Sclerodermatous Renal Crisis in a Patient With Mixed Connective Tissue Disease

Sclerodermatous Renal Crisis in a Patient With Mixed Connective Tissue Disease Ken Satoh, MD, Hirokazu Imai, MD, Tadashi Yasuda, MD, Hideki Wakui, MD, Akira B. Miura, MD, and Yasushi Nakamoto, MD • We report a patient with mixed connective tissue disease who developed accelerated hypertension, acute renal insufficiency, and microangiopathic hemolytic anemia. A renal biopsy specimen showed marked vascular changes in small arteries consisting of laminated endothelial cell proliferation and luminal thrombosis, which were similar to those of sclerodenna renal crisis. This patient was successfully treated with an angiotensin-converting enzyme inhibitor as well as analogues of prostaglandin E1 and prostaglandin 12 , In patients with mixed connective tissue disease, a fatal complication like sclerodenna renal crisis should be considered when the blood pressure rapidly increases. The combined administration of angiotensin-converting enzyme inhibitors and analogues of prostaglandin E1 and prostaglandin 12 may be an effective treatment for this complication. © 1994 by the National Kidney Foundation, Inc. INDEX WORDS: Mixed connective tissue disease; scleroderma renal crisis; prostaglandins.

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HARP ET ALl described the clinical and serologic findings in 25 patients with an apparently distinct rheumatic disease syndrome, and they termed this syndrome " mixed connective tissue disease" (MCTD). MCTD is characterized by overlapping clinical features of two or more connective tissue diseases and by the presence of serum antibodies against the nuclear ribonucleoprotein in high titers. Since the original description, the spectrum ofMCTD has been delineated with several reports2 .3 on the clinical manifestations, course, and prognosis. Although the initial report l emphasized the rarity of renal involvement in patients with MCTD, subsequent studies3 - 6 demonstrated a high prevalence of nephropathy of up to 40% in adult patients. The main renal disorders in patients with MCTD are mesangial proliferative glomerulonephritis and membranous nephropathy, which are usually benign and responsive to steroid therapy. On the other hand, vascular renal diseases are quite infrequent. We describe a patient with MCTD who developed a sclerodermatous renal exacerbation due to prominent vascular injuries.

changed. In addition. the patient had mild liver dysfunction, which was treated with glycyrrhizic acid. The blood pressure was 158/90 mm Hg. the pulse rate was 84 beats/min with regular rhythm , and the body temperature was 36.8°C. There was tightness over the hands. the forearms, and around the mouth with inability to pinch the skin, sparing the truncal skin. Several rice-sized lymph nodes were palpable in the axillary and inguinal regions. No crackles or rhonchi were audible in the chest and the heart sounds were normal. No abnormal findings were observed in the abdomen. Neurologic examination was negative. Laboratory studies on admission disclosed erythrocyte sedimentation rate of25 mm/hr, hemoglobin 11.9 g/dL, leukocyte count 4.700/ ILL platelet count 117,000/ ILL. blood urea nitrogen 13 mg/dL, serum creatinine 0.6 mg/dL. uric acid 3.2 mg/ dL, serum sodium 141 mEq/L. serum potassium 3.1 mEq/ L, serum chloride 104 mEq/L, total bilirubin 0.4 mg/dL, lactate dehydrogenase 510 U/ L, asparate aminotransferase 84 U/L. alanine aminotransferase 41 U/L, and creatine kinase 1,092 U/L Serum total protein was 7.6 g/dL albumin 3.6 g/ dL, immunoglobulin G (lgG) 2,859 mg/dL, 19A 458 mg/dL, and IgM 309 mg/dL Plasma renin activity was 1.6 ng/mL/ hr (normal range. 0.3 to 2.9 ng/mL/hr) and plasma aldosterone was below 10 pg/mL (normal range, 35.7 to 240 pg/mL) at rest. Antinuclear antibody was 1,280-fold positive with a speckled pattern. The titer of anti-RNase-sensitive extractable nuclear protein antibody was 163,840-fold positive by the passive hemagglutinin method and the titer of anti-nuclear ribonucleoprotein antibody was 16-fold positive by the immunodiffusion method. Serum antibodies against double-

CASE REPORT A 47-year-old woman with recently diagnosed MCTD was admitted to Akita University Hospital on January 20. 1992. for further evaluation because of a IO-kg weight loss. The patient was in a stable state of health until 10 months before admission, when she developed Raynaud's phenomenon, swollen fingers, sclerodactyly, and lymphadenopathy. She was diagnosed as having MCTD at another facility based on the recent criteria, 7 which were fulfilled by the above clinical findings and a positive test for serum anti-nuclear ribonucleoprotein antibody. The patient was treated with a small dose of prednisolone (10 mg/d), but her symptoms remained un-

