The term 'Goodpasture's syndrome' is used for the clinical entity of DAH and rapidly progressive glomerulonephritis associated with anti-GBM antibodies 1920.

Goodpasture's syndrome is extremely rare (one case per 1,000,000 population per year). The disease predominantly affects Caucasians of every age but mostly those in the second to third decades and the fifth to sixth decades of life, with a slight predominance of males. Although rare, this syndrome is responsible for about 20% of acute renal failure cases due to rapidly progressive glomerulonephritis 19. Both genetic and environmental factors have been implicated in the pathogenesis of Goodpasture's syndrome. The disease has been described in brothers and in identical twins. More than 80% of patients carry the HLA alleles DR15 or DR4 whereas the alleles DR7 and DR1 are rarely found, suggesting that the latter may play a protective role 21. The fact that most cases present sporadically implies an additional aetiology beyond hereditary predisposition. Environmental factors, such as smoking, infections and previous hydrocarbon exposure, have been implicated in triggering the disease 22.

Human anti-GBM antibodies belong mostly to the IgG class and reactwith a limited number of epitopes (E_A and E_B) on the noncollageneous domain of the α3 chain of type IV collagen (NC1 α3 IV), a molecule expressed in the basement membranes of renal glomerulus, renal tubule, alveoli, chorioid plexus, retinal capillaries and Bruchs's membrane 1620. Anti-GBM antibodies bind the glomerular basement membrane, activating compliment and proteases, resulting in the disruption of the filtration barrier and Bowman's capsule and causing proteinuria and crescent formation 2324. The pathogenetic role of anti-GBM has been proved in multiple studies 20. As an example, in genetically engineered mice that produce human IgG antibodies, immunization with the NC1 α3 IV domains leads to the production of human anti-GBM antibodies and proliferative glomerulonephritis 25.

Circulating ANCA autoantibodies are detected in the majority of patients presenting with Pulmonary–renal syndrome 2627. ANCA do not confirm a specific entity but practically lead the differential diagnosis to three major systemic vasculitides syndromes: Wegener's granulomatosis, microscopic polyangiitis and Churg–Strauss syndrome 26.

Wegener's disease or Wegener's granulomatosis is characterized by the triad of systemic necrotizing vasculitis, necrotizing granulomatous inflammation of the upper and lower respiratory tract, and necrotizing glomerulonephritis 28. The incidence of the disease is estimated up to 8.5/million (range 5.2–12.9/million) with a male-to-female ratio of 1:1. The disease usually involves Caucasians (80–97%) with a mean age at the time of diagnosis of 40–55 years, although persons of every age may be affected 29. The lungs are involved in 90% of cases. In a small percentage of patients, a limited form of the disease that spares the kidney has been described 2930.

Microscopic polyangiitis is a systemic small-vessel vasculitis manifested by pauci-immune necrotic glomerulonephritis (80–100% of patients), pulmonary capillaritis (10–30%), skin lesions and arthralgias 31.

Churg–Strauss syndrome is a systemic disease, typically presenting with an initial asthma/sinusitis phase, followed by eosinophilia and vasculitis 9. In Churg–Strauss syndrome, renal involvement is milder compared with Wegener's disease, Goodpasture's syndrome and microscopic polyangitis 32.

ANCA include three categories of antibodies based on their pattern of indirect immunofluorescence on ethanol-fixed neutrophils: a diffuse cytoplasmic granular pattern, a perinuclear pattern, and an atypical pattern 333435. The antigenic target for cytoplasmic ANCA is proteinase 3 (Pr3), and that for perinuclear ANCA is myeloperoxidase (MPO).

ANCA are detected both through indirect immunofluorescence and ELISA 3637.

Several lines of evidence suggest that ANCA are involved in the pathogenesis of ANCA-associated diseases. Xiao and colleagues demonstrated that anti-MPO IgG administration in mice causes focal necrotizing and crescentic glomerulonephritis 38. In humans, a newborn developed glomerulonephritis and pulmonary haemorrhage after intrauterine transplacental transfer of ANCA IgG against MPO 3940. On the other hand, administration of anti-Pr3 antibodies in mice alone does not induce glomerulonephritis. This administration does, however, aggravate TNF-α-elicited inflammation, suggesting that Pr3 ANCA have a proinflammatory activity in conjunction with a primary inflammatory stimulus 41. In addition, ANCA were shown to enhance interactions between leukocytes and endothelial cells and to cause microvascular haemorrhage 4243. More precisely, the majority of target antigens of ANCA such as Pr3 and MPO are proteolytic enzymes of the azurophilic granules of neutrophils 44. Fixation of ANCA with Pr3 on the endothelial surface induces expression of adhesion molecules and release of IL-8 that causes recruitment and attachment of neutrophils on the endothelial cell surface, leading to vessel wall inflammation, obliteration and damage 45.

Pulmonary–renal syndrome in ANCA-negative systemic vasculitis is very rare and has been described only occasionally in Behçet's disease, in Henoch–Schönlein purpura, in IgA nephropathy and in mixed cryoglobulinaemia 46. In Henoch–Schönlein purpura, acute capillaritis and DAH involve deposition of IgA immuno-complexes along the pulmonary alveoli 47.

This entity includes the patients presenting with DAH, rapidly progressive glomerulonephritis and positive ANCA (either Pr3 or MPO), but with no other manifestation of systemic vasculitis. Fever, malaise, weight loss, myalgias and arthralgias may coexist. Mortality during the first episode of the syndrome exceeds 50%. It is argued that the syndrome represents either a limited type of microscopic polyangiitis or a variant of Wegener's syndrome 5.

