KDIGO慢性腎臟病礦物質(zhì)及骨代謝紊亂實踐指南,.,CKDdeath,心血管并發(fā)癥；其他并發(fā)癥,慢性腎臟病危險因素的篩查,減少CKD的危險因素;慢性腎臟病危險因素的篩查,診斷和治療;治療合并癥;延緩進(jìn)展,估計進(jìn)展;治療并發(fā)癥;準(zhǔn)備替代治療,透析替代治療或移植,正常人群,高危人群,腎衰竭,損傷, GFR,慢性腎臟病發(fā)生發(fā)展及干預(yù)的模式圖,Am J Kidney Dis 2003 ;42:1-202.,.,DOQI,KDIGO,K/DOQI,DialysisAnemiaAccess,Nutrition (00)Dialysis (01)*Anemia (01)*Access(01)*CKD class. (02)Bone/Mineral (03) Lipids (03)Htn (04)CV (05)Diabetes (07),Hep C (08)Bone/Mineral (09),1997,2005,*updates,/professionals/kdoqi,1999,/welcome.htm,.,內(nèi)容,第一章：引言、 CKDMBD的定義。第二章：研究方法第三章：CKD-MBD的診斷 第四章：CKDMBD的治療 第五章：腎移植骨病的評價和治療 第六章：小結(jié)及研究建議,.,建議和證據(jù)分級 (GRADE標(biāo)準(zhǔn)),.,升高FGF-23PTH血磷降低:活性維生素D血鈣,冠狀動脈鈣化主動脈鈣化異常鈣質(zhì)沉積,骨組織學(xué)異常礦化轉(zhuǎn)換容量骨密度減低,Moe S, et al. Kidney Int. 2006;69:1945-1953.KDIGO Overview slide presentation at: /pdf/KDIGO%20Overview%20Slide%20Set.ppt,慢性腎臟病礦物質(zhì)機(jī)骨代謝紊亂(CKD-MBD),.,CKD-MBD的定義：由腎功能下降引起的礦物質(zhì)和骨代謝異常的系統(tǒng)性病變?？捎校?.鈣、磷、PTH和維生素D代謝異常。2.骨的轉(zhuǎn)換、礦化、容量、線性生長或強(qiáng)度的異常。3.血管或其他軟組織的鈣化。,Moe S, et al. Kidney Int. 2006;69:1945-1953.,.,3.1章:CKD-MBD的診斷:生化異常,3.1.1我們推薦CKD3期開始監(jiān)測血清鈣、磷、PTH和堿性磷酸酶活性水平（1C）。3.1.2. 對于CKD3期-5D患者血清鈣、磷和PTH的監(jiān)測頻率，可以根據(jù)其檢測的異常及嚴(yán)重性以及CKD進(jìn)展的速度來決定（未分級）。,.,3.1.3. 在CKD3期5D的患者，我們建議檢測25羥維生素D (骨化二醇)水平，并根據(jù)基線水平和治療干預(yù)情況進(jìn)行重復(fù)檢測（2C）。我們建議采用對一般人群建議的方法糾正維生素D的缺乏和不足（2C）。3.1.5. 在CKD3期5D的患者，我們建議對個體的血清鈣和磷的水平共同評估，來指導(dǎo)臨床治療，而不以鈣磷乘積(Ca X P)這個數(shù)學(xué)計算的結(jié)果指導(dǎo)臨床(2D)。,.,CKD各期鈣、磷、PTH異常的發(fā)生率,Levin A, et al. Kidney Int. 2007;71:31-38.,100806040200,80 7970 6960 5950 4940 3930 2920 65 pg/mL,Patients (%),.,隨著CKD的進(jìn)展鈣和磷的變化,Martinez I, et al. Am J Kidney Dis. 1997;29:496-502.,*P 100 and CrCl 50-59, N = 157,.,1,25(OH)2D3的變化,Martinez et al. NDT 1996;11:22-28.,N=150,.,血清磷水平與全因及心血管死亡率from DOPPS,Am J Kidney Dis. 2008 Sep;52(3):519-30.,.,鈣、磷、PTH水平與死亡率 from DOPPS,Am J Kidney Dis. 2008 Sep;52(3):519-30.,.,Vitamin D 水平與血透病人的早期死亡率,*P0.05 for comparison of individual vitamin D levelvitamin D treatment groups with corresponding referent groups.Wolf M et al. Kidney International. Advance online publication, August 8, 2007.,Odds ratio ofall-cause mortality,25-hydroxyvitamin D (ng/mL),30,Odds ratio ofCV mortality,25-hydroxyvitamin