From the Third Department of Internal Medicine, Akita University School of Medicine, Akita, Japall; and the Department of Internal Medicine, Mitaka-kitaguchi Hospital, Tokyo, Japan. Received December 9, 1993; accepted in revised form February 21, 1994. Address reprint requests to Ken Satoh, MD, Third Departm ent of Internal Medicine, Akita University School of Medicine, 1-1-1 Hondo, Akita, Akita 010, Japan. © 1994 hy the National Kidney Foundation, Inc.

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American Journal of Kidney Diseases, Vol 24, No 2 (August), 1994: pp 215-218

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strand DNA, Sm, Sjogren's syndrome-A, Sjogren's syndromeB, scleroderma-70, and centromeres were all negative. C3 was 42 mg/dL (normal range, 60 to 116 mg/dL). C4 was 16 mg/ dL (normal range, 15 to 44 mg/dL), and CH50 was 26.3 CH50U/mL (normal range, 30 to 40 CH50U/mL). The rheumatoid factor and cryoglobulins were not detected in her serum. Activated partial thromboplastin time was 40.0 seconds (normal range, 31.8 to 48.8 seconds). Serologic tests for syphilis were negative and serum antibodies against cardiolipin were not detected. The urine volume was 1,600 mL/d and the total urinary protein was 0.5 g/d with a scanty urinary sediment. The creatinine clearance was 120 mL/min. Pulmonary function tests were normal: vital capacity (percentage of predicted value) 91.4%, first-second vital capacity/vital capacity 89.3%, and carbon monoxide diffusing capacity (percentage of predicted value) 116%. Upper gastrointestinal radiographs revealed a normal barium swallow. The concentration of serum potassium was normalized after the cessation of glycyrrhizic acid administration. On the fifth hospital day, the blood pressure suddenly increased to 170/ 110 mm Hg. In addition, the levels of blood urea nitrogen, serum creatinine, and plasma renin activity were also elevated, and reached maximum levels of 34 mg/dL, 1.2 mg/dL, and 11 ng/mL/hr, respectively. on the 15th hospital day. Her highest blood pressure was 210/130 mm Hg. Anemia with reticulocytosis and red blood cell fragmentations were also observed. Ophthalmoscopic examination revealed grade 3 retinopathy according to the Keith-Wagener's classification. M-mode and two-dimensional echocardiographs did not demonstrate any findings of pulmonary hypertension. Treatment with an angiotensin-converting enzyme (ACE) inhibitor and a calcium channel blocker was started on the 24th hospital day. The blood pressure decreased to 156/90 mm Hg on the next day, and a percutaneous renal biopsy was performed. The biopsy specimen was routinely processed. The renal histology, in which there were 22 glomeruli, showed mild glomerular ischemic changes with reduction in the patency of capillary lumens and wrinkling of the glomerular basement membranes. The glomeruli displayed no deposits, segmental lesions, crescents, or reduplications of the capillary

Fig 2. Light micrograph of the kidney. (A) A small artery is completely occluded by thrombi. (Azan-Mallory stain; original magnification X400.) (8) Another small artery shows mild intimal proliferation. (Jones' periodic acid-methenamine silver stain; magnification X400.)

Fig 1. Light micrograph of the kidney, showing mild ischemic changes of the glomerulus. (Periodic acid-Schiff stain; original magnification X400.)

walls (Fig 1). On the other hand, prominent vascular changes were observed in two small arteries obtained in the specimen. One of the affected arteries was completely occluded by thrombi (Fig 2A) and another artery showed mild intimal proliferation (Fig 2B). Immunofluorescence microscopy showed a faint staining ofIgM in the glomerular mesangium. Based on the clinical signs and laboratory findings, we con-

SCLERODERMATOUS RENAL CRISIS IN MCTD

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Table 1. Case Reports of Patients With MCTD and Sclerodermatous Renal Crisis

Authors Age/Sex Onset after the diagnosis of MCTD Blood pressure (mmHg) BUN (mg/dL) Creatinine (mg/dL) Plasma renin activity (ng/mL/hr) Glomerular changes LM

IF

Kumagai et al [1981],0 44/F 14 mo

220/140 40 2.7

Crapper et al [1987]" 34/F

11 Y

Vascular changes

Fibrinoid necrosis

Treatment

PSL

Outcome

Died

210/130

NA (hypertension)

