A case of early onset normotensive scleroderma renal crisis in a patient with diffuse cutaneous systemic sclerosis.

Abstract: Scleroderma renal crisis (SRC) has classically been defined as a new onset of accelerated arterial hypertension associated with a rapid increase in serum creatinine concentration and/or microangiopathic hemolytic anemia. SRC occurs in approximately 20% of patients with systemic sclerosis who have diffuse cutaneous manifestations. In addition, 10% of reported cases of SRC with diffuse cutaneous involvement have normal blood pressures; in the majority of these cases, SRC occurs after treatment with corticosteroids. We describe a patient who presented with an early onset SRC in the setting of diffuse cutaneous systemic sclerosis in evolution without prior accelerated arterial hypertension or corticosteroid use.

Key Words: scleroderma renal crisis, normotensive renal crisis, systemic sclerosis

Case Report

A 51-year-old white woman with a history of anxiety presented to the emergency department with an acute onset of shortness of breath of one-day duration. She reported a 3-week history of increasing fatigue and a 10-pound weight loss. She also reported having stiff fingers for a few months. There was no history of fever, chills, cough, chest pain or palpitations. Her primary care provider reported that she had normal blood pressure. Upon entering the emergency department, her blood pressure was 164/98 and her pulse was 95, although these returned within normal limits shortly thereafter on repeat testing and were presumed to be due to anxiety. The patient was initially administered a dose of ceftriaxone for presumed pneumonia. Within 15 minutes, she became bradycardic, hypotensive and had a cardiac arrest requiring intubation and support. It was subsequently elucidated that she had a history of penicillin allergy. She responded promptly to atropine and remained hemodynamically stable. The patient had no history of other medical illnesses, and was on escitalopram for anxiety. Social and family histories were unremarkable. While she was on mechanical ventilation, her blood pressure remained at 125/70, and pulse was 95 and regular. Examination was remarkable for normal optic fundi, multiple small telangiectasias on her face, diminished breath sounds at both lung bases with coarse crackles; her extremities were remarkable for swelling of both hands with sclerodactyly. There were palpable tendon friction rubs over the flexor and extensor tendons of the fingers of both hands. She had a skin thickness score of 12 (fingers 6+, hands 4+, and forearms 2+, using original Rodnan method). (1)

At admission, laboratory data was remarkable for elevated BUN (58 mg/dL) and creatinine (2.5 mg/dL). Her WBC was 26,500/[mm.sup.3], and her hematocrit was 28.6%, with a platelet count of 234,000/[mm.sup.3]. Her baseline BUN and creatinine were 16 mg/dL and 0.7 mg/dL, respectively, before admission. A peripheral smear showed schistocytes, anisocytosis and polychromasia suggesting microangiopathic hemolytic anemia. Urinalysis showed small blood, trace protein, and granular casts, WBC 5.0/hpf. ANA titer was strongly positive at 1:320 with a speckled pattern. Anti ds-DNA, anticentromere and antiscleroderma-70 antibodies were negative. Chest CT revealed symmetric, bilateral, moderate pleural effusions with patchy infiltrates. Transthoracic echocardiogram showed an ejection fraction of 45%, and mild pericardial effusion. Bilateral renal ultrasound showed normal kidney size without hydronephrosis.

Renal biopsy obtained later in the course of hospitalization revealed thrombotic microangiopathy with severe, chronic and ongoing involvement of the small arteries and arterioles, consistent with scleroderma.

The patient's renal failure was initially thought to be due to acute tubular necrosis. Despite management, her renal function worsened with an increase in her BUN and creatinine to 81 mg/dL and 8.1 mg/dL, respectively, and she was subsequently started on hemodialysis. She was discharged to a subacute rehabilitation facility on an ACE inhibitor for sclerodermal renal crisis (SRC) management. The patient presented to the emergency room one week after discharge in cardiopulmonary arrest and was pronounced dead the same day.

Scleroderma renal crisis (SRC) is defined as the new onset of accelerated arterial hypertension associated with a rapid increase in serum creatinine concentration and/or microangiopathic hemolytic anemia. It is typically characterized by malignant hypertension, severe glomerular damage, and intravascular hemolysis. SRC is the second most common cause of death after pulmonary hypertension for patients with scleroderma. Since the advent of ACE inhibitor treatment, the one-year survival for SRC patients has significantly improved to 76%, as compared with patients not treated with ACE inhibitors who have an 18% one-year survival rate. (2)

The pathogenesis of renal disease in scleroderma is incompletely understood. The primary process is thought to be an injury to the endothelial cells resulting in intimal thickening and proliferation of the renal intralobular and arcuate arteries (See Fig.).

