It has been suggested that there are two types of scleroderma renal crisis (SRC) though it remains controversial among some researchers. One is the typical type of SRC, a syndrome consisting of acute onset of malignant hypertension accompanied by rapidly progressive renal failure, hypertensive retinopathy, and elevated plasma renin activity, which often occurs in diffuse cutaneous scleroderma (1). The other is the normotensive type of renal failure which is generally accompanied by anti-neutrophil cytoplasmic autoantibody (ANCA)-positive crescentic glomerulonephritis and it often occurs in limited cutaneous scleroderma (2). As 10 cases of normotensive and ANCA-positive type of renal failure in scleroderma patients have been reported (Table 1) since Endo et al first reported 6 such cases (2), it seems necessary to pay closer attention to this unique renal problem, and it will be of great value to disclose the clinico-pathological characteristics in detail in the clinical cases already treated.

It was generally believed that systemic sclerosis is always accompanied by unique dermatological changes such as progressive fibrosis of the skin, intimal proliferation of small and medium sized arteries, and widespread skin thickening (3). Recently, however, it has been reported that there are a group of patients who have visceral scleroderma lesions without skin involvement or who later develop typical skin lesions of systemic sclerosis after the onset of this disease. This type of scleroderma without sclerodermatous skin change has come to be recognized, and is now called systemic sclerosis sine scleroderma (ssSSc) by many researchers (4). As far as we know, there are few reports on ssSSc, and further, most of the previous cases with ssSSc had typical SRC if any (5–13).

Here, we report a very rare case of crescentic glomerulonephritis and rapidly progressive renal failure with positive ANCA and without malignant hypertension, which might be included in the newly proposed normotensive subset of SRC, in a scleroderma patient without marked dermatological change.

A 64-year-old woman visited our hospital in August 2001 complaining of swelling of bilateral lower extremities. In 1972, she was diagnosed in another hospital as scleroderma by serological tests and by the episodes of Raynaud's phenomenon which had occured every winter. Her serum creatinine level was 1.1 mg/dl on her first visit to our hospital but it gradually became elevated to 2.3 mg/dl in November 2001. Angiotensin II receptor antagonist (Candesartan) was started, since she had mild hypertension (164/90 mmHg). The myeloperoxidase-specific anti-neutrophil cytoplasmic antibody (MPO-ANCA) concentration was found to be elevated to 757 EU/ml. Rapidly progressive glomerulonephritis (RPGN) was suspected and she was hospitalized for treatment on November 12, 2001. On admission, her blood pressure was 156/80 mmHg, heart rate 66 beats per minute, and body temperature 36.2ºC. Her skin did not reveal any characteristics compatible with scleroderma such as thickening of the skin. Fine crackles were audible over the bilateral lower lung fields. Her palpebral conjunctiva was anemic. She had no complaint of dysphagia. There was no pitting edema in the bilateral lower extremities. Laboratory data on admission indicated that serum creatinine was elevated to 2.3 mg/dl. Anemia was found, but microangiopathic hemolytic anemia was not suspected based on the following data: hemoglobin 8.1 g/dl, lactic dehydrogenase (LD) 174 IU/l, total bilirubin 0.3 mg/dl. Urinalysis showed 3+ blood, 3+ protein, and the sediment contained many red blood cells per high-power field. The 24-hour urinary protein excretion was 0.72 g. Creatinine clearance was 24.1 ml/min. The test of anti-nuclear antibody was positive, and anti-topoisomerase I antibody (anti-Scl-70 antibody) was positive. An enzyme-linked immunosorbent assay (ELISA) comfirmed a MPO-ANCA concentration of 757 ELISA units per milliliter (EU/ml). Proteinase-3-specific ANCA and anti-glomerular basement membrane antibody (anti-GBM antibody) were below the detection limits. The plasma active renin concentration was within normal limits (Table 2). A computed tomographic (CT) scan of the chest showed mild pulmonary fibrosis consistent with interstitial pneumonia (Fig. 1).

RPGN was diagnosed clinically, and methylprednisolone pulse therapy (500 mg/day for 3 days) followed by oral prednisolone (PSL) 30 mg/day was given from the time of admission. Anticoagulant therapy using intravenous heparin sodium injection was started simultaneously and then dipyridamole was given continuously after the therapy. Candesartan was discontinued prior to the pulse therapy.

Two months after the commencement of the therapy, a percutaneous renal biopsy was performed, and 25 glomeruli were found in the specimen; 17 showed global sclerosis and 6 showed segmental sclerosis. Moreover, 17 glomeruli showed fibrocellular crescent formation. Fibrinoid necrosis was not seen around the walls of arteries. Uriniferous tubules were atrophic, and inflammatory cell infiltration was seen in the interstitium (Fig. 2). Immunofluorescence studies showed no remarkable deposition of immunogloblin and no significant deposition of complement, which were consistent with pauci-immune type crescentic glomerulonephritis. Her skin had no significant characteristic of scleroderma, and a skin biopsy sample from her left forearm showed neither proliferation of collagenous connective tissue nor findings of leukoclastic vasculitis in the specimen (data not shown).

