Systemic sclerosis (SSc) is an autoimmune disease of uncertain cause, which manifests as inflammation and fibrosis of the skin and internal organs. Scleroderma renal crisis (SRC) is a rare but severe complication of systemic sclerosis; occurring in 5-10% of cases. It constitutes a medical emergency, requiring prompt and aggressive treatment. Despite advances in treatment with angiotensin-converting enzyme (ACE) inhibition and aggressive blood pressure control, mortality at one year remains approximately 30%.¹ SRC is characterised by the sudden onset of moderate-to-severe hypertension, with progressive renal impairment (> 30% reduction in eGFR). As many as 10% of patients may have ‘normal’ blood pressures at presentation, but closer inspection will invariably show that their blood pressure is high compared to their usual baseline.²

Aetiology

The pathogenesis of SRC remains incompletely understood. Injury to endothelial cells occurs resulting in intimal thickening and intimal proliferation of the renal intralobular and arcuate arteries. The thickened vessel wall encourages platelet aggregation and adhesion. Increased collagen and fibrin deposition, driven by the release of platelet factors, contribute to luminal narrowing. Narrowing of the arterial blood vessels, leads to decreased cortical perfusion. Decreased perfusion results in excessive renin release from the juxtaglomerular apparatus. Renin subsequently undergoes conversion to angiotensin II. Hyper-reninaemia is thought to be the driving factor behind hypertension in SRC.³ This leads to further vasoconstriction, hypertension and further renal ischaemia. Despite this, hyper-reninaemia is not predictive of SRC.⁴ Although a variety of imaging techniques have demonstrated reduced renal blood flow in SRC, these have not yet proven useful in predicting future renal crises either. 

The so-called ‘renal Raynaud’s phenomenon’ – episodic intrarenal vasospasm, demonstrated in scleroderma in response to cold stimulation of the hands – is of uncertain clinical significance.^5,6 While the perpetuation and escalation of the hypertensive response seems dependent on hyper-reninaemia, the factor which precipitates the ischaemic/hyper-reninaemic/hypertensive cascade remains obscure – there are several potential precipitants. Cardiac dysfunction which could result in renal hypoperfusion, such as pericardial effusion, congestive cardiac failure or arrhythmia may precede SRC, but could also be a result of hyper-reninaemia. Pregnancy may be a trigger.⁷ Sepsis and dehydration with consequent hypovolaemia and hypotension may contribute to SRC. Several drugs may lead to decreased renal perfusion, they include: calcium channel blockers (CCBs), ACE inhibitors, NSAIDs. However, none of these medications have been shown to trigger SRC. Corticosteroids have been implicated in the development of SRC in up to 60% of cases.⁸ The mechanism for this may be via the effect of corticosteroids on prostacyclin inhibition and increased ACE activity. 

Pathology

Gross examination of the scleroderma kidney reveals areas of infarction, haemorrhage and cortical necrosis.  These changes are non-specific, and may also be seen in a wide range of kidney pathology, including HUS, TTP and malignant hypertension. Microscopic changes occur predominantly in the small vessels. Small interlobular arteries show intimal oedema with proliferation of intimal cells. Fibrinoid necrosis may be seen in the arterial walls. Intramural fibrin deposition or thrombi may be seen. Adventitial and periadventitial fibrosis has been seen, which helps to distinguish SRC from other forms of malignant hypertension.⁹

Glomeruli show ischaemic changes with thickening and collapse of capillary loops. Juxtaglomerular cell hyperplasia may occur due to hyper-reninaemia. Flattening and degeneration of tubular cells occurs, due to ischaemia from arterial luminal occlusion. The majority of these changes are also seen, though to a lesser extent, in patients with scleroderma in the absence of SRC.¹⁰

Symptoms

Patients may be asymptomatic initially. Common symptoms at presentation include fatigue, dyspnoea, headache or blurred vision. Seizures may also occur, even in normotensive SRC. Progressive renal dysfunction leads to its own set of symptoms, including confusion, nausea and vomiting. SRC may present with symptoms of congestive cardiac failure (dyspnoea, paroxysmal nocturnal dyspnoea and pulmonary oedema) due to hypertensive pressure on the myocardium, hyper-reninaemia and fluid overload related to oliguria. Anaemia due to microangiopathic haemolytic anaemia may precipitate congestive heart failure. Other cardiac complications, such as ventricular arrhythmias or pericardial effusions, may occur. 