D (ng/mL),30,Odds ratio ofall-cause mortality,1,25-dihydroxyvitamin D (pg/mL),13,Odds ratio ofCV mortality,1,25-dihydroxyvitamin D (pg/mL),13,*,*,*,R,R,R,*,*,*,*,*,*,.,堿性磷酸酶水平與死亡率,All-cause death hazard ratio,Alkaline phosphatase (U/I),50,5069.9,7089.9,90109.9,110129.9,130149.9,1550169.9,170189.9,190209.9,210,Frequency,Fixed co-variate modelwith baseline values,All-cause death hazard ratio,Time-dependent modelwith repeated measures,Alkaline phosphatase (U/I),50,5069.9,7089.9,90109.9,110129.9,130149.9,1550169.9,170189.9,190209.9,210,Kalantar-Zadeh K et al. Kidney Int. 2006;70:771-780.,.,Kidney International (2008) 74, 655663,.,3.2章：CKD-MBD的診斷：骨,3.2.1. 在CKD3期5D的患者，存在如下但不限于以下各種情況下，進(jìn)行骨活檢是合理的：不能解釋的骨折、持續(xù)骨痛、不能解釋的高鈣血癥、不能解釋的低磷血癥、可能的鋁中毒及CKD-MBD患者接受二膦酸鹽治療前（未分級）。3.2.2. 有CKD-MBD證據(jù)的CKD3期5D患者，我們不建議常規(guī)進(jìn)行BMD測定，因為不同于普通人群，BMD不能預(yù)測骨折風(fēng)險，而且BMD不能預(yù)測腎性骨營養(yǎng)不良的類型。3.2.3. 在CKD3期5D的患者，血清PTH或骨特異性堿性磷酸酶測定可用于評價骨病，因為其水平的顯著增高或降低能夠預(yù)測潛在的骨轉(zhuǎn)化水平（2B）。,.,Spectrum of Renal Osteodystrophy,鈣, Vitamin D,PTH,高轉(zhuǎn)換型,低轉(zhuǎn)換型,Normal bone formation,動力缺失型,骨軟化,Mild,纖維性骨炎,鋁,混合型骨病,300-400 pg/mL,Sherrard DJ, et al. Kidney Int. 1993;43:436-442.Wang M, et al. Am J Kidney Dis. 1995;26:836-844.,.,Classification of ROD,T M V,Turnover High Normal Low,Mineralization Normal Abnormal,Volume High Normal Low,Slide courtesy of Susan Ott,.,(OM, 骨軟化)、(AD, 無力型)、(OF,纖維性骨炎，高轉(zhuǎn)換型）、(MUO,混合型)、(mild HPT, 輕微甲旁亢相關(guān)型),Moe S, et al. Kidney Int. 2006;69:1945-1953.,根據(jù)骨的轉(zhuǎn)換(turnover,T)、礦化(mineralization,M)、容量(volume,V)對骨病進(jìn)行分級,.,橄欖球運動衫外觀帶,.,骨質(zhì)稀少,.,骨吸收,.,Hypercellularity of hyperparathyroidism (HPT)/renal osteodystrophy (ROD),High Bone Turnover (HPT),ROD ASA Acid Solochrome Azurin Positive Stain for Aluminum,Marrow fibrosis HPT/ROD,.,Kidney International (2006) 70, 13581366,骨折的發(fā)生率From DOPPS,.,PTH水平與骨折風(fēng)險,Coco M, Rush H. Am J Kidney Dis. 2000;36:1115-1121.,Fracture-free survival,PTH subgroups (pg/dL)501+196-50066-19565,Time (mo),.,堿性磷酸酶水平與骨折的Hazard ratios,0,0.5,1,1.5,2,2.5,3,1.0nAP1.4,nAPnAP,3.5,HR,U/L,Kidney International (2008) 74, 655663,.,3.3: CKDMBD的診斷：血管鈣化,3.3.1. 對于CKD 3期-5D患者，建議可以使用側(cè)位腹部X線片檢測是否存在血管鈣化，使用超聲心動圖檢測是否存在瓣膜鈣化，作為替代CT為基礎(chǔ)的成像檢查的合理選擇（2C）。