She had mild hypertension but her systolic blood pressure did not exceed 200 mmHg and her diastolic blood pressure did not exceed 130 mmHg with nifedipine at a dose of 20 mg/day. At the time of discharge, the MPO-ANCA level was decreased from 757 to 152 EU/ml, and the serum creatinine concentration was decreased from 2.3 to 1.2 mg/dl. Urinary protein secretion was also decreased to below the detection limit (Fig. 3).

SRC is one of the life-threatening complications of scleroderma, which was originally reported to be accompanied by rapidly progressive renal failure and malignant hypertension (1). The typical SRC is characterized by a sudden rise of blood pressure, hypertensive retinopathy, and elevated plasma renin activity. Also, it occurs in the early onset phase of scleroderma, usually within 4 years from the first symptom of scleroderma, and it is often found as the diffuse cutaneous type (1, 2, 14). In 1989, Helfrich et al reported 131 patients who developed SRC, but 15 (11%) did not have accompanying malignant hypertension (15). Moreover, Endo et al first reported a unique subset of renal failure in scleroderma patients associated with MPO-ANCA without malignant hypertension (2). This unique and different subset of rapidly progressive renal failure in scleroderma patients has come to be recognized. The previous reports of ANCA-related crescentic glomerulonephritis and rapidly progressive renal failure in patients with scleroderma and normotensive SRC are listed in Table 1; 58 cases with this unusual renal failure in scleroderma patients have been reported in the English language literature. In the earlier reports, most of the renal pathology of normotensive renal failure in scleroderma patients showed the typical type of scleroderma kidney like narrowing of the lumen of interlobular arteries and fibrinoid necrosis of the arterial wall. Although, a different subset of rapidly progressive renal failure associated with MPO-ANCA, crescentic glomerulonephritis in scleroderma has recently been reported since the first report by Endo et al (2). Similar reports have also appeared in Internal Medicine (26). Another 22 cases of ANCA-related or normotensive renal failure in scleroderma patients have been reported in the Japanese language literature. It has only been since 1994 that researchers have begun to report this unique subset of renal failure in scleroderma patients. One reason for this trend is that the measurement of ANCA has become easier in the recent 10–15 years, and it might have been difficult in earlier studies to notice this rare subset.

Endo et al compared ANCA-positive and ANCA-negative scleroderma patients with renal disorders (2). Unlike typical SRC, ANCA-related rapid deterioration of renal function has no signs of malignant hypertension, hypertensive retinopathy, or hyperreninemia in most cases, and it shows various types of auto-antibodies (anti-DNA antibody, anti-Scl-70 antibody, anti-nRNP antibody), and mostly occurs later in the disease. In addition, the histopathological findings differ in these two types. The typical scleroderma kidney shows narrowing of the lumen of interlobular arteries and fibrinoid necrosis of the arterial wall. The ANCA-related subset, however, shows no change in the arteries but develops necrotizing crescentic glomerulonephritis. Alveolar hemorrhage occurs more frequently in ANCA-related renal failure in scleroderma patients (2).

In general, these two types of renal deficiencies are treated differently. For the typical scleroderma kidney, the application of angiotensin-converting enzyme (ACE) inhibitors markedly improves mortality (16). On the other hand, the ANCA-related renal failure in scleroderma patients is usually treated with high doses of corticosteroids, cyclophosphamide, and plasmapheresis (2). Helfrich et al (15) suggested that high doses of steroids or pulse therapy may precipitate renal crisis in scleroderma, especially the normotensive type. Based on this report, Omote et al reduced the dosage of PSL (methylprednisolone pulse: mPSL therapy 500 mg/day for three days) and added an immnosuppressant (mizoribine). Despite the therapy, the renal function deteriorated necessitating DFPP (double-filtration plasmapheresis) which was effective (26). Huong et al used mPSL pulse therapy (1 g/day for three days) and high-dose corticosteroid regimen (1 mg/kg/day PSL) in combination with monthly intravenous cyclophosphamide (700 mg), which led to remission (25). Hillis started PSL 60 mg/day and cyclophosphamide 100 mg/day for 3 months which was effective (27). Villaverde et al treated with corticosteroid (1 mg/kg/day) and cyclophosphamide (0.75 g/m² monthly for 6 months and then every 3 months for 1 year), and the renal function improved and ANCA became negative (30). Katrib et al treated one patient with 50 mg PSL and 50 mg cyclophosphamide daily which decreased the creatinine level and the MPO-ANCA level became negative. But another patient treated with mPSL therapy (500 mg/day for three days) and cyclophosphamide (50 mg/day) developed renal failure (31). Immunosuppressive regimens were used with steroid in all of these reports, and many of the scleroderma patients with ANCA-related renal failure responded well. We used only steroid and did not use immunosuppressive therapy, but the serum creatinine and MPO-ANCA titers decreased. This indicated that steroids are definitely effective in some patients. We can not conclude whether or not steroid therapy without additional immunosuppressive treatment is always effective for this subset of renal crisis, but it is worth trying at first.

