Hypocomplementaemic urticarial vasculitis syndrome and acute renal failure with cryoglobulin (–) hepatitis C infection

Sir,

Hypocomplementaemic urticarial vasculitis syndrome (HUVS) is a rarely observed disease. Diagnostic criteria are the presentation of chronic urticaria and hypocomplementaemia, with at least two of the following: vasculitis findings from dermal biopsies, arthralgia or arthritis, glomerulonephritis, uveitis or episcleritis, repeated abdominal pain and the presence of C1q precipitating factor in the plasma [1]. Infection with hepatitis C virus (HCV) has been associated with a variety of extrahepatic disorders, including renal disease and vasculitis [2]. The association of cryoglobulin (–) HCV infection and HUVS is rare. We present a patient with cryoglobulin (–) HCV infection and severe renal failure observed in HUVS which did not respond to classical treatment.

Case. A 53-year-old woman was admitted to our hospital because of dermal eruptions and abdominal pain. She had an 8 year history of hypertension, recurrent urticaria and peptic ulcers. Examination revealed generalized palpable purpuric weals and bilateral pre-tibial oedema. Blood pressure of 150/80 mmHg and axillary temperature of 37.3°C were observed. Her laboratory tests showed an increased erythrocyte sedimentation rate (73 mm/h). Leukocyte, neutrophil and haemoglobin values were found to be 14.3 x 103/µl, 13.2 x 103/µl and 9.66 g/dl, respectively. Urinalysis showed 2+ protein and a large number of red blood cells, 8–10 leukocytes and 5–6 epithelia cells per high power field. Creatinine clearance was 32.6 ml/min and proteinuria was 1 g/day. Serum urea was 83 mg/dl, creatinine 2.07 mg/dl, total protein 4.5 g/dl and albumin 1.78 g/dl. Serum complement levels were markedly diminished (C3, 67.48 mg/dl, normal 90–180; and C4, 2.10 mg/dl, normal 10–40). Cryoglobulinaemia was absent. C1q inactivator level (0.52 g/l, normal 0.15–0.35), C-reactive protein (80.2 mg/dl, normal 0–8) and rheumatoid factor (390 IU/ml, normal 0–20) were positive. Anti-neutrophil antibody, anti-double-stranded DNA, p-anti-neutrophil cytoplasnic antibody (ANCA), c-ANCA and autoimmune liver tests were negative. Anti-HCV was positive and HCV RNA was positive by polymerase chain reaction (2.0 x 105 genomes/ml). Urticarial vasculitis in the skin biopsy, regenerative activity findings in the liver biopsy, acute interstitial nephritis and acute proliferative glomerulonephritis in the kidney biopsy were determined. Immunofluorescence was positive for C3 in renal biopsy. Erosive antral gastritis was observed via upper gastrointestinal system endoscopy. On the fifth day of the patient's admission to the clinic, the serum urea and creatine values were observed to be 210 and 5.09 mg/dl, respectively, and with the development of anuria, the patient was submitted to haemodialysis and a 0.8 mg/kg dose of methylprednisolone was started. On the sixth day of treatment, due to the moderate increase of transaminases and widespread development of oesophagial candidiasis, the steroid treatment was terminated and mycostatin suspension was included in the treatment. In the 24 h control urine examination, 3 g of protein and a creatinine clearance of 22.1 ml/min was found. The patient, whose transaminase values reached normal borders, was given, together with low dose (10 mg/day) methylprednisolone, 3 x106 U of interferon-{alpha} treatment subcutaneously, three times a week. On the 14th day of interferon administration, due to the increase of urea and creatinine values, this treatment was terminated and haemodialysis was started. The patient was given 500 mg/day of 1 x 1 pulse methylprednisolone intravenously for 3 days, and a dose of 1 mg/kg/day orally was continued. Intravenous cyclophosphamide at a dose of 500 mg/kg 1 x 1 was also started. Although oral food intake, diuresis and the general condition of the patient had partially improved, cardiopulmonary arrest occurred after ventricular fibrillation on the 4th day of pulse steroid treatment, and the patient died.

Comments. The association of cryoglobulin (–) with HUVS and severe acute renal failure has not, to our knowledge, been reported previously. Hypocomplementaemia and deposition of IgM and C3 in the glomeruli suggested that immune complex disease played a role in the pathogenesis of extrahepatic manifestations independent of cryoglobulin. Progression to end-stage renal failure (ESRF) that requires dialysis in HUVS is relatively rare (~10% of cases). The majority of these patients die of cardiovascular disease, systemic vasculitis or infections before they reach ESRF [1,3]. In many patients, the cause of HUVS remains unknown or cannot be treated directly. In order to suppress the immunopathogenic mechanism responsible for vascular inflammation, both immunomodulatory and immunosuppressive drugs are used in the treatment of this disease [1,4]. However, most patients with HUVS seem to respond to moderate or high dose prednisone, with or without cytotoxic drug therapy. Both interferon and ribavirin have been used in the treatment of hepatitis C-associated glomerulonephritis [2,5]. Our patient had a complete remission of her cutaneous, rheumatological and gastric problems with only 16 mg of prednisone. Despite steroid and interferon-{alpha} therapy, the patient developed end-stage renal disease leading to haemodialysis therapy. She died of cardiac arythmia.



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Fig. 1. (a) Acute proliferative glomerulonephritis. (b) Acute interstitial nephritis.

 


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Fig. 2. Urticarial vasculitis on the skin.

 


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Fig. 3. Eruptions on the left hand.

 


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Fig. 4. Regenerative activity in liver biopsy.

 
In conclusion, our case demonstrates that the cyclophosphamide–methylprednisolone pulse regimen and interferon is not efficient in the treatment of HUVS with cryoglobulin (–) HCV. HUVS with cryoglobulin (–) HCV may be a potentially severe multisystem disease.

Conflict of interest statement. None declared.

Omer Toprak, Mustafa Cirit1, Halil Uzunel, Rifki Ersoy, Murat Ermete, Belkis Unsal and Fusun Guven

1 Nephrology2 Pathology3 Gastroenterology4 Dermatology Ataturk Training and Research Hospital Izmir Turkey Email: info{at}omertoprak.com

References

  1. Schwartz HR, McDuffie FC, Black LF, Schroeter AL. Hypocomplementemic urticarial vasculitis: associated chronic obstructive pulmonary disease. Mayo Clin Proc 1982; 57: 231–238[ISI][Medline]
  2. Cacoub P, Renou C, Resenthal E et al. Extrahepatic manifestations associated with hepatitis C virus infection: a prospective multicenter study of 321 patients. Medicine 2000; 79: 47–56[CrossRef][ISI][Medline]
  3. Wisnieski JJ, Baer AN, Christensen J et al. Hypocomplementemic urticarial vasculitis syndrome. Clinical and serological findings in 18 patients. Medicine 1995; 74: 24–41[CrossRef][ISI][Medline]
  4. Soma J, Sato H, Ito S, Saito T. Nephrotic syndrome associated with hypocomplementaemic urticarial vasculitis syndrome: successful treatment with cyclosporin A. Nephrol Dial Transplant 1999; 14: 1753–1757[Abstract]
  5. Johnson RJ, Wilson R, Yamabe H et al. Renal manifestations of hepatitis C virus infection. Kidney Int 1994; 46: 1255–1263[ISI][Medline]




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