32 2.3

34

1.2 11

NA

2.8

Fibrinoid degeneration NA

Present case 47/F 10 mo

Ischemic changes Faint IgM and C3 (mesangial pattern) Endothelial proliferation and luminal thrombosis Plasmaphesis, cyclophosphamide, PSL, and ACE inhibitor Alive

Ischemic changes Faint IgM (mesangial pattern) Endothelial proliferation and luminal thrombosis PSL, PGs, and ACE inhibitor Alive

Abbreviations: NA, not available; BUN, blood urea nitrogen; LM, light microscopy; IF, immunofluorescence; IgM, immunoglobulin M; PSL, prednisolone; ACE, angiotensin converting enzyme; PGs, prostaglandins.

sidered that this patient with MCTD developed an acute sclerodermatous renal crisis. Following the commencement of antihypertensive drugs. the blood pressure was 150 to 170/ 80 to 100 mm Hg. The patient did not become oliguric during her presentation with renal crisis. but the level of creatinine clearance had decreased to 38 mL/min. Treatment with warfarin and analogues of prostaglandin E! (pOE!) and prostaglandin 12 (POI 2) was started on the 39th hospital day. These treatments were effective in further control of the blood pressure (120 to 140/70 to 90 mm Hg) and the level of creatinine clearance increased up to 50 mL/ min on the 62th hospital day. There were not any side effects associated with the administration of prostaglandin analogues. After the improvement of her other symptoms, such as Raynaud's phenomenon and thickness of the skin. she was discharged on June I, 1992 to be followed in our outpatient clinic. The levels of both blood urea nitrogen and serum creatinine returned to near normal ranges: 22 mg/dL and 1.0 mgjdL, respectively.

DISCUSSION

In our female patient with MCTD, an acute deterioration with hypertension, renal insufficiency, and microangiopathic hemolytic anemia occurred 10 months after the onset of MCTO. A renal biopsy specimen showed prominent vascular damage similar to that of patients with scleroderma renal crisis (SRC). We treated the patient with an ACE inhibitor and analogues of PGE 1 and PGI 2 , and her condition improved with stabilization of renal function. Sclerodermatous renal crisis in patients with MCTO is a considerably severe complication, although the incidence is extremely low. In addition to our patient, seven patients associated with

MCTO and sclerodermatous renal crisis have been reported. 8- 14 Among these patients, there are only two definite cases in which detailed information about the clinical data is available and in which marked vascular changes were confirmed (Table 1). The three patients, including our case, are women aged from 34 to 47 years. Although the intervals to the onset of sclerodermatous renal crisis after the diagnosis of MCTO are variable, they were commonly characterized by an abrupt onset of hypertension and renal dysfunction. Renal histologic findings of these patients are closely similar to those seen in SRc. 15 The renal lesions that develop in SRC predominantly affect small arteries. Fibrin depositions within vessels is the first step in the formation of intimal proliferation, which causes severe narrowing of the affected arteries. Glomerular lesions in SRC show ischemic changes in association with the severity of arterial lesions. Among the three patients summarized in Table I, the first reported patient appeared to have the most prominent renal lesions. This patient did not respond to steroid therapy and suddenly died from an unknown reason. The second case was successfully treated with plasmapheresis, cyclophosphamide, and an ACE inhibitor. In our case, the combined administration of an ACE inhibitor and analogues of PGE 1 and PGI 2 was effective, without the use of plasmapheresis or immunosuppressive agents.

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SRC is a life-threatening complication in patients with systemic sclerosis and often develops during the first 4 years after diagnosis. 16 Prior to 1979, most patients with SRC died within 1 to 3 months after onset. The availability of ACE inhibitors has dramatically improved the prognosis of SRC, but almost half of the patients treated with ACE inhibitors still have a poor outcome. 17 The factors of poor outcome in these patients include the gender (male), a serum creatinine level greater than 3.0 mg/dL at the start of therapy with ACE inhibitors, and the presence of low platelet count or microangiopathic hemolytic anemia. 16 From our experience, PGE I and PGh analogues may be useful to prevent a fatal course of SRC-like complication in patients with MCTD, in addition to antihypertensive drugs such as ACE inhibitors. In an animal model for renal ischemia, Paller et al 18 demonstrated beneficial effects of both PGE I and PGI 2 to spare ischemic renal injury. These prostaglandins increased the renal blood flow and protected injured cells in this model. The prognosis of patients with MCTD has been considered benign, except in patients developing pulmonary hypertension. Sullivan et al 3 examined pulmonary involvement in 34 patients with MCTD and described autopsy findings in the lungs of three patients who had developed pulmonary hypertension. The most prominent finding was marked intimal proliferation of pulmonary arteries with consequent narrowing of the vascular lumens. Furthermore, similar proliferative vascular lesions were observed in the kidneys of these patients, although they did not develop significant renal dysfunction. An SRC-like renal involvement in patients with MCTD is also caused by progressive vascular abnormalities, and this should be noted as a life-threatening complication. We propose the term "malignant-type MCTD" for such a serious vascular complication.

