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強皮症腎クリーゼ

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強皮症腎クリーゼ

  1. 1. Scleroderma Renal Crisis (SRC)  強皮症患者で生じる, 悪性高血圧と急性腎不全.  強皮症患者の5%で合併し, 主にDiffuse typeで生じる. 高血圧脳症や微小血管内溶血所見を伴う.  組織所見では血管内皮がタマネギの皮状の肥厚を示し, 発症機序としては腎血流障害が示唆されている. また, 血管の過敏性も認められており, “Renal Raynaud’s phenomenon”と呼ばれる急性の腎血管攣縮に伴う 血流低下も関与すると考えられている. 1 Clinic Rev Allerg Immunol (2011) 40:84–91
  2. 2.  SRCはそのような状態で, さらに腎血流が低下することが発症トリガーとなる.  敗血症や心不全, 脱水症等. また, 腎毒性を示す薬剤(NSAID)や, ステロイドもトリガーとなる.  PSL≥15mg/dの投与はSRC OR 4.37, SRCの60%が発症時にPSLを内服していたとの報告もある.  SRCの疫学  報告により様々. USAでは年間200-260例/100万,  アジアでは20-50例/100万, 西欧では100-200例/100万との報告がある.  SScの4-6%で合併し, 主にDiffuse SScで合併する. Limited cutaneous SScでは2%未満との報告がある. ACE阻害薬の内服にてさらに頻度は低下してきている. 2 Clinic Rev Allerg Immunol (2011) 40:84–91
  3. 3.  SSc患者におけるSRCのリスク因子 3 after 2 years, except for a subgroup with an initial skin score of about 40, whose scores remain high throughout Table 1 Risk factors for scleroderma renal crisis Diffuse skin involvement Rapid progression of skin involvement Disease duration <4 y Recent cardiac event: pericarditis, left ventricular insufficiency Recent onset of anemia Anti-RNA-polymerase III antibodies Treatment with >15 mg/d prednisone within the previous 3 months Treatment with cyclosporine within the previous 3 months Adapted from Steen [14] Curr Rheumatol Rep (2011) 13:37–43
  4. 4. SRCの臨床症状 Clinic Rev Allerg Immunol (2011) 40:84–91 Table 1 Main clinical and biological manifestations of scleroderma renal crisis Steen et al. [2] Walker et al. [6] DeMarco et al. [5] Penn et al. [8] Teixeira et al. [7] Number of patients 195 16 18 110 50 Age 50 54 45 51 53 Sex, % males 25 31 17 21 26 Symptoms <4 years, % 76 69 100 66 (<1an) 86 Diffuse SSc, % 83 100 100 78 86 Anti-topoisomerase 1 Abs, % 20 6 ND 17.2 32 Anticentromère Abs, % 1 ND ND 1.8 0 Hypertension, % 90 94 ND ND 88 Systolic/diastolic BP, mmHg 184/108 203/113 130/76 193/114 189/111 Pericarditis, % 53 ND ND ND 6 Left ventricular insufficiency, % 25 56 39 31 46 Arrythmia, % ND ND ND ND 18 Seizures, % 8 12 ND ND 10 Hypertensive encephalopathy, % ND ND ND ND 34 Intra-cerebral hemorrhage, % ND ND ND ND 10 Thrombotic microangiopathy, % 30 81 ND 59 46 Platelet count<150,000/mm3 , % 39 ND ND 50 ND Hematuria, % 38 ND ND ND 42a Proteinuria, % 63 (>0.25 g/j) ND ND ND 53 (>0.5 g/j) SSc systemic sclerosis, Abs antibodies, BP blood pressure, ND not documented a Hematuria documented with dip stick or urinalysis 86 Clinic Rev Allerg Immunol (2011) 40:84–91
  5. 5.  SRCの90%が発症時BP 150/90以上.  症状は高血圧性脳症, CHF, 不整脈が多い.  微小血管内血栓症は30-81%, タンパク尿は軽度なものを含めれば約半数で認められる.  頭蓋内出血や肺胞出血が致死的となり得る合併症.  Normotensive SRC (血圧正常SRC)  10%は高血圧を伴わないSRC.  大半がステロイド投与中の発症であり, 2/3が血栓性微小血管障害を伴い, 予後も悪い.  TTP-HUSとの鑑別が重要となり, 治療も異なる. ADAMTS-13活性が鑑別に有用の可能性がある. 5 Clinic Rev Allerg Immunol (2011) 40:84–91