3.3.2.建議將已知存在血管/瓣膜鈣化的CKD 3期-5D患者視為心血管的最高危人群（2A）。應(yīng)用這一信息指導(dǎo)CKD-MBD的治療是合理的（未分級）。,.,血管鈣化的機(jī)制,高磷血癥高鈣血癥Elevated Ca x P,骨代謝異常,基質(zhì)沉積,尿毒癥毒素,血管平滑肌細(xì)胞,成骨樣細(xì)胞,刺激因子Cbfa-1BMP-2,鈣化抑制因子的缺失Fetuin-AMatrix Gla Protein,血管鈣化,骨喪失了對鈣磷緩沖的能力,GRF下降,.,冠狀動脈鈣化與血透時間,Goodman WG et al. N Engl J Med. 2000;343:1478.,Proportion with calcification,Duration of dialysis (yrs),.,血管鈣化與死亡率,鈣化積分: 0,鈣化積分: 1,鈣化積分: 2,鈣化積分: 3,鈣化積分: 4,Probability of Survival,Duration of Follow-up (months),020406080,Blacher J et al. Hypertension. 2001;38:938.,1.00,0.75,0.00,0.25,0.50,Comparison between curves was highly significant (x2 = 42.66, P 0.0001),.,MV = 二尖瓣RCA = 右冠狀動脈LAD = 左前降支EBT = 電子束CT左側(cè) = 單層右側(cè) = 多層,電子束CT,.,動靜脈內(nèi)瘺(AVF),CT,MSCT,.,DSA,平片,.,X-線平片椎旁動脈鈣化積分,Abdominal Aorta calcification were measured by Plain X-Ray film via the Kauppilas method(Kauppila et al Atherosclerosis 1997;132:235-240),Raggi et al. Kidney International 2007,.,指南將超聲評價瓣膜鈣化的地位提升,Bi-dimensional echocardiographic studies were performed utilizing Sequoia 512 (Siemens, Erlangen, Germany) or Vivid 7 (General Electric, Milwaukee, WI) equipment. Aortic and mitral valve calcification were simply assessed as present or absent without applying any quantification method,Raggi et al. Kidney International 2007,.,脈搏波速度（Pulse Wave Analysis）,P2,P1,AG,PP,TR,Incisura,TF,AIx = AG/PP,TR,.,4.1章:CKDMBD的治療目標(biāo)為降低高血磷和維持血鈣,4.1.1. CKD 3-5期患者，建議血清磷維持在正常范圍（2C）。對CKD 5D患者建議將升高的血磷降至正常范圍（2C）。4.1.4. 透析（2B）患者，建議使用磷結(jié)合劑治療高磷血癥。4.1.5. CKD 3期-5D伴高磷血癥患者，如果存在持續(xù)或反復(fù)的高鈣血癥，動脈鈣化（2C）和/或動力缺失性骨?。?C）和/或持續(xù)低血清PTH（2C），應(yīng)限制含鈣的磷結(jié)合劑劑量和/或骨化三醇或維生素D類似物的劑量（1B）。4.1.8.治療CKD 5D患者存在的持續(xù)性高磷血癥時，建議增加透析對磷的清除（2C）。,.,不同類型的磷結(jié)合劑的比較,Cannata-Andia JB. Nephrol Dial Trans. 2002;17(Suppl 11):1619.Ritz EJ. J Nephrol. 2005;18;221-228.Goodman WG. Neph Dial Trans. 2003;18(Suppl 3):iii2-iii8.,.,Ca,PO4,PTH,磷結(jié)合劑,(含鈣的),含鈣的磷結(jié)合劑有升高血鈣的風(fēng)險,.,Hypercalcemia 10.5 mg/dL (2.63 mmol/L),Percentage of Patients,Study Week,-2,0,3,6,9,12,16,20,24,28,32,36,40,44,48,52,0,5,10,15,20,25,Sevelamer與鈣劑比高鈣血癥的發(fā)生率低,Kidney Int. 2002;62:245-252.,.,碳酸鑭（Lanthanum）,Hutchison AJ, et al. Nephron Clin Pract. 