1,138.99 mg/day and -1.48 +/- 0.80, respectively. Serum and urine phosphate levels and TPR were found to be significantly different before and after dipyridamole therapy (p < 0.05).
CONCLUSION: Short-term dipyridamole therapy increased TPR and serum phosphate levels and decreased urinary phosphate excretion. We did not observe negative effect on renal functions in these cases. Although the number of the cases included in this study is small, dipyridamole is an effective choice in management of hypophosphatemic RTRs.

PMID 15732176  Clin Nephrol. 2005 Feb;63(2):87-91.
著者: J N Fisher, A E Kitabchi
雑誌名: J Clin Endocrinol Metab. 1983 Jul;57(1):177-80. doi: 10.1210/jcem-57-1-177.
Abstract/Text The use of phosphate therapy in the management of diabetic ketoacidosis (DKA) has been controversial, particularly with respect to the effect of phosphate intermediates on tissue oxygenation. In a prospective randomized study we evaluated the effect of phosphate (8.5 mmol/h or approximately 6 g phosphate/24 h) (experimental group) vs. no phosphate therapy (control group) in 30 DKA patients, 15 in each group. Various determinations including erythrocyte 2,3-diphosphoglycerate (2,3-DPG), oxyhemoglobin dissociation (p50), serum phosphate, calcium, lactate, pyruvate, electrolytes, and response time to reach predetermined values for glucose, bicarbonate, and pH were measured at frequent intervals during the first 24 h of therapy and daily for 5 days after metabolic control. Initial electrolytes, glucose, pH, erythrocyte 2,3-DPG, lactate, and p50 were not different in either group. Whereas the experimental group had a greater level of 2,3-DPG than the control group by 48 h, the difference was not statistically significant. Recovery indices, including hours to reach glucose of 250 mg/dl, bicarbonate greater than 15 meq/liter, pH greater than 7.3, and mental alertness, were not different in the two groups nor were the p50 or lactate measurements. The experimental group exhibited significantly lower plasma ionized calcium values during therapy. We conclude that phosphate therapy may accelerate regeneration of erythrocyte 2,3-DPG but in the relatively small number of patients studied it had no demonstrable influence on tissue oxygenation or clinical response to low dose insulin therapy of DKA. Furthermore, the exaggeration of hypocalcemia seen in phosphate-treated patients may be reason for caution in the use of such therapy.

PMID 6406531  J Clin Endocrinol Metab. 1983 Jul;57(1):177-80. doi: 10・・・
著者: U Keller, W Berger
雑誌名: Diabetes. 1980 Feb;29(2):87-95.
Abstract/Text
PMID 6766411  Diabetes. 1980 Feb;29(2):87-95.
著者: H K Wilson, S P Keuer, A S Lea, A E Boyd, G Eknoyan
雑誌名: Arch Intern Med. 1982 Mar;142(3):517-20.
Abstract/Text To determine the efficacy of phosphate replacement in the therapy for diabetic ketoacidosis (DKA), 44 patients were randomly assigned to three treatment groups: those who received no phosphate replacement, those who received 15 mmole of sodium phosphate at the fourth hour, or those who received 15 mmole of sodium phosphate at 2, 6, and 10 hours. All patients were treated with intravenous insulin injection (0.1 units/kg/hr), fluids, and potassium. Four hours after a 15-mmole sodium phosphate infusion, the serum phosphate level was 2.8 +/- 0.8 mg/dL vs 2.1 +/- 0.8 mg/dL in the control patients; however, this dose was insufficient to maintain the serum phosphate level at 16 and 24 hours. Forty-five millimoles of phosphate prevented severe hypophosphatemia in all but one patient and produced substantially higher phosphate levels at 8, 16, and 24 hours. Phosphate therapy did not affect the duration of DKA, dose of insulin required to correct the acidosis, abnormal muscle enzyme levels, glucose disappearance, or morbidity and mortality. Although theoretically appealing, phosphate therapy is not an essential part of the therapy for DKA in most patients.

PMID 6802095  Arch Intern Med. 1982 Mar;142(3):517-20.
著者: M M Barsotti
雑誌名: Diabetes Care. 1980 Jul-Aug;3(4):569.
Abstract/Text
PMID 6780287  Diabetes Care. 1980 Jul-Aug;3(4):569.
著者: R A Kreisberg
雑誌名: Hosp Pract. 1977 Mar;12(3):121-8.
Abstract/Text Low serum phosphorus levels, sometimes associated with depletion of phosphorus stores, can engender a variety of serious, often life-threatening physiologic changes. The proximate cause of this dangerous situation is usually medical intervention in such conditions as alcoholism and diabetic ketoacidosis, which can produce a shift of phosphorus within the body unless preventive measures are instituted.

PMID 402311  Hosp Pract. 1977 Mar;12(3):121-8.

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