今日の臨床サポート

高りん血症

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:2020/05/21

概要・推奨   

  1. 非CKD患者においても、高P血症は心血管イベントの発症と関連する可能性がある(推奨度2)
  1. リン酸水素Na・リン酸二水素Na配合錠(ビジクリア)を使用する際には、急性リン酸腎症の発症に注意する(推奨度2)
  1. 新たな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)
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. 定期レビューを行い、慢性高P血症の治療薬に関し加筆した。

病態・疫学・診察

疫学情報・病態・注意事項  
  1. 高りん(P)血症は、血清P濃度が基準値を超過する場合を指し、一般に基準値は2.5~4.5mg/dl程度とされている。
  1. 健常人では1日りん(P)摂取量が4,000mg(130mmol)までは血清P値の上昇を認めず、これを超えてもわずかに上昇するのみである。
  1. 高P血症を来す機序として、①大量Pの急性負荷、②慢性腎不全、③近位尿細管でのP再吸収の増加が挙げられる。
  1. 実臨床にて遭遇する高P血症の原因として、慢性腎臓病に伴う骨・ミネラル代謝異常(CKD-MBD)が最も多い。慢性腎臓病では早期の段階からP蓄積傾向を示すが、当初血清P値は上昇せず、GFR(糸球体濾過量)が25~40ml/分以下に低下した場合に初めて高P血症が顕在化するとされている[1][2](慢性腎臓病を原因とする低Ca血症(CKD-MBD)の詳細は、“ 低カルシウム血症 ”を参照)。
 
  1. 非CKD患者においても、高P血症は心血管イベントの発症と関連する可能性がある(推奨度2O
  1. 近年、慢性腎臓病(CKD)に伴う骨ミネラル代謝異常が骨病変だけではなく、血管石灰化をはじめとした異所性石灰化を介して生命予後やQOLに大きな影響を及ぼすことが明らかとなり、CKD-MBD(CKD-mineral and bone disorder)という疾患概念が提唱された。このCKD-MBDにおける骨ミネラル代謝異常のなかでも、高P血症は心血管イベントの発症や生命予後に強く影響を与える因子であることが報告されている[3][4](詳細は 低カルシウム血症 を参照)。
  1. さらに、血清P値と心血管イベントの発症との関連性が非CKD患者においても成立することが、3,000人以上を対象とした大規模観察研究において示されている[5]。この研究で注目すべきは、腎機能正常で血清P値が正常値内であっても、正常高値で心血管イベントが増加するという点である。血清P値が体内総P量のよい指標ではないことから、たとえ血清P値が正常範囲でも体内総P値がすでに上昇している可能性が示唆される。
問診・診察のポイント  
  1. 薬剤歴:活性型ビタミンD製剤、P含有製剤(特に、大腸鏡の前処置に使用されるリン酸水素Na・リン酸二水素Na配合錠[ビジクリア])、ビスホスホネート製剤

今なら12か月分の料金で14ヶ月利用できます(個人契約、期間限定キャンペーン)