2006;102:c61-c71.,Ca x P decreased,Serum phosphate decreased,0,50,100,150,200,0,49,75,101,128,154,0,1,2,3,4,5,6,7,n,Ca x P (mM2),Weeks,10.0,9.0,8.0,7.0,5.0,4.0,2.0,0.0,0,1,2,3,4,5,9,13,17,21,25,29,33,37,41,45,49,Modal use of lanthanum carbonate: 1,500 mg/day,Modal use of calcium carbonate: 3,000 mg/day,Weeks on Treatment,Serum phosphate (mg/dL),Continued-lanthanum group,Calcium group,Switch group (calcium to lanthanum),Comparator-controlled trial,6.0,3.0,1.0,.,4.2章:異常PTH水平的治療,4.2.1. CKD 3-5期非透析患者的最佳PTH水平尚不清楚。然而，我們建議對于全段甲狀旁腺激素（iPTH）水平超過正常上限的患者，應(yīng)首先評價高磷血癥、低鈣血癥和維生素D缺乏的情況（2C）。4.2.2. CKD 3-5期非透析患者在糾正了可變因素后，血清PTH仍進(jìn)行性升高及持續(xù)高于正常值上限，建議給予骨化三醇或維生素D類似物治療（2C）。4.2.3. 建議血透患者的iPTH水平維持于正常值高限的大約二到九倍（2C）。4.2.4. 透析伴PTH升高的患者，建議給予骨化三醇或維生素D類似物，或聯(lián)合應(yīng)用鈣敏感受體激動劑,以降低PTH水平（2B） 對于高鈣血癥的患者，推薦減量或停用骨化三醇或其他維生素D制劑（1B）。4.2.5. CKD 3-5D期伴嚴(yán)重甲狀旁腺功能亢進(jìn)患者藥物治療無效時，建議行甲狀旁腺切除（2B）。,.,不同指南的鈣、磷、PTH在CKD-5期的目標(biāo)值,Am J Kidney Dis. 2008 Sep;52(3):519-30.,.,PTH目標(biāo)值難定的原因,1.CKD病人的橫斷面研究顯示iPTH的中位數(shù)及范圍會隨著CKD的進(jìn)展而增大。2.目前iPTH的測定方法還存在差異（放射免疫發(fā)光法、化學(xué)免疫發(fā)光法、雙位點免疫放射法），在標(biāo)準(zhǔn)化上還存在一定的困難。3.隨著腎功能的下降，骨骼對PTH抵抗。4.目前仍缺乏CKD病人的隨機(jī)對照（RCTs）研究以證實降低PTH水平可改善臨床預(yù)后以及對這些措施的副作用做充分的描述。,Kidney International 2009; 76: 1130.,.,Normal,Secretory Cells,Early Nodularity,Diffuse Hyperplasia,Nodular,Adapted from Rodriguez M, et al. Am J Physiol Renal Physiol. 2005;288:F253-F265.,Decreased VDR and CaSR,甲狀旁腺在CKD進(jìn)程中的變化,.,治療甲旁亢的靶點,PTH 分泌 鈣敏感受體激動劑（Cinacalcet）PTH 合成 Vitamin D, Cinacalcet甲狀旁腺增生 甲狀旁腺切除術(shù)（PTX）礦物質(zhì)代謝 飲食、補(bǔ)鈣、磷結(jié)合劑,National Kidney Foundation. KDOQI clinical practice guidelines for chronic kidney disease: evaluation, classifcation, and stratification. Am J Kidney Dis. 2002;39(Suppl 1):S1-S266.,.,49,49,Vitamin D的利與弊,PTH reduction,Ca homeostasis,Hypercalcaemia,Hyperphosphataemia,Vascular calcification,.,0,1,2,3,6.0,5.8,5.6,5.4,5.2,5.0,4.6,4.8,Mean P (mg/dL) (95% CI),Phosphorus,Months After Initiation of IV Vitamin D,Calcitriol (n = 2,667),Paricalcitol(n = 1,697),Doxercalciferol(n = 2,010),Tentori F, et al. Kidney Int. 2006;70:1858-1865.,0,1,2,3,400,350,300,250,200,150,100,Mean iPTH (pg/mL) (95% CI),0,1,2,3,9.6,9.4,9.2,9.0,8.8,8.2,8.0,8.6,8.4,Mean Ca (mg