  6. 6. SRCの所見  Creは血圧正常化した後も上昇し得る.  尿所見では軽度のタンパク尿(0.5-2.5g/L), Microscopic hematuria.  微小血管内溶血, PLT低下は43%で認められ, PLT低下は通常軽度 (5万を下回らない). 血圧正常化後には改善する.  抗核抗体陽性も多く認められる.  Anti-topoisomerase Ab(Scl-70)はSRCとは関連性無し.  Anti-RNA polymerase III Ab陽性例はSRCの9.4-59%  Anti-RNA polymerase III AbはDiffuse SScに関連する抗体.  Anti-RNA polymerase III Ab陽性 + ステロイド使用は25%でSRCを発症  一方で両者(-)ならば2%のみとの報告もある. 6 Clinic Rev Allerg Immunol (2011) 40:84–91 Curr Opin Rheumatol 2012, 24:669 – 676
  7. 7. SRC vs non-SRC SSc  Swedish systemic sclerosis cohortにおいて, 16例のSRCと112例のnon-SRC SSc症例を比較.  SRC例は11/16がDiffuse type, Anti-RNAP Absは7/16で陽性. Scand J Rheumatol 2012;41:39–43 Outcome Renal outcome was good in three patients with no need of dialysis. Dialysis was started in 13 patients: haemodialysis in 10 patients and peritoneal dialysis in three. In three patients the renal function improved and dialysis was terminated after 0.7, 0.9, and 1.9 years, respectively. Four patients underwent a renal transplantation 2.7, 3.6, 4.7, and 6.4 years, respectively, after the onset of SRC. In one case a living donor was used and in three cases a deceased donor. All patients received treatment by mycophenolate mofetil but in one patient the treatment was changed to azathioprine due to intolerance. In addition, one patient was treated with cyclosporin and three with tacrolimus. Only one patient differed in these tests: this was a female patient with SRC who was positive in the IP test but negative in the EliA test. However, her EliA titre was 12.5 μg/L, which was close to the cut-off of 15.0 μg/L. She was negative to antinuclear antibodies (ANA) and extractable nuclear antigen (ENA) and thus had neither centromeric antibodies nor Scl-70 antibodies. Risk factors Anti-RNAP Abs was a strong predictor of SRC (Table 2). The sensitivity and specificity for development of SRC were 0.44 and 0.92, respectively. Centromeric antibodies were protective for SRC (Table 2). Table 2. Serological features of cases and controls and odds ratios for SRC. Cases:controls SRC (n ¼ 16) SSc without SRC (n ¼ 112) OR (95% CI) p†yes:no yes:no Anti-centromere Abs 0:16 37:75 na 0.006 Anti-Scl-70 Abs 3:13 13:93 1.65 (0.41–6.58) 0.44 Anti-RNAP Abs 7:9 9:103 8.90 (2.68–29.6) 0.001 Male 6:10 16:96 3.60 (1.15–11.2) 0.033 dcSSc 11:5 21:91 9.53 (2.99–30.4) < 0.001 Prednisolone* 6:10 34:77 1.36 (0.46–4.04) 0.58 NSAID* 3:11 23:88 1.04 (0.27–4.05) 1.00 ACE inhibitor* 1:15 12:99 0.55 (0.067–4.54) 1.00 NSAID, non-steroidal anti-inflammatory drug; na, not applicable. *Treatment prior to the advent of SRC in cases and during the first year after diagnosis of SSc in the controls. † Fisher’s exact test.