11月30日(火)までにお申込みいただくと、
通常12ヵ月の使用期間が2ヶ月延長となり、14ヵ月ご利用いただけるようになります。

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文献 

著者: J A Delmez, E Slatopolsky
雑誌名: Am J Kidney Dis. 1992 Apr;19(4):303-17.
Abstract/Text Control of phosphorus accumulation in chronic renal insufficiency is crucial to the prevention of secondary hyperparathyroidism and metastatic calcification. In early renal failure, calcitriol levels are normal and parathyroid hormone levels are elevated. The phosphorus levels are maintained in the normal range by the phosphaturia induced by hyperparathyroidism. In this situation, dietary phosphorus restriction increases calcitriol levels and suppresses parathyroid hormone secretion. As renal failure progresses into late stages, hyperphosphatemia is evident along with low levels of calcitriol and worsening hyperparathyroidism. Phosphorus restriction will not affect calcitriol concentrations, yet parathyroid levels may decline. During long-term dialysis, urinary excretion of phosphorus is usually minimal. Therefore, phosphorus balance is determined primarily by the net amount absorbed by the bowel and the quantity removed during dialytic therapy. Given an adequate diet, no form of conventional dialysis is able to fully compensate for the gastrointestinal absorption of phosphorus. Hence, compounds that bind phosphorus in the bowel are often necessary. With the realization that the use of phosphorus binders containing aluminum leads to aluminum accumulation and its sequelae: osteomalacia, dementia, myopathy, and anemia, other phosphorus binders have been evaluated. Calcium carbonate has been investigated the most thoroughly and is in wide use. It is inexpensive and contains a high percent of elemental calcium. However, it is only modestly potent in the binding of phosphorus, and large doses are often necessary to attain satisfactory control of phosphorus. This may lead to hypercalcemia. One approach to this problem is to decrease the concentration of calcium in the dialysate. Alternatively, a more effective phosphorus binder may be used. Calcium acetate has been shown in acute studies to have twice the binding capacity of phosphorus per calcium absorbed than calcium carbonate. Whether use of this compound decreases the incidence of hypercalcemia is unproven. Calcium citrate increases the gastrointestinal absorption of aluminum and offers no advantage over calcium carbonate. Other compounds, such as calcium ketoacids and calcium alginate, have not been extensively studied and are not generally available. The use of phosphorus binders containing magnesium in conjunction with a dialysate low in magnesium may be efficacious. Large doses of magnesium will cause diarrhea and thus limit its use as a single agent. Reasons for failure to control hyperphosphatemia include poor compliance, improper prescription of binders, poor dissolution rates seen with some generic brands of calcium carbonate, and the presence of severe hyperparathyroidism. Optimal control of serum phosphorus in dialysis patients should always be viewed in the context of adequate nutrition and protein intake.

PMID 1562018  Am J Kidney Dis. 1992 Apr;19(4):303-17.
著者: A Levin, G L Bakris, M Molitch, M Smulders, J Tian, L A Williams, D L Andress
雑誌名: Kidney Int. 2007 Jan;71(1):31-8. doi: 10.1038/sj.ki.5002009. Epub 2006 Nov 8.
Abstract/Text Abnormalities of mineral metabolism occur early in chronic kidney disease. Quantification of the prevalence of these abnormalities has not been described using current assays nor in large unselected populations. This outpatient cohort cross-sectional study was conducted in 153 centers, (71% primary care practices). Blood for parathyroid hormone (PTH), vitamin D metabolites, creatinine, calcium (Ca), and phosphorus (P) were drawn between June and October 2004. Low 1,25-dihydroxyvitamin D (1,25 OH2 D3) was defined as <22 pg/ml. The 1814 patients had a mean age of 71.1 years old; 48% had diabetes mellitus (DM). Low 1,25 OH2 D3 was evident at all estimated glomerular filtration rate (eGFR) levels: 13% in those with eGFR >80 ml/min, >60% in those with eGFR <30 ml/min. High PTH (>65pm/dl) occurred in 12% with eGFR >80 ml/min. Serum Ca and P were normal until eGFR was <40 ml/min. Significant differences in the mean and median values of 1,25 OH2 D3, PTH, but not 25(OH)D3 levels, were seen across deciles of eGFR (P<0.001). Multivariate analysis revealed that DM, increased urinary albumin/creatinine ratio and lower eGFR predicted lower values of 1,25 OH2 D3. A high prevalence of mineral metabolite abnormalities occurs in a large unreferred US cohort. Low 1,25 OH2 D3 and elevated PTH are common at higher eGFR than previously described. As bone, cardiovascular disease, and mineral metabolite are correlated; further studies are necessary to determine the importance of these findings relative to outcomes.

PMID 17091124  Kidney Int. 2007 Jan;71(1):31-8. doi: 10.1038/sj.ki.500・・・
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: 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: Ravi Dhingra, Lisa M Sullivan, Caroline S Fox, Thomas J Wang, Ralph B D'Agostino, J Michael Gaziano, Ramachandran S Vasan
雑誌名: Arch Intern Med. 2007 May 14;167(9):879-85. doi: 10.1001/archinte.167.9.879.
Abstract/Text BACKGROUND: Higher levels of serum phosphorus and the calcium-phosphorus product are associated with increased mortality from cardiovascular disease (CVD) in patients with chronic kidney disease (CKD) or prior CVD. However, it is unknown if serum phosphorus levels influence vascular risk in individuals without CKD or CVD.
METHODS: We prospectively evaluated 3368 Framingham Offspring study participants (mean age, 44 years; 51% were women) free of CVD and CKD. We used multivariable Cox models to relate serum phosphorus and calcium levels to CVD incidence.
RESULTS: On follow-up (mean duration, 16.1 years), there were 524 incident CVD events (159 in women). In multivariable analyses and adjusting for established risk factors and additionally for glomerular filtration rate and for hemoglobin, serum albumin, proteinuria, and C-reactive protein levels, a higher level of serum phosphorus was associated with an increased CVD risk in a continuous fashion (adjusted hazard ratio per increment of milligrams per deciliter, 1.31; 95% confidence interval, 1.05-1.63; P=.02; P value for trend across quartiles = .004). Individuals in the highest serum phosphorus quartile experienced a multivariable-adjusted 1.55-fold CVD risk (95% confidence interval, 1.16%-2.07%; P=.004) compared with those in the lowest quartile. These findings remained robust in time-dependent models that updated CVD risk factors every 4 years and in analyses restricted to individuals without proteinuria and an estimated glomerular filtration rate greater than 90 mL/min per 1.73 m(2). Serum calcium was not related to CVD risk.
CONCLUSION: Higher serum phosphorus levels are associated with an increased CVD risk in individuals free of CKD and CVD in the community. These observations emphasize the need for additional research to elucidate the potential link between phosphorus homeostasis and vascular risk.

