Department of Nephrology and Rheumatology and
1 Department of Pathology, University of Göttingen, Germany
SIR, Systemic vasculitides are a heterogeneous group of diseases with varied and frequently overlapping modes of clinical manifestation. In this case report a severe form of recurrent polyangiitis overlap syndrome in a renal transplant recipient is presented. Despite initiation of combination therapy with cyclophosphamide and prednisolone, the disease course was complicated by rapid onset of fulminant alveolar haemorrhage, leading to the patient's death.
A 71-yr-old woman presented in March 1999 with a history of malaise, acute bronchitis, severe arthralgia and vasculitic skin rash over a period of several weeks. The patient's history revealed a similar episode of polyarthralgia and skin lesions in conjunction with acute renal failure in 1987. Histopathological examination of renal biopsy revealed a focalsegmental necrotizing vasculitis, but no deposits of immune complexes. Since antineutrophil cytoplasmic antibodies (ANCA) were not detected, a clinicopathological diagnosis of systemic vasculitis was made. Despite initiation of cyclophosphamide and prednisolone pulse therapy, renal function could not be improved and chronic haemodialysis therapy had to be initiated. In 1991 the patient received successful renal allograft transplantation, and renal function remained stable for the following 8 yr. Her post-transplant immunosuppressive regimen included corticosteroids (prednisolone 7.5 mg/day) and cyclosporin A (10 mg/kg per day).
On admission, clinical examination revealed livid erythemata and haemorrhagic blisters on both the ventral and dorsal aspects of her feet. Her temperature was subfebrile (37.5°C). No lymphadenopathy, hepato- or splenomegaly was noted.
Laboratory data demonstrated highly elevated inflammatory parameters (erythrocyte sedimentation rate 60 mm/h, C-reactive protein concentration 144 mg/l). The leukocyte count was 15.6 x 109/l with 21% of eosinophils in the differential blood cell analysis. Retention parameters revealed impaired renal function (creatinine 2.4 mg/dl, urea nitrogen 49 mg/dl, creatinine clearance 16 ml/min). The urine sediment contained >100 red blood cells per high-power field and microalbuminuria (45 mg/l, 492 mg/day) was detected by urine protein electrophoresis. Cytoplasmic ANCA (cANCA) were recorded at a high titre (1:1024, PR3-ANCA 37 U/ml). Rheumatoid factor, complement levels and antinuclear antibodies were normal and cryoglobulinaemia was not present. Coincidental infections were excluded by negative results for both blood culture and virus-specific serology (EpsteinBarr virus, Cytomegalovirus).
Histological examination of the skin biopsy specimen revealed a dermal necrotizing vasculitis with dense infiltrates of neutrophilic granulocytes near small arteries, venules and capillaries. Notably, singular eosinophils were scattered throughout the inflammatory infiltrate. Three days after admission the chest roentgenogram revealed bilateral pulmonary infiltrates. Because of these findings, cyclophosphamide (20 mg/kg) and prednisolone pulse therapy (7 mg/kg per day for 3 days) was initiated immediately. After 2 days of treatment, the leukocyte count and the C-reactive protein concentration declined and clinical symptoms improved temporarily. However, 4 days after initiation of therapy the patient experienced fulminant pulmonary haemorrhage requiring mechanical ventilation, but all attempts at resuscitation were unsuccessful.
At autopsy, massive alveolar haemorrhage was recognized. The right lung (Fig. 1A) weighed 1000 mg and showed confluent haemorrhagic areas. Histopathological examination revealed a necrotizing alveolar capillaritis (Fig. 1B
). Fibrin and red blood cells appeared to be spilling into the alveolar lumen via the disrupted segments of necrotic capillaries. Prominent accumulation of inflammatory cells, predominantly neutrophils, lymphocytes and histiocytes, was detected at the necrotic alveolar septal wall.