Clinical studies have identified several factors as predictors of the development of SRC including new unexplained anemia, new cardiac events, use of corticosteroids, diffuse skin disease and pregnancy. (3)

On presentation, 90% of patients with SRC have consistent blood pressure levels greater than 150/90 mm Hg. In some cases, however, a normal blood pressure is noted upon presentation (normotensive renal crisis). (4) A vast majority of these reported cases have also been previously treated with glucocorticoids. Kohno et al (5) and Villaverde et al (6) reported patients who presented with normotensive renal failure and hemolytic anemia a few weeks after being treated with high doses of corticosteroids. Haviv and Safadi (7) reported a patient who developed rapidly progressive systemic sclerosis manifested by worsening skin lesions, diffuse interstitial restrictive lung disease, progressive renal failure with normal blood pressure, and microangiopathic hemolytic anemia that occurred within a few weeks of oral corticosteroids and penicillamine therapy.

Helfrich et al (8) reported on 140 systemic sclerosis patients with diffuse skin involvement and SRC; 11% had normal blood pressures. In comparison with patients presenting with hypertension, the normotensive patients had significantly more microangiopathic hemolytic anemia (90% versus 38%), thrombocytopenia (83% versus 21%) and history of treatment with high doses of corticosteroids (64% versus 16%). One-year survival was significantly reduced in normotensive patients versus those with hypertensive SRC (13% versus 35%). The vicious cycle of decreased blood flow, ischemia, hyperreninemia, hypertension, and further vasoconstriction almost invariably led to a fatal outcome before the availability of ACE inhibitor therapy. The key to management of SRC, therefore, is early detection and treatment with an ACE inhibitor. Studies have shown that if the diagnosis of SRC is delayed or if ACE inhibitors are not used aggressively, irreversible kidney damage and death are more likely to result. (9) In our particular case, the presence of sclerodactyly, tendon friction rubs, pulmonary symptoms, the absence of Raynaud phenomenon and the development of hypotension likely from antibiotic allergy should have increased the suspicion of impending renal crisis.

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Conclusion

Patients with diffuse cutaneous systemic sclerosis can present with normotensive SRC early in the course of the disease. This unique presentation is unusual and alarming considering the rapid and sudden death of this patient. It is likely that many such patients are encountered but not reported because death precludes full appreciation of the natural history of the disease.

References

1. Medsger Jr, TA Steen VD, et al. The natural history of skin involvement in progressive systemic sclerosis [abstract]. Arthritis Rheum 1980;23:720-721.

2. Steen VD, Costantino 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.

3. DeMarco PJ, Weisman 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. Salyer WR, Salyer DC, Heptinstall RH. Sclerodema and microangiopathic hemolytic anemia. Ann Intern Med 1973;78:895-897.

5. 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.

6. Villaverde M, Gonzalez A, Orellano P, et al. Normotensive scleroderma renal crisis. Medicina (B Aires) 2003;63:49-50.

7. Haviv YS, Safadi R. Normotensive scleroderma renal crisis: case report and review of literature. Renal Fail 1998;20:733-736.

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

9. Steen VD. Scleroderma renal crisis. Rheum Dis Clin North Am 2003;29:315-333.

Hany G. Bashandy, MD, Jason S. Javillo, MD, and Steven R. Gambert, MD

From the Department of Medicine, Johns Hopkins University School of Medicine and Johns Hopkins University/Sinai Hospital Program in Internal Medicine. Baltimore, MD.

Reprint requests to Steven R. Gambert, MD, Professor of Medicine, Johns Hopkins University School of Medicine, Chairman, Department of Internal Medicine, Sinai Hospital of Baltimore, 2401 West Belvedere Avenue, Baltimore, MD 21215. Email: [e-mail]

Accepted March 30, 2006.

RELATED ARTICLE: Key Points

* Patients with diffuse cutaneous systemic sclerosis can present with normotensive scleroderma renal crisis, early in the course of the disease, even before full appreciation of the nature of their systemic disease.

* The key to management of scleroderma renal crisis is early detection and treatment with angiotensin-converting enzyme inhibitor.

* Delay in the diagnosis and treatment of scleroderma renal crisis can result in irreversible kidney damage and death.