PMID 17502528  Arch Intern Med. 2007 May 14;167(9):879-85. doi: 10.100・・・
著者: L A Hebert, J Lemann, J R Petersen, E J Lennon
雑誌名: J Clin Invest. 1966 Dec;45(12):1886-94. doi: 10.1172/JCI105493.
Abstract/Text
PMID 5953818  J Clin Invest. 1966 Dec;45(12):1886-94. doi: 10.1172/JC・・・
著者: Stefan Russmann, Lois Lamerato, Stephen P Motsko, John C Pezzullo, Mark D Faber, Judith K Jones
雑誌名: Am J Gastroenterol. 2008 Nov;103(11):2707-16. doi: 10.1111/j.1572-0241.2008.02201.x. Epub 2008 Oct 17.
Abstract/Text OBJECTIVES: The aim of this study was to estimate the risk of further creatinine increase in patients with preexisting renal disease after the use of oral sodium phosphate (OSP) versus polyethylene glycol (PEG), and to study usage patterns of OSP in relation to renal function.
METHODS: A cohort study was done using clinical records and electronic patient information from the Henry Ford Health System (HFHS) in patients who had used either OSP or PEG for colonoscopy between February 1999 and April 2006. Among patients with an estimated GFR < 60 ml/min before colonoscopy, we identified cases with an unexplained creatinine increase of > or = 0.5 mg/dl within 14 days after colonoscopy.
RESULTS: We identified 7,971 OSP and 1,511 PEG users. Relative use of OSP versus PEG decreased from 88.0% before 2004 to 48.4% in 2006. 70.2% of OSP users had no recorded creatinine determination within 60 days before colonoscopy, and this proportion did not decrease over time. The study population included 317 patients with a baseline GFR < 60 ml/min, and we identified one case with an unexplained creatinine increase > or = 0.5 mg/dl among 191 PEG users (0.5%) versus eight cases among 126 OSP users (6.3%). Unadjusted and adjusted relative risk estimates on comparing OSP with PEG were 12.1 (95% CI, 1.5-95.8) and 12.6 (95% CI, 1.5-106.5), respectively.
CONCLUSIONS: In patients with preexisting renal disease, OSP use was associated with an increased risk of aggravated renal dysfunction versus PEG. Creatinine measurement with GFR estimation should be done before OSP administration in order to avoid its use in patients with renal disease.