  8. 8.  腎組織所見  典型例であれば腎生検は不要. 非典型例ならば腎生検でSRCかどうかの判断はつく.  生検する場合は血圧を正常化し, PLT低下がある場合は要注意.  微小血管の内皮の肥厚所見が典型的. タマネギ皮状変化が認められる. 小血管は問題ないことが多い. Clinic Rev Allerg Immunol (2011) 40:84–91 manifestation. However, anti-RNA polymerase III abs which have been detected almost exclusively in diffuse SSc identify patients at risk. Thirty-three percent of these patients will develop SRC [41]. Anti-RNA polymerase III abs are particularly useful in patient who have no skin involvement, notably in very early diffuse SSc. It is remarkable, that patients with anti-centromere abs have very rarely been reported to experience SRC. Renal pathology Renal biopsy is not necessary to confirm the diagnosis of SRC in classical forms. However, a number of research groups are performing systematic renal biopsy in order to better evaluate the prognosis of SRC [8]. In atypical clinical presentation, renal biopsy is mandatory to confirm the diagnosis of SRC. In all cases, renal biopsy will be performed after control of blood pressure. In case of severe thrombocytopenia, renal biopsy can be performed through jugular vein catheterism. In severe SRC, vascular occlusion and tissue ischemia may lead to grossly visible renal infarcts and subcapsular hemorrhages [42]. Characteristic changes in the arteries and arterioles are the pathologic hallmarks of SRC. Larger arteries appear normal or may reveal nonspecific changes, whereas small arteries and arterioles, especially in the interlobular and arcuate arteries, undergo severe changes. The characteristic pathologic lesion is mucoid intimal thickening with concentrically arranged myointimal cellular Juxtaglomerular hyperplasia may be documented, that is the consequence of the hyperrenemia that can be encoun- tered during SRC. Immunoglobulin and complement deposits may be detected in small arteries. However, it is important to keep in mind that many of these pathologic changes can also be observed in SSc patients who do not develop SRC or in patients experiencing malignant hyper- tension in the absence of SSc. Fig. 1 Masson green light trichrome: chronic injury in an interlobular artery with mucoid changes and endothélial prolifération. Magnifica- tion ×250 Fig. 4 Masson green light trichrome: glomerulus with thrombotic microangiopathy (fibrin in capillary lumens, preglomerular artérioles with thrombosis). Magnification ×100 Fig. 2 Jones staining: interlobular artery with mucoid changes and concentric intimal fibroplasia with so-called onion skinning changes, enlargement of the vascular diameter, perivascular fibrosis, and ischemic glomerulus. Magnification ×250 88 Clinic Rev Allerg Immunol (2011) 40:84–91
  9. 9.  血栓性微小血管障害を伴う糸球体  糸球体は虚血となる. 9 Fig. 4 Masson green light trichrome: glomerulus with thrombotic microangiopathy (fibrin in capillary lumens, preglomerular artérioles with thrombosis). Magnification ×100 y with mucoid changes and led onion skinning changes, perivascular fibrosis, and 0 Clinic Rev Allerg Immunol (2011) 40:84–91 Clinic Rev Allerg Immunol (2011) 40:84–91
  10. 10. 10 these characteristics should be followed very closely and monitor their blood pressure themselves in at least weekly intervals. A past history of hypertension, urinary abnormalities, increased serum creatinine, anti-topoisomerase 1, or anti- SRC almost always resulted in renal failure and death, usually within months. The use of ACEi dramatically improved the prognosis of SRC. Steen et al. identified risk factors that were associated with a bad outcome: male gender, older age, presence of congestive heart failure, Fig. 5 Jones staining: extensive réduplication of glomerular basse- ment membrane and mesangiolysis. Magnification ×400 Fig. 3 Masson green light trichrome. Focal necrosis of the vascular wall with fibrin deposit. And mucoid obstruction of an artériole. Magnification ×400 Clinic Rev Allerg Immunol (2011) 40:84–91
