Department of Renal Medicine and Transplantation, Guy's Hospital, London, UK
Keywords: antineutrophil cytoplasmic antibody-associated systemic vasculitis; pauci immune crescentic glomerulonephritis; perinuclear antineutrophil cytoplasmic autoantibody; relapsing polychondritis; renal transplantation
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Introduction |
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It is now well recognized that antibody-associated systemic vasculitis (AASV) can recur post-alloengraftment despite the immunosuppressive effects of drugs for rejection prophylaxis. Most series and case reports describe relapse of c-ANCA vasculitis post alloengraftment, with only two reports documenting recurrence of p-ANCA vasculitis.
We report the case of a patient who had a full-blown relapse of p-ANCA-associated systemic vasculitis 9 years after alloengraftment, despite good compliance with prednisolone, azathioprine and cyclosporin immunosuppression. The relationship with the original RPC presentation some 24 years earlier (which had led to renal impairment then end-stage renal failure and dialysis) is discussed.
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Case |
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The presence of ANCA was first sought in this patient in 1989, and was found to be weakly positive (unknown specificity 19%; normal range <16%). However, ANCA could not be detected on two subsequent occasions in 1990 and 1993.
In 1990 the patient received a cadaveric renal transplant. Over the following 9 years there was excellent allograft function on standard triple immunosuppressive therapy with azathioprine, cyclosporin A and prednisolone. Baseline serum creatinine was 130 µmol/l with no microscopic haematuria or proteinuria.
In July 1999 the patient developed a middle ear infection requiring treatment with amoxycillin. Over the following 2 weeks progressive shortness of breath and increasing peripheral oedema ensued, prompting her presentation to hospital.
On arrival, respiratory distress was evident. The blood pressure was normal (120/80) but the body temperature high (38 °C). Central venous pressure was raised and peripheral oedema present. Course inspiratory crepitations were audible throughout both lung fields. Profound hypoxia (PaO2 6.6 kPa/FiO2 21%) with partially compensated metabolic acidosis (pH 7.3; pCO2 2 kPa; HCO3 8.6 mmol/l) was confirmed on blood gas analysis. Renal function had deteriorated sharply. Dysmorphic red blood cells with occasional white blood cells (wbc) but no casts were found on urine microscopy. Anaemia (Hb 9 g/dl) and a neutrophil leucocytosis (wbc 12.2; neutrophils 10.2x109) were present. C reactive protein was elevated (130 mg/l) and plasma albumin low (34 mg/dl). Liver function tests were normal.
The chest radiograph demonstrated dense shadowing throughout both lung fields, raising the possibility of a number of differential radiological diagnoses including infection, oedema and pulmonary haemorrhage.
Following transfer to the intensive therapy unit, mechanical ventilatory support was required. In the presence of oliguria, deteriorating renal function and increasing metabolic acidosis, continuous venoveno haemodiafiltration (CVVHDF) was commenced.
In view of the patient's previous history of ANCA positivity and crescentic glomerulonephritis, a renal transplant biopsy was performed. Histological examination confirmed the presence of pauci-immune necrotizing glomerulonephritis, with fibrocellular crescents being present in 75% of glomeruli. p-ANCA was subsequently detected (titre 1:160) with specificity for myeloperoxidase.
In light of the histological diagnosis, 3 g of pulsed methylprednisolone and 1 g of cyclophosphamide were given intravenously. In addition, 10 3-l volume plasma exchanges with 4.5% human albumin solution were performed. Subsequent maintenance immunosuppression comprised prednisolone 60 mg/day, reducing to 20 mg/day over 1 month, 4 weeks of oral cyclophosphamide (50 mg/day), followed by maintanance mycophenolate mofitil (250500 mg bd).
Serum creatinine stabilized at 450 µmol/l, allowing independence from dialysis support for a further 2 months. At this time ANCA became undetectable.
Unfortunately, subsequent slow progressive deterioration in renal function ensued, necessitating peritoneal dialysis. In view of the severity of the systemic vasculitic illness, maintenance immunosuppressive therapy with prednisolone 10 mg/day and mycophenolate mofitil 250 mg twice a day was continued. Twelve months after the start of CAPD the patient remained free from any evidence of AASV and was ANCA-negative, but then developed abdominal pain and pancreatitis, and was shown to have a large pancreatic adenocarcinoma to which she succumbed.