The typical SRC is accompanied by malignant hypertension. In contrast, ANCA-related renal failure in a scleroderma patient has previously been thought to show normotension. As in our case, however, mild to moderate hypertension might exist in some of the ANCA-related renal failure in scleroderma patients. Four of six patients reported by Endo et al also had mild hypertension (2). Because the untypical type of renal failure does not show such markedly high blood pressure as that seen in malignant hypertension and the pathogenetic mechanism might be quite different from that in the typical SRC, the therapeutic role and significance of ACE inhibitors remain open to question (15).

Systemic sclerosis is characterized by progressive fibrosis of the skin, intimal proliferation of small and medium sized arteries, and visceral involvement. There is a broad spectrum of disease ranging from widespread skin thickening (diffuse cutaneous involvement) to skin thickening limited to the distal extremities and/or face (limited cutaneous involvement) (3). According to Poormoghim et al, there are a group of patients with visceral scleroderma without skin involvement, which is called "progressive systemic sclerosis sine scleroderma (ssSSc)" (4), which should be suspected if a patient has all of the following features: 1) "Raynaud's phenomenon or peripheral vascular equivalent (digital pitting scars, digital-tip ulcers etc.) 2) positive ANA, 3) any one of the following: distal esophageal hypomotility, small bowel hypomotility, pulmonary interstitial fibrosis, primary pulmonary arterial hypertension, cardiac involvement, renal failure consistent with scleroderma crisis, and 4) no other connective tissue disease or other disease as the cause of 1) 2) or 3). The diagnosis is convincing if the ANA specificity is due to an scleroderma-associated auto-antibody (4). Poormoghim et al (4) compared 48 ssSSc patients and 507 limited cutaneous involvement (lcSSc) patients, but there were no significant differences between them except that lung involvement was more frequent in ssSSc patients. Therefore, they concluded that ssSSc and lcSSc should be considered within the same spectrum of disorder. Ten cases have been reported as ssSSc accompanied by acute renal failure, however, nine were the typical type with malignant hypertension (5–13, 31). Katrib et al first reported ANCA-related renal failure in a scleroderma patient who had no cutaneous signs of scleroderma. The patient had reflux esophagitis, non-specific arthralgia, myalgia, and anticentromere antibodies (ACA) (31). To the best of our knowledge, the present case is the second case to be reported of ANCA-related renal failure in a scleroderma patient without marked skin involvement.

The cause of ANCA-related renal failure in scleroderma patients is still not clear, but there are some specific features in patients with ANCA compared to those of typical SRC. Endo et al reported that the duration of the disease before the occurrence of renal failure was much longer in ANCA-related patients (7.8 years/mean) than in typical SRC patients (3.2 years/mean), and pulmonary hemorrhage as well as the occurrence of multiple autoantibodies were markedly more frequent in patients with ANCA than in those without ANCA (2). D-penicillamine is used to treat scleroderma and, hypersensitivity to D-penicillamine is also considered a trigger of crescentic nephritis with pulmonary hemorrhage, which has likewise been shown to coincide with perinuclear ANCA (pANCA) and anti-MPO antibodies (27). Although there are many cases without the use of D-penicillamine, such as the present case. As Katrib et al (31) reported 3 patients with scleroderma concomitant with both ANCA and ACA, some further or additional immunological problems might cause ANCA-related renal failure in some scleroderma patients.

Although many cases of normotensive and ANCA-related renal failure in scleroderma patients, like our case, have been reported, it still may be not well recognized by some specialists. More reports and further discussion based on the clinical, immunological and pathological aspects will be necessary to establish it as the new subset of scleroderma renal crisis.

Although no skin change characteristic of scleroderma was found in the present patient, she had been diagnosed earlier as scleroderma with certainity because she had complained of Raynaud's phenomenon every winter, shown interstitial pneumonia, and anti-topoisomerase I antibodies had consistently been positive. About 30 years later, she developed ANCA-related renal failure without malignant hypertension. Taken together, it is significant to note that renal failure might occur even long after the onset of scleroderma, and that such renal failure is quite different from the typical one and it pathologically resembles regular ANCA-related crescentic glomerulonephritis. In the untypical type of renal failure in a scleroderma patient without malignant hypertesion, steroid therapy and/or other immunosuppressive therapies other than ACE inhibitors are highly effective as seen in the present case.