A 65 year old woman investigated for malaise by her GP and found to have a creatinine of 993 and urea of 47.3. She was admitted to hospital to await renal assessment and commencement of dialysis, but became acutely breathless and hypoxic. CXR showed bilateral pulmonary consolidation. She was intubated due to her respiratory failure and frank blood was suctioned from her tracheal tube. Investigations for pulmonary-renal syndromes led to a positive cANCA and a presumptive diagnosis of Wegener’s granulomatosis. She was pulsed with methylprednisolone and commenced plasmapheresis. Despite this she continued to deteriorate and subsequently died.
What is the role of plasmapheresis in pulmonary vasculitides and pulmonary haemorrhage?
Wegener’s granulomatosis forms part of a larger group of vasculitic syndromes and affects the lungs, kidneys and other organs. It is associated with circulating ANCA (antineutrophil cytoplasmic) antibodies, in particular those that react with the enzyme proteinase 3 (cANCA). In the kidneys, it is characterised by a rapidly progressive glomerulonephritis and in the lungs, it causes pulmonary haemorrhage.
Treatment of Wegener’s granulomatosis is aimed at preventing the formation of further antibodies by immunosuppresant agents and removing circulating antibodies and other mediators of inflammation through the use of plasmapheresis (1).
Before the advent of steroid therapy, mortality within one year was over 90% (2). With the introduction of newer immunosuppresants, Wegener’s granulomatosis and associated pulmonary haemorrhage has a mortality of 50%.
Plasmapheresis is an extracorporeal blood purification technique which is used to remove large molecular weight substances such as autoantibodies and cryoglobulins from the plasma. The recommended duration of plasmapheresis is between 2 to 3 weeks. Further plasmapheresis may be required if the patient still has haemoptysis or antibody titres are still elevated. Plasmapheresis must be accompanied by immunosuppressive therapy with steroids and cyclophosphamide. Aggressive doses are warranted due to the high mortality associated with the disease as well as a high risk of permanent renal failure.
Despite the theoretical benefits of plasmapheresis in patients with Wegener’s, there is a lack of definitive evidence of this. A review by Gaskin and Pusey (3) failed to show any effect on renal prognosis or mortality benefit from plasmapheresis. Earlier works such such as Johnson et al (1). showed that 2 out of 8 patients who received plasmapheresis, compared to 6 out of 9 patients in the immunosuppression alone group, became dialysis dependent.
The European Union Vasculitis Study Group (EUVAS) MEPEX trial (4) randomised 137 patients with a new diagnosis of ANCA positive vasculitis and serum creatinine over 500umol/l to plasma exchange or 1gm methylprednisolone for 3 days. This is in addition to standard therapy of oral cyclophosphamide and prednisolone. At the end of the study period, mortality between the two groups were not significantly different. However, the plasma exchange group had a significant reduction in risk of progression to end stage renal disease at one year (19% vs 43%) and were more likely to be alive with independent renal function at 3 months (69% vs 49%).
More recently, Frasca et al (5). showed improved prognosis in patients with ANCA-associated glomerulonephritis when treated with plasma exchange compared to those without (both groups received steroids and cyclophosphamide). However the study only involved 26 patients from a single centre.
The recently launched PEXIVAS trial (6) is an international, randomised controlled trial comparing plasma exchange and glucocorticoid dosing in the treatment of anti-neutrophil cytoplasm antibody associated vasculitis hopes to shed further light on the role of plasma exchange.
With regards to pulmonary haemorrhage, there are no randomised, controlled trials which looked at the effect of plasmapharesis on such patients. Klemmer et al (7). reported their experience of using plasmapharesis in patients with pulmonary haemorrhage due ANCA positive small vessel vasculitis. These patients received daily and then alternate-day plasmapharesis until haemorrhage resolved. In addition, all patients received methylprednisolone and most received cyclophosphomide. With this regimen, all patients had resolution of their pulmonary haemorrhage with no complications from plasmapharesis.
1. Al Bshabshe A, Al-Khalidy H, Omer H et al. Pulmonary renal syndrome associated with Wegener’s granulomatosis: a case report and review of literature. Clin Exp Nephrol 2010; 14: 80-84.
2. Johnson JP et al. Therapy of anti-glomerular basement membrane antibody disease: analysis of prognostic significance of clinical, pathologic and treatment factors. Medicine 1985; 64: 219.
3. Gaskin G and Pusey CD. Plasmapheresis in Antineutrophil Cytoplasmic Antibody-Associated Systemic Vasculitis. Therapeutic Apheresis 2001; 5: 176-181.
4. Jayne DR et al. European Vasculitis Study Group. Randomized trial of plasma exchange or high-dosage methylprednisolone as adjunctive therapy for severe renal vasculitis. J Am Soc Nephrol 2007; 18: 2180-2188.
5. Frasca GM, Soverini ML, Falaschini A et al. Plasma exchange treatment improves prognosis of antineutrophil cytoplasmic-associated crescenteric glomerulonephritis: a study of 26 patients from a single centre. Ther Apher Dial 2003: 7(6): 540-546.
6. PLEXIVAS trial website – http://www.bctu.bham.ac.uk/pexivas/
7. Klemmer PJ et al. Plasmapharesis therapy for diffuse alveolar haemorrhage in patients with small-vessel vasculitis. American J of Kidney Diseases 2003; 42: 1149-1153.