Laboratory findings

Urinalysis reveals proteinuria and microscopic haematuria. Microscopy may yield granular casts. Serum creatinine is typically elevated at presentation and increases rapidly. Serum creatinine may continue to rise for several days after commencing antihypertensive treatment. Marked hyper-reninaemia is a hallmark feature. 

Microangiopathic haemolytic anaemia occurs in up to 50% of SRC cases.¹¹ Blood films reveal fragmented red cells, reticulocytosis and thrombocytopenia. The platelet count rebounds quickly with control of blood pressure. 

Vulnerable populations

Patients at increased risk of developing scleroderma have a recognisable profile; patients with these characteristics should be closely followed for SRC.¹² Patients with diffuse cutaneous systemic sclerosis (dcSSc) are at significantly higher risk for SRC, 65-86% of SRC occurs in this group.¹³ They require particular monitoring in the first four years of disease, the time of highest incidence of SRC. SRC may develop in the absence of clear signs of dcSSc in patients with early dcSSc, who have not yet developed the full clinical spectrum. 

Features which may help to identify patients with potential dcSSc include symptom duration of < 1 year, acute onset of symptoms with fatigue, weight loss and polyarthritis, swollen hands and lower legs, carpal tunnel syndrome and skin thickening progressing beyond the elbows/knees. Up to 20% of patients with SRC have it as their presenting symptom, making early identification of dsSSc important. Patients recently commenced on high doses of corticosteroids are at increased risk, although the role of low-dose chronic steroids is less clear.¹⁴ The immunological profile of patients at risk of SRC is also distinct; anti-RNA polymerase III antibody positivity confers an increased risk of SRC,¹⁵ while anti-topoisomerase one does not. Patients who are anti-centromere positive rarely develop SRC.

Treatment

Prior to the advent of ACE inhibitors, SRC was almost invariably fatal. Aggressive blood pressure control and dialysis formed the mainstay of treatment. Bilateral nephrectomy was employed to eliminate hyper-reninaemia.

In the late 1970s, the introduction of ACE inhibitors fundamentally altered the treatment of SRC. First described in 1979 by Lopez-Ovejero, aggressive ACE inhibition saw five-year survival rise to 65%. ACE inhibition counters the effect of hyper-reninaemia, by preventing the conversion of angiotensin I to angiotensin II.  Although ACE inhibitors are also used in normotensive variants, the dose may be limited by hypotension.

Captopril, with its short half-life, allows for flexibility in dosing. Other ACE inhibitors have not proven superior to captopril. Optimal blood pressure is approximately 120/70 although this is preferably achieved in a gradual fashion to avoid sudden drops in blood pressure and further renal hypoperfusion. Other types of antihypertensives may be added if this target is not met. Serum creatinine may continue to rise after blood pressure is controlled; however it is critical that therapy is not stopped.

ACE inhibition should be used with caution in patients with scleroderma, as their use in the absence of SRC may increase mortality.¹⁶ Given that a mortality rate persists, research is ongoing for new therapies. 

Prognosis

Approximately two-thirds of patients presenting with SRC require renal replacement therapy. Half of these will recover independent renal function. Renal recovery may be delayed for as long as 24 months.¹⁷ Severe renal crisis, requiring chronic dialysis, remains a predictor of poor outcome. Five-year survival rates for these patients is 50%. However, patients with renal crisis not requiring dialysis or temporary dialysis only have better outcomes, with a five-year survival of 90% (this is similar to patients with dcSSc without renal crisis).¹⁸

Summary

Scleroderma renal crisis is a potentially fatal complication of systemic sclerosis. Narrowing of small arteries of the renal cortex result in ischaemia, hyper-reninaemia and hypertensive emergency. SRC tends to occur more commonly in those with dcSSc, early in the course of disease. High-dose corticosteroids are a potential trigger factor.¹⁹ Patients present with end organ damage due to accelerated hypertension, including cardiac failure, renal failure and seizures. Treatment with ACE inhibitors has altered the natural history of the condition, improving outcomes and allowing for discontinuation of dialysis in many cases. Early diagnosis and prompt treatment remains essential.

