Scleroderma renal crisis: a high index of suspicion speeds diagnosis and life-saving treatment.

Scleroderma renal crisis (SRC) is a life-threatening visceral complication of systemic sclerosis (SSc) characterized by the abrupt onset of malignant hypertension and rapidly progressive, oliguric renal failure. Microangiopathic hemolytic anemia and thrombocytopenia are often found. Typical SRC patients have widespread (diffuse) skin thickening. Occasionally, however, the presentation is subtle, as illustrated by the case report of Bashandy et al (1) in this issue of the Journal, delaying diagnosis and proper treatment. Therefore, a high index of suspicion is necessary when a patient with established SSc suddenly becomes ill.

The frequency of SRC in several series is 3 to 10% for all SSc patients and considerably higher, at 13 to 20% among those with diffuse cutaneous (dc) involvement. (2-4) Early disease, rapidly progressive skin thickening, antecedent corticosteroid use, large joint contractures, cardiac enlargement and the presence of anti-RNA polymerase III antibody have been identified as predictors of SRC. (5,6)

In our published (5) and unpublished cases combined, the median time from the first symptom attributable to SSc until renal crisis in 315 SRC cases was 1.4 years. Only 11 (6%) of the 186 patients that we ourselves examined at the time of SRC had either limited cutaneous (lc) SSc or no skin involvement ("scleroderma sine scleroderma" or ssSSc). (7) In our experience the majority of such patients either develop dcSSc during follow-up or have clinical features suggesting evolution to dcSSc such as rapid progression of skin thickening or palpable tendon friction rubs. The patient of Bashandy et al, had she lived, would most likely have progressed to dcSSc since numerous tendon rubs were detected on physical examination. (8)

In research studies, several serum autoantibodies identify patients at increased risk for SRC, including anti-RNA polymerase III, anti-topoisomerase I and anti-U3 RNP. (9) Unfortunately, some of these tests are not commercially available today, but promise to be very useful in the future. (10)

It is noteworthy that there are case reports and case series that include SSc patients who developed SRC with normal blood pressure, (2) ssSSc (11) or both. (12) These atypical cases pose a diagnostic challenge and may delay ACE inhibitor treatment, which is crucial to survival. Even when the diagnosis of SSc has been made, the presentations of SRC are varied and not always interpreted correctly. Several clinical scenarios include:

(1) Profound fatigue due to microangiopathic hemolytic anemia and thrombocytopenia mimicking hemolytic-uremic syndrome, thrombotic thrombocytopenic purpura or vasculitis. This could lead to mistaken treatment with corticosteroids and plasmapheresis instead of ACE inhibitors.

(2) Severe headache, visual loss and seizures due to hypertensive encephalopathy. Cerebral vasculitis could be incorrectly diagnosed and corticosteroids prescribed.

(3) Rapidly progressive dyspnea on exertion due to congestive heart failure from hypertension-precipitated left ventricular dysfunction (not scleroderma affecting the heart). Investigation for other forms of heart disease or lung involvement could delay the correct diagnosis and treatment.

Prompt recognition of SRC and initiation of ACE-inhibitor therapy (once renal artery stenosis has been ruled out) offer the best opportunity for a good outcome from this true medical emergency. (13) Nevertheless, some patients with SRC die or require permanent dialysis, particularly those who are male, of older age, present with a serum creatinine over 3 mg/dL or have blood pressure elevation which can not be easily controlled. (13) Provided ACE inhibition is used promptly and continuously, one-third to one-half of patients require only temporary dialysis. (13) Renal transplantation is often performed successfully in SSc patients, although long-term outcome is not as good as in persons without systemic diseases. (14) Angiotensin receptor blockers offer theoretical benefit, but clinical experience with these agents has been variable; current wisdom is that they may be used as an adjunct but not as the primary treatment. (15)

The use of prophylactic ACE inhibitors should not be encouraged since there are SSc patients who have developed SRC while taking these agents. (6) Instead, SSc patients with clinical and/or serologic features associated with an increased risk of SRC should have their blood pressure monitored frequently, particularly during the first 2 to 3 years after disease onset. Any abrupt deterioration of clinical status should be a warning to the managing physician to consider the advent of renal crisis.

References

1. Bashandy HG, Javillo JS, Gambert SR. A case of early onset normotensive scleroderma renal crisis in a patient with diffuse cutaneous systemic sclerosis. South Med J 2006;99:870-872.

2. Helfrich DJ, Banner B, Steen VD, et al. Normotensive renal failure in systemic sclerosis. Arthritis Rheum 1989;32:1128-1134.

3. DeMarco PJ, Weismann MH, Seibold JR, et al. Predictors and outcomes of scleroderma renal crisis: the high-dose versus low-dose D-penicillamine in early diffuse systemic sclerosis trial. Arthritis Rheum 2002;46:2983-2989.

4. Walker JG, Ahern MJ, Smith MD, et al. Scleroderma renal crisis: poor outcome despite aggressive antihypertensive treatment. Intern Med J 2003;33:216-220.

5. Steen VD, Medsger TA Jr. Long-term outcomes of scleroderma renal crisis. Ann Intern Med 2000;133:600-603.

6. 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.

7. Poormoghim H, Lucas M, Fertig N, et al. Systemic sclerosis sine scleroderma: demographic, clinical and serologic features and survival in forty-eight patients. Arthritis Rheum 2000;43:444-451.

8. Steen VD, Medsger TA Jr. The palpable tendon friction rub: an important physical examination finding in patients with systemic sclerosis. Arthritis Rheum 1997;40:1146-1151.

9. Steen VD. Autoantibodies in systemic sclerosis. Semin Arthritis Rheum 2005;35:35-42.

10. Kuwana M, Okano Y, Pandley JP, et al. Enzyme-linked immunosorbent assay for detection of anti-RNA polymerase III antibody: analytical accuracy and clinical associations in systemic sclerosis. Arthritis Rheum 2005;52:2425-2432.

11. Molina JF, Anaya JM, Cabrera GE, et al. Systemic sclerosis sine scleroderma: an unusual presentation in scleroderma renal crisis. J Rheumatol 1995;22:557-560.

12. Korzets Z, Schneider M, Savin H, et al. Intriguing presentation of scleroderma renal crisis (scleroderma renal crisis sine scleroderma sine hypertension). Nephrol Dial Transplant 1998;13:2953-2956.

13. Steen VD, Constantino JP, Shapiro AP, et al. Outcome of renal crisis in systemic sclerosis: relation to availability of angiotensin converting enzyme (ACE) inhibitors. Ann Intern Med 1990;113:352-357.

14. Bleyer AJ, Donaldson LA, McIntosh M, et al Relationship between underlying renal disease and renal transplantation outcome. Am J Kidney Dis 2001;37:1152-1161.

15. Steen VD. Renal involvement in systemic sclerosis. In: Clements PJ, Furst DE, editors. Systemic Sclerosis. 2nd Edition. Philadelphia, Lippincott Williams & Wilkins, 2004, pp. 279-292.

I won't take my religion from any man who never works except with his
mouth.
--Carl Sandburg

Thomas A. Medsger, Jr, MD and Tatiana S. Rodriguez-Reyna, MD

From the Division of Rheumatology and Clinical Immunology, University of Pittsburgh, School of Medicine, Pittsburgh, PA.

Reprint requests to Thomas A. Medsger, Jr, MD, Division of Rheumatology and Clinical Immunology, University of Pittsburgh School of Medicine, 3500 Terrace Street; Room S711 Biomedical Science Tower, Pittsburgh, PA 15261. Email: [e-mail]

Accepted April 20, 2006.