1. Scleroderma Renal Crisis
Mathini Jayaballa
Renal Advanced Trainee

2. Scleroderma Overview Uncommon F>M, peak onset 3rd - 5th decade
Uncontrolled accumulation of collagen and other CT proteins which leads to fibrosis in the skin and other visceral organs
Widespread vascular lesions
Classification
Localised Scleroderma
Systemic Scleroderma – Limited and Diffuse

3. Scleroderma Renal Crisis
Renal involvement 50%, usually mild:
proteinuria
mild elevation in Cr HT
Severe renal disease 10-20%
diffuse cutaneous SSc >> LcSSc

4. Clinical Features of Scleroderma Renal Crisis (SRC):
Occurs early – within 5 yrs
Can be the initial presentation
SRC:
Progressive ARF
Abrupt onset mod-severe HTN
Urine sediment – usually bland

5. Normal Renal Biopsy (H&E stain)

6. Figure 77-7 Histologic appearance of scleroderma renal crisis
Figure 77-7  Histologic appearance of scleroderma renal crisis. A and B, Typical histologic features are present, including interstitial fibrosis (A), occlusion of intrarenal arteries with neointima formation, fibrinoid necrosis of the vessel wall, and reduplication of the internal elastic lamina (B). C, The glomeruli are shrunken and lack inflammatory cells or proliferative changes. D, In severe cases, there is evidence of intravascular thrombosis resembling the changes of thrombotic thrombocytopenic purpura.
The renal sample contained 14 glomeruli, two of which were globally sclerotic (arrow).
The other glomeruli  showed a shrinking of the glomerular tuft, which caused an apparent increase of the Bowman’s space (arrows), and lack inflammatory cells. Between the two glomeruli you can see a small artery, which shows a thickening of the media and a narrowing of the lumen (arrowhead).
In addition, there was interstitial fibrosis, which in some areas was more prominent than in others.
The lesions shown till now are all consistent with the diagnosis of  nephrosclerosis secondary to arterial hypertension.
However, when a subarcuate artery was examined, it was noted that besides a proliferation of the media there also was a proliferation of the intima (arrows).
This lesion, together with the clinical findings and mild urinary changes led us to the diagnosis of progressive systemic sclerosis (PSS).
In cases of PSS other possible renal lesions, such as fibrinoid necrosis, thrombosis in the arterioles and in the glomeruli can be present.
SRC Renal Biopsy

7. Renal Angiogram Normal SRC
Lost of end arterioles in a pruned-tree pattern

8. Risk Factors for SRC Diffuse or advancing skin involvement
Glucocorticoid >15mg/day
Large joint contractures
New cardiac conditions
New onset anemia
Anti-RNA polymerase or fine speckled ANA pattern
Decreased prevalence of anti-centromere Ab

9. Characteristic Findings
New onset BP > 150/85
Decline in renal function
New proteinuria +/- hematuria
Retinal changes of malignant hypertension
Flash pulmonary edema
MAHA +/- thrombocytopenia
CNS involvement - seizures

10. Differentials: TTP/HUS ANCA-associated crescentic GN
D-penicillamine-related GN

11. SRC Management Untreated  ESKD 1-2mths, death in 1 yr
Prompt & aggressive BP control is mainstay of Rx
reduce BP <72hrs
ACE-I is 1st choice
Better renal function recovery & improves survival
Resistant / Malignant HTN – Add IV agent
Long term, low-dose ACE-I even if BP controlled
10% normotensive
Steen Ann Intern Med 1990; 113:352.
Helfrich DJ, Arthritis Rheum 1989; 32:1128.

12. SRC Progress 20-50% progress to ESKD despite ACE-I
Inferior 5YS DSSc on dialysis:
40% with SRC
90% w/out SRC
Survival SSc on dialysis is worse than others
Delayed renal recovery possible
can take up to 18m
Penn H, QJM 2007; 100:485.
Abbott KC, J Nephrol 2002; 15:236.

13. Transplantation Better survival cf dialysis 3YS 80% vs 55%
Total
SSc
Dialysis
14,010 33 Tx
4,254 8
Better survival cf dialysis
3YS 80% vs 55%
Worse survival than other primary diseases
Risk factors for recurrence/damage to allograft:
progressive skin thickening
new onset anemia
cardiac complications
Strategies to reduce recurrent disease
Avoid CNI, high dose steroids
Continue ACE-I indefinitely
Incident patients ANZ (ANZDATA)
Gibney Am J Transplant 2004; 4:2027.

14. Imatinib in Systemic Sclerosis
A protein tyrosine kinase inhibitor
Interferes with the signaling PDGF, TGF-β
Limited data on use in SSc or its effect on renal function
PDGF
Impaired angiogenesis / cell division

15. Imatinib in Systemic Sclerosis
Case Report - Rx of refractory DcSSc
Improvement in skin thickening, physical function, FVC
Within 3m, maintained at 9m
Spiera et al - open-label prospective study
30 patients with DcSSc, no controls
Improvement in skin thickening, FVC after 12m
Pope et al – double-blind RCT, proof-of-concept pilot study
Single center, active DcSSc
Only 10 pts enrolled
Early termination: poor tolerability, AE++
No benefit in skin thickening, CRP/ESR, global assessment at 6m
Sfikakis PP, Rheumatology (2008) 47 (5): 
Spiera RF, Ann Rheum Dis 2011; 70:1003.

16. Take home messages about SRC:
Rare but high M&M
Mainstay of Rx is BP control with ACE-I
High rate of progression to ESKD
Delayed renal recovery possible
Renal transplant should be considered

17. References
Steen VD, Costantino JP, Shapiro AP, Medsger TA Jr. Outcome of renal crisis in systemic sclerosis: relation to availability of angiotensin converting enzyme (ACE) inhibitors. Ann Intern Med 1990; 113:352.
Helfrich DJ, Banner B, Steen VD, Medsger TA Jr. Normotensive renal failure in systemic sclerosis. Arthritis Rheum 1989; 32:1128.
Penn H, Howie AJ, Kingdon EJ, et al. Scleroderma renal crisis: patient characteristics and long-term outcomes. QJM 2007; 100:485.
Abbott KC, Trespalacios FC, Welch PG, Agodoa LY. Scleroderma at end stage renal disease in the United States: patient characteristics and survival. J Nephrol 2002; 15:236.
Gibney EM, Parikh CR, Jani A, et al. Kidney transplantation for systemic sclerosis improves survival and may modulate disease activity. Am J Transplant 2004; 4:2027.
Spiera RF, Gordon JK, Mersten JN, et al. Imatinib mesylate (Gleevec) in the treatment of diffuse cutaneous systemic sclerosis: results of a 1-year, phase IIa, single-arm, open-label clinical trial. Ann Rheum Dis 2011; 70:1003.
Kay J, High WA. Imatinib mesylate treatment of nephrogenic systemic fibrosis. Arthritis Rheum 2008; 58:2543.
Sfikakis PP, Gorgoulis VG, Katsiari CG, et al. Imatinib for the treatment of refractory, diffuse systemic sclerosis. Rheumatology (2008) 47 (5):