References

1. Cozzi F et al. Prognosis of scleroderma renal crisis: a long-term observational study. Nephrol Dial Transplant 2012; 27(12): 4398-4403
2. Kohno K, Katayama T, Majima K et al. A case of normotensive scleroderma renal crisis after high-dose methylprednisolone treatment. Clin Nephrol 2000; 53: 479-482
3. Stone RA, Tisher CC, Hawkins HK, Robinson RR. Juxtaglomerular hyperplasia and hyperreninaemia in progressive systemic sclerosis complicated acute renal failure. Am J Med 1974; 56: 119-123
4. Fleischmajer R, Gould AB. Serum rennin and rennin substrate levels in scleroderma. Proc Soc Exp Biol Med 1975; 150: 374-379
5. Cannon J, Hassar M, Case DB et al. The relationship of hypertension and renal failure in scleroderma (progressive systemic sclerosis) to structural and functional abnormalities of the renal cortical circulation. Medicine 1974, 53: 1-46
6. Parekh S, Iyer R, Sequeira W. Transient renal dysfunction with Raynaud’s phenomenon: is there a connection? J Clin Rheumatol 2003; 9(2): 88-91
7. Steen VD. Pregnancy in women with systemic sclerosis. Obstet Gynecol 1999; 94(1): 15-20
8. Penn H, Howie AJ, Kingdon EJ et al. Scleroderma renal crisis: patient characteristics and long term outcome. QJM 2007; 100: 485-494 
9. Batal I, Domsic RT, Medsger Jr TA. Scleroderma renal crisis: a pathology perspective. Int J Rheumatol 2010; 543704 doi:10.1155/2010/543704
10. Trostle DC, Bedetti CD, Steen VD et al. Renal vascular histology and morphometry in systemic sclerosis. A case-control autopsy study. Arthritis and Rheum 1988; 31(3): 393-400
11. Steen VD, Medsger TA Jr. Long-term outcomes of scleroderma renal crisis. Ann Intern Med 2000; 133: 600-03
12. Penn H, Howie AJ, Howie AJ. Scleroderma renal crisis: patient characteristics and long-term outcomes. QJM 2007; 100(8): 485-494
13. Teixeira L, Mouthon L, Mahr A et al. Mortality and risk factors of scleroderma renal crisis: a French retrospective study of 50 patients. Ann Rheum Dis 2008; 67: 110-116
14. Penn H, Howie AJ, Kingdon EJ et al. Scleroderma renal crisis: patient characteristics and long-term outcomes. QJM 2007; 100: 485-494
15. Parker JC, Burlingame RW, Webb TT, Bunn CC. Anti-RNA polymerase III antibodies in patients with systemic sclerosis detected by indirect immunofluorescence and ELISA. Rheumatology 2008; 47: 976-979
16. Hudson M. Does the use of angiotensin converting enzyme inhibitors prior to scleroderma renal crisis affect prognosis? Results of the International Scleroderma Renal Crisis Survey. ACR 2012; 728
17. Penn H, Denton CP. Diagnosis, management and prevention of scleroderma renal disease. Curr Opin Rheumatol 2008; 20(6): 692–696
18. Steen VD, Medsger TA Jr. Long-term outcomes of scleroderma renal crisis. Ann Intern Med 2000; 133: 600-603
19. Steen VD, Medsger TA Jr. Case-control study of corticosteroids and other drugs that either precipitate or protect from the development of scleroderma renal crisis. Arthritis Rheum 1998; 41: 1613-1619