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We present a severe form of recurrent polyangiitis overlap syndrome in a renal transplant recipient. The diagnosis was based upon the finding of pulmonary infiltrates, elevated cANCA levels, marked peripheral blood eosinophilia, the previous history of biopsy-proven rapidly progressive glomerulonephritis and cutaneous necrotizing vasculitis. According to the Chapel Hill Consensus Conference for the nomenclature of primary systemic vasculitis syndromes [1], the differential diagnosis of small vessel vasculitides has to include (1) the so-called pauci-immune vasculitis types [Wegener's granulomatosis (WG)], microscopic polyangiitis (MPA), ChurgStrauss syndrome CSS), (2) the immune complex-mediated diseases (SchönleinHenoch purpura, cryoglobulinaemic vasculitis), and (3) the Goodpasture syndrome. In the present case, the last two vasculitic syndromes were excluded because of missing pathognomonic laboratory values. For the differential diagnosis of the pauci-immune vasculitides, ANCA have previously been shown to be strongly associated with certain types of small vessel vasculitides. In particular, cANCA were detected in >90% of cases with WG, whereas perinuclear ANCA (pANCA) were predominantly present in cases of MPA and CSS [2]. In the case presented here, the clinical symptoms, histopathology of the skin biopsy and pathological findings in the lungs (non-granulomatous alveolar capillaritis) strongly suggest that the patient suffered from MPA. However, her elevated cANCA levels were more characteristic of WG. Marked peripheral blood eosinophilia and eosinophilic infiltration of skin lesions could also argue for the CSS, but the patient had no history of allergy and her serum IgE levels were normal. The case may thus be characterized as a polyangiitis overlap syndrome presenting clinical and histopathological features of WG, MPA and CSS. Two of these overlap syndromes have been described in a review of the literature [3, 4].
Lung involvement is seen in most patients with small vessel vasculitides [5]. However, rapid onset of massive alveolar haemorrhage is a very rarely described symptom of systemic vasculitis syndrome [6]. Different mechanisms could account for fulminant alveolar haemorrhage. In this case, the histopathology of the lungs at autopsy revealed a severe form of acute non-granulomatous necrotizing alveolar capillaritis involving almost all parts of the lungs as the underlying cause of acute respiratory failure. The severity and rapid onset of pulmonary haemorrhage after initiation of cyclophosphamide pulse therapy is very unusual and has not yet been described in a renal transplant recipient.
Renal involvement is most often seen in cases of WG and MPA [7]. The majority of patients present with rapidly progressive glomerulonephritis. Although cyclophosphamide is known to inhibit the progression of disease in most cases [5], some patients may develop end-stage renal disease (ESRD), as demonstrated in this case. During the period of haemodialysis therapy our patient received no immunosuppressive therapy and there were no signs of vasculitic disease activity. Others have reported similar remission in extrarenal disease manifestations in WG once chronic haemodialysis is begun despite cessation of immunosuppressive therapy [8]. It has been postulated that renal failure may itself be immunosuppressive or that haemodialysis may remove circulating immune complexes.
There are several reports about successful renal transplantation in cases of ESRD [9]. The survival rate, renal survival and graft function in patients with WG were similar to those of other transplanted patient groups. In addition, graft loss due to the underlying disease is rare, but recurrence of small vessel vasculitis after renal transplantation is not infrequent: Curtis et al. [10] demonstrated that both respiratory and renal lesions of WG can recur in transplanted patients while on routine post-transplant immunosuppressive therapy.
To summarize, our case report reveals that kidney transplantation and subsequent immunosuppressive therapy did not protect against the recurrence of small vessel vasculitis syndrome. Since late and life-threatening relapses may occur, clinical follow-up of transplant recipients should include short-term control of vasculitic disease activity.
Notes
Correspondence to: S. Blaschke, Georg August University of Göttingen, Department of Nephrology and Rheumatology, Robert-Koch Strasse 40, 37075 Göttingen, Germany.
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