PMID 18945285  Am J Gastroenterol. 2008 Nov;103(11):2707-16. doi: 10.1・・・
著者: Glen S Markowitz, M Barry Stokes, Jai Radhakrishnan, Vivette D D'Agati
雑誌名: J Am Soc Nephrol. 2005 Nov;16(11):3389-96. doi: 10.1681/ASN.2005050496. Epub 2005 Sep 28.
Abstract/Text The findings of diffuse tubular injury with abundant tubular calcium phosphate deposits on renal biopsy are referred to as nephrocalcinosis, a condition typically associated with hypercalcemia. During the period from 2000 to 2004, 31 cases of nephrocalcinosis were identified among the 7349 native renal biopsies processed at Columbia University. Among the 31 patients, 21 presented with acute renal failure (ARF), were normocalcemic, and had a history of recent colonoscopy preceded by bowel cleansing with oral sodium phosphate solution (OSPS) or Visicol. Because the precipitant was OSPS rather than hypercalcemia, these cases are best termed acute phosphate nephropathy. The cohort of 21 patients with APhN was predominantly female (81.0%) and white (81.0%), with a mean age of 64.0 yr. Sixteen of the 21 patients had a history of hypertension, 14 (87.5%) of whom were receiving an angiotensin-converting enzyme inhibitor or angiotensin receptor blocker. The mean baseline serum creatinine was 1.0 mg/dl, available within 4 mo of colonoscopy in 19 (90.5%) patients. Patients presented with ARF and a mean creatinine of 3.9 mg/dl at a median of 1 mo after colonoscopy. In a few patients, ARF was discovered within 3 d of colonoscopy, at which time hyperphosphatemia was documented. Patients had minimal proteinuria, normocalcemia, and bland urinary sediment. At follow-up (mean 16.7 mo), four patients had gone on to require permanent hemodialysis. The remaining 17 patients all have developed chronic renal insufficiency (mean serum creatinine, 2.4 mg/dl). Acute phosphate nephropathy is an underrecognized cause of acute and chronic renal failure. Potential etiologic factors include inadequate hydration (while receiving OSPS), increased patient age, a history of hypertension, and concurrent use of an angiotensin-converting enzyme inhibitor or angiotensin receptor blocker.

PMID 16192415  J Am Soc Nephrol. 2005 Nov;16(11):3389-96. doi: 10.1681・・・
著者: Y Gumurdulu, E Serin, B Ozer, A Gokcel, S Boyacioglu
雑誌名: J Gastroenterol Hepatol. 2004 Jan;19(1):68-72.
Abstract/Text BACKGROUND AND AIM: It has been reported that oral phosphosoda (OPS), commonly used in bowel cleansing, may cause complications such as hyperphosphatemia and hypocalcemia. This has been observed in patients with normal kidney function and in those with renal insufficiency. Few controlled studies have been performed with respect to age on healthy subjects after OPS administration.
METHODS: Seventy patients (38 men and 32 women; mean age 47 +/- 12 years, range 25-80 years) were enrolled in the present study. Half of the 90 mL total volume of OPS was ingested 18 h before colonoscopy, and the other half 6 h before the procedure. Creatinine clearance rate (CCR) and serum levels of sodium, potassium, calcium and phosphate were measured before and after OPS administration.
RESULTS: After OPS administration, serum calcium and potassium were significantly lower (P < 0.05), and serum phosphate and sodium were significantly higher than pretreatment levels (P < or = 0.01). The statistically significant changes in serum sodium, potassium and calcium were within normal laboratory ranges. The mean change in serum phosphate was positively correlated with age (Pearson's r = 0.705; p < 0.001).
CONCLUSION: Administration of OPS causes a significant rise in serum phosphate, even in patients with normal CCR. The elevation is significantly greater in elderly patients. Administration of OPS can be considered safe for young and middle-aged patients with normal renal function; however, it should be used with caution in elderly patients, even in those with normal CCR and serum creatinine values.

PMID 14675245  J Gastroenterol Hepatol. 2004 Jan;19(1):68-72.
著者: E J Ainley, P J Winwood, J P Begley
雑誌名: Dig Dis Sci. 2005 Jul;50(7):1319-23.
Abstract/Text Our purpose was to observe the effects of sodium phosphate (NaP) colonoscopy preparation on serum electrolytes, phosphate, and calcium and to identify factors associated with any adverse effects. In an unselected group of 100 consecutive patients attending for out patient colonoscopy, 45% of patients had raised serum phosphate, which was positively correlated with creatinine and age. There was a negative association of phosphate with calcium; 16% of patients had hypocalcemia and 26% had hypokalemia. Patients taking ACE inhibitors, AT2 antagonists, or diuretics were associated with hyperphosphatemia. Significant electrolyte and metabolic disturbance from colonoscopy preparation has been shown with NaP preparation, without overt clinical effects. We recommend that elderly patients and those with significant comorbidity have their electrolytes and calcium measured, and diuretics and ACE inhibitors stopped, before NaP administration. Endoscopy units should be alert for patients who might be suffering from electrolyte disturbance postpreparation and be prepared to measure their electrolytes.

PMID 16047480  Dig Dis Sci. 2005 Jul;50(7):1319-23.
著者: R J Walton, O L Bijvoet
雑誌名: Lancet. 1975 Aug 16;2(7929):309-10.
Abstract/Text
PMID 50513  Lancet. 1975 Aug 16;2(7929):309-10.
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・・・

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