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.  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.
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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. 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.  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. 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.
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Clinic Rev Allerg Immunol (2011) 40:84–91
Curr Opin Rheumatol 2012, 24:669 – 676

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.  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.  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
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Clinic Rev Allerg Immunol (2011) 40:84–91

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. 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
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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. 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.
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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. 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
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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