  11. 11. SRCの鑑別疾患  SSc患者の急性腎不全;  腎動脈閉塞や脱水症(SScに伴う腸管障害等), 不整脈, HFは  それそのものが腎不全を来たし, またSRCのトリガーにもなり,  鑑別が難しい.  また血管炎の合併(ANCA関連)もあり得るが,  その場合は血管内溶血や悪性高血圧は来さない.  NSAIDによる腎障害ではネフローゼ域のタンパク尿を来し得る. 11 Clinic Rev Allerg Immunol (2011) 40:84–91
  12. 12. 12 Copyright © Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited. Table 1. Spectrum and associations of renal complications in scleroderma Renal complication Associations Scleroderma renal crisis Rapidly progressive skin disease Tendon friction rubs Corticosteroid exposure (!15 mg per day in preceding 6 months) Anti-RNA polymerase III antibodies HLA-DRB1Ã 0407 HLA-DRB1Ã 1304 Normotensive renal crisis Prior use of ACEi and calcium channel blockers Myocardial involvement ANCA-associated glomerulonephritis MPO-ANCA Longstanding limited scleroderma Penicillamine-associated renal disease 20% of patients treated with D-Penicillamine Proteinuria and microalbuminuria Reported in 25% of scleroderma patients Isolated reduction in glomerular filtration rate Correlates with vasculopathic manifestations and prognosis in scleroderma ACEi, angiotensin-converting enzyme inhibitors; MPO-ANCA, myeloperoxidase-specific antineutrophil cytoplasmic antibodies. 670 www.co-rheumatology.com Volume 24 Number 6 November 2012SScに合併する腎障害 Curr Opin Rheumatol 2012, 24:669 – 676
  13. 13. SRCの治療  ACE阻害薬が最もアウトカムを改善させる.  ACE阻害薬は腎機能障害が進んでも継続すべき薬剤. 治療ゴールは直ちに血圧を安定化させること. ARBsも理論的には良いが, 臨床経験が未だ少ない.  Prostacyclinの持続投与も行われるが, 予後を改善させるという強いEvidenceは無し.  ACE阻害薬最大量でも血圧コントロール不良の場合に 他の降圧薬とともに考慮すべき薬剤.  血漿交換や免疫抑制剤もNo Evidence.  ステロイドはむしろ避けるべき薬剤と言える. 13 Clinic Rev Allerg Immunol (2011) 40:84–91
  14. 14.  血圧目標値は120/80以下.  ACE阻害薬は 2-3日で極量まで増量し,  他の降圧薬も必要ならば併用する Start captoprila between 6.25 and 12.5 mg three times daily, then increase until 50 mg three times daily Early dialysis in case of renal failure Early diffuse cutaneous systemic sclerosis with Continue captopril and maintain normal blood pressure (120–140/70–90 mm Hg) Weaning from dialysis in case of renal function improvement; otherwise, consider renal transplantation after 2 years on dialysis hypertension (diastolic blood pressure 100 mm Hg) If insufficient at 72 hours, add intravenous calcium channel blocker to captopril If insufficient, add minoxidil to calcium channel blocker and captopril and discuss early dialysis Fig. 1 Proposed treatment of hypertension occurring during the course of systemic sclerosis. a Or another angiotensin-converting enzyme inhibitor of relatively short half-life Curr Rheumatol Rep (2011) 13:37–43
  15. 15. SRCの予後  予後予測因子は以下の通り  尿所見やCr値は予後予測に関与しない.  予後は60%で良好.  透析となった患者も半数は2年間で離脱できる. 1年死亡率は15%, 5年死亡率は30-40% 15 serum creatinin greater than 3 mg/dl at the initiation of treatment, and a time period of more than 3 days to control blood pressure [4, 45]. Table 2 Risks factors of scleroderma renal crisis (from [2]) Rapid progression of skin involvement Disease duration 4 years Recent cardiac event Pericarditis Left ventricular insufficiency Recent onset anemia Anti-RNA polymerase III antibodies Treatment with 15 mg/d prednisone within the three preceding months Clinic Rev Allerg Immunol (2011) 40:84–91 Clinic Rev Allerg Immunol (2011) 40:84–91
  16. 16. 16 Table 3 Prognosis of scleroderma renal crisis Steen et al. [2] Walker et al. [6] DeMarco et al. [5] Penn et al. [8] Teixeira et al. [7] Number of patients 195 16 18 110 50 Dialysed patients, % 43 31 ND 64 56 Temporarily, % 23 6 ND 23 16 Permanently, % 19 25 ND 42 22 Deceased on dialysis, % ND ND ND 18 18 Deceased at 5 years, % 19a 31 50 41 31 ND not documented a Early deaths Clinic Rev Allerg Immunol (2011) 40:84–91

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