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Discussion |
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RPC is a rare condition characterized by recurrent episodes of inflammation involving tissues rich in glycosaminoglycans (cartilage, aorta, sclera, cornea and pinna) [2]. In addition to causing inflammation and destruction of cartilaginous structures throughout the body, it is frequently associated with the presence of other multi-system diseases, of which vasculitis is the most common [3]. ANCA (with specificity for both myeloperoxidase and proteinase 3) is found in up to 25% of patients with RPC; however, only 10% of this group have clinical manifestations of vasculitis.
Renal involvement in RPC is well documented, with reported incidence varying in different series from 6 to 22% [2]. The commonest histopathological diagnoses found are necrotizing glomerulonephritis with crescent formation, mild mesangial proliferation and interstitial nephritis [4]. More infrequently, other renal lesions have been reported including IgA nephropathy [5] and focal sclerosing glomerulosclerosis [6].
The occurrence of AASV in association with RPC has important therapeutic implications. Although RPC responds well to steroid therapy alone, this treatment in isolation has been shown to be inadequate in inducing sustainable remission in the presence of a co-existent systemic vasculitis. Therapy with cyclophosphamide or azathioprine has been found to be superior to steroids alone in the presence of systemic vasculitis [7]. Thus, as in this case, where ANCA occurs in the presence of RPC, careful surveillance for features of systemic vasculitis should be sought and appropriate immunosupressive therapy adopted at an early stage.
It is now well recognized that AASV can recur post-alloengraftment despite the immunosuppressive effects of drugs for rejection prophylaxis. The relapse rate has been reported to be 0.02 per patient per year [8] to as high as 0.24 per patient per year [9]. Most series and case reports describe relapse of c-ANCA vasculitis post-alloengraftment, with only two reports documenting recurrence of p-ANCA vasculitis. Le Mao described a patient who had four episodes of relapse affecting the lung and allograft kidney over a 30 month period post-transplantation. Proposed contributing factors to the recurrent episodes of relapse were persistently high p-ANCA levels pre- and post-transplantation, and the early cessation of azathioprine and subsequently cyclophosphamide therapy in the face of leucopenia [10].
Haubitz et al. reported recurrent disease involving the allograft kidney, lungs and small intestine in a patient with p-ANCA vasculitis 24 months post-transplantation [11]. As in the case described by Le Mao, azathioprine had been ceased a few months prior to the relapse, supporting other reports that steroid therapy alone is insufficient to prevent relapse and that additional immunosuppressive adjuvant agents are important in controlling relapsing disease [12].
The other issue raised by this case is the requirement for continuation of immunosuppression in patients with AASV on dialysis [13]. Potentially fatal disease activity can continue after the onset of ESRD despite the immunosuppressive effects of uraemia. In a recent publication, a reduced rate of relapse (0.09 relapses/patient/year) was reported when a policy of continued immunosuppression was adopted [8] compared with other series where the rate of relapse per patient per year was higher at 0.24 [11] and 0.3 [14]. In Nachman's recent pooled analysis, 17% of ANCA-positive patients relapsed after renal transplantation, with no protection by from cyclosporin A therapy, and with no evidence that circulating ANCA at transplantation conferred a worse outcome [15]. Rostaing et al. reported a 12% recurrence rate, and looked more favourably upon cyclosporin A therapy.
In summary, we present a case with unique features and which has implications for many patients: (i) the presence of a systemic component to vasculitis, which presents initially in one organ system; (ii) the relapse of AASV but with p-ANCA positivity, in contrast to virtually all other cases; (iii) which immunosuppression regimen is best at relapse prevention (in 2000 there are now numerous new immunosuppressives from which to choose, but the anti-proliferative, antibody-suppressing effects of mycophenlyate mofetil seem well suited to this task); and finally (iv) the need for continued vigilance against relapse, even many years later, especially in the context of acute infection as an immunological trigger.
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Notes |
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References |
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