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3. Sullivan WD, Hurst DJ. Harmon CE, Esther JH, Agia GA, Maltby JD, Lillard SB. Held CN. Wolf JF. Sunderrajan EY, Maricq HR. Sharp GC: A prospective evaluation emphasizing pulmonary involvement in patients with mixed connective tissue disease. Medicine 63:92-107, 1984 4. Sharp GC, Irvin WS. May CM, Holman HR. McDuffie FC, Hess EY, Schmid FR: Association of antibodies to ribonucleoprotein and Sm antigens with mixed connective-tissue disease. systemic erythematosus and other rheumatic diseases. N Engl J Med 295:1149-1154, 1976 5. Bennett RM, Spargo BH: Immune complex nephropathy in mixed connective tissue disease. Am J Med 63:534-541, 1977 6. Kitridou RC, Akmal M, Turkel SB, Ehresmann GR, Quismorio FP. Massary SG: Renal involvement in mixed connective tissue disease: A longitudinal clinicopathologic study. Semin Arthritis Rheum 16:135-145. 1986 7. Kasukawa R. Tojo T, Miyawaki S. Yoshida H. Tanimoto K, Nobunaga M. Suzuki T, Takasaki Y, Tamura K: Preliminary diagnostic criteria for classification of mixed connective tissue disease. in Kasukawa R. Sharp GC (eds): Mixed Connective Tissue Disease and Anti-nuclear Antibodies. Amsterdam, The Netherlands, Elsevier, 1987, pp 41-47 8. Nimelstein SH. Brody S. McShane D. Holman HR: Mixed connective tissue disease: A subsequent evaluation of the original 25 patients. Medicine 59:239-248, 1980 9. Grant KD, Adams LE, Hess EY: Mixed connective tissue disease-A subset with sequential clinical and laboratory features. J Rheumatol 8:587-598, 1981 10. Kumagai Y. Abe C, Hirano T, Fukuda Y, Shiokawa Y: Mixed connective tissue disease after breast augmentation which terminated in scleroderma kidney. Ryumachi 21: 171176, 1981 11. Crapper RM, Mackay IR, Dowling JP. Whitworth JA: Acute scleroderma in stable mixed connective tissue disease: Treatment by plasmapheresis. Aust N Z J Med 17:327-329, 1987 12. Kumagai I, Takatori K, Nishimura M, Theng LZ, Takaoka M, Makino H, Takahashi K, Miyawaki S, Ota Z: Mixed connective tissue disease (MCTD) with deteriorating renal function. Nippon Naika Gakkai Zasshi 78:846-847. 1989 13. Takeda K. Takagi N, Tokita Y, Yabana M, Ishii M: A case of mixed connective tissue disease complicated with malignant hypertension. Nippon Jinzo Gakkai Shi 32:111116, 1990 14. Kuwana M. Suzuki H, Takayama S, Tominaga N: Accelerated hypertension in a patient with mixed connective tissue disease. J Rheumatol 19:826-828, 1992 15. Kincaid-Smith P: Participation of intravascular coagulation in the pathogenesis of glomerular and vascular lesions. Kidney Int 7:242-253. 1975 16. Traub YM. Shapiro AP. Rodnan GP. Medsger TA, McDonald RH, Steen YD, Osial TA. Tolchin SF: Hypertension and renal failure (scleroderma renal crisis) in progressive systemic sclerosis. Medicine 62:335-352, 1983 17. Steen YD. Costantino JP, Shapiro AP, Medsger T A: Outcome of renal crisis in systemic sclerosis: Relation to availability of angiotensin converting enzyme (ACE) inhibitors. Ann Intern Med 113:352-357, 1990 18. Paller MS, Manivel JC, Patten M, Barry M: Prostaglandins protect kidneys against ischemic and toxic injury by a cellular effect. Kidney Int 42: 1345-1354. 1992