Drugs provide one of the potentially reversible causes of ANCA-positive vasculitis. Most frequently they cause perinuclear ANCA/MPO ANCA vasculitis, although cytoplasmic ANCA/Pr3 ANCA vasculitis has also been described 48. The drugs most frequently implicated in the pathogenesis of the syndrome are propylthiouracil and hydralazine. ANCA are detected in 20% of patients receiving propylthiouracil, but only a minority of these patients develop clinical manifestations of systemic vasculitis including Pulmonary–renal syndrome 49. D-Penicillamine, allopurinol and sulfasalazine have also been associated with Pulmonary–renal syndrome.

Discontinuation of the causative drug most frequently leads to regression of the disease; however, some patients continue to present positive ANCA or even recurrent disease, requiring long-term immunosuppressive treatment. In general, drug-induced disease has a more benign course than ANCA-positive Pulmonary–renal syndrome of other aetiology 50. Drugs should therefore be considered a potential cause of MPO vasculitis, particularly among patients with high titres of these antibodies 48.

In patients with Pulmonary–renal syndrome, anti-GBM antibodies are occasionally detected simultaneously with ANCA, most frequently MPO ANCA 5152. The significance of this finding is unknown. No cross-reactivity between the targets of ANCA and anti-GBM antibodies has been found. It has been speculated that ANCA-associated damage of the glomerular membrane uncovers 'hidden antigen' inducing the formation of anti-GBM antibodies 53.

Pulmonary–renal syndrome has been reported more often in systemic lupus erythematosus and systemic sclerosis, and rarely in rheumatoid arthritis and mixed connective tissue disease. DAH ± glomerulonephritis occurs in 2% of systemic lupus erythematosus patients and rarely is the first manifestation of the disease 5455. Immune complex deposition is frequently detected in both the pulmonary and renal vessels with mortality rates between 70% and 90%, among the highest of all causes of Pulmonary–renal syndrome 5455. Pulmonary–renal syndrome is a rare but potentially lethal complication of systemic sclerosis, and often coexists with pulmonary fibrotic disease 56. In this case, renal failure is normotensive, in contrast to the hypertensive nephropathy characterizing systemic sclerosis. ANCA, more often the perinuclear ANCA or MPO ANCA, have been detected in some systemic sclerosis patients 57.

Pulmonary–renal syndrome has been described in the context of diseases characterized by thrombotic microangiopathy, such as antiphospholipid syndrome (APS), thrombotic thrombocytopenic purpura, malignancies and infections.

The term 'pauci-immune' glomerulonephritis has mainly been used to indicate that no immunoglobulins, immune complexes or complement can be detected in renal biopsy, either by immunofluorescence or by electronic microscopy. Rarely, the course of patients with idiopathic pauci-immune glomerulonephritis may be complicated by DAH 56.

Immunosuppression is the cornerstone of treatment in ANCA-associated Pulmonary–renal syndrome. Standard induction-remission regimens include pulse intravenous methylprednisolone (500–1,000 mg) for 3–5 days. As the life-threatening features subside, the dose can then be reduced to 1 mg/kg prednisone (or equivalent) daily for the first month, tapered over the next 3–4 months. Glucocorticoid therapy is combined with cytotoxic agents. Cyclophosphamide is the treatment of choice in critically ill patients with generalized disease, at a dose of 0.5–1 g/m² administered intravenously as a pulse per month or orally (1–2 mg/kg/day) 8788. Severe disease defined by major renal impairment (serum creatinine > 5.7 mg/dl) was recently suggested to be treated with corticosteroids and cyclophosphamide coupled with plasma exchange at least for the first week to increase the likelihood for renal function restoration 9697. There are reports suggesting that extracorporeal membrane oxygenation and activated human factor VII may be beneficial in some critically ill patients with DAH 9899100.

With this treatment, approximately 85% of patients achieve remission 9495. Transition to maintenance therapy may occur 6–12 months after the initiation of induction therapy or after clinical remission 101. The maintenance therapy includes low-dose corticosteroids coupled with cytotoxic agents

Relapse will occur in 11–57% of patients in remission. Some relapses are severe, resulting in end-organ damage. Female or black patients and those patients with severe kidney disease, lung disease or upper airway disease and anti-Pr3 serum antibodies are shown to be more resistant to initial treatment 95. In these cases, the use of alternative agents must be considered. Recent investigation has focused on TNF-α inhibitors, B-cell depletion agents, mycophenolate mofetil, leflunomide and antithymocyte globulin 102103104105106107108109110111112113. As indicated in Table 3, new agents are shown to be effective in certain cases but are followed by high relapse and complication rates. Most data are preliminary and further studies are needed for definite conclusions.

Immunosuppressive treatment should also be urgently initiated in the case of Goodpasture's syndrome. Daily plasma exchange should be started; if tests for anti-GBM antibodies are found to be negative, plasmapheresis is then discontinued. A mean of 14 courses of treatment is usually needed until the anti-GBM antibody titre is normalized. Prompt and aggressive plasmapheresis for ANCA-positive, anti-GBM-positive patients may portend a greater likelihood of renal recovery 11114.

DAH due to systemic lupus erythematosus carries a grave prognosis, and lupus nephritis needs immediate immunosuppressive treatment with cyclophosphamide to prevent end-stage renal disease 115. To avoid the severe side effects of the treatment of systemic lupus erythematosus, including bone marrow suppression, haemorrhagic cystitis, opportunistic infections, malignant diseases and premature gonadal failure, new agents such as mycophenolate mofetil and rituximab are under investigation. Both drugs have led to effective disease remission with low toxicity but with a high relapse rate 116117.

In Pulmonary–renal syndrome related to acute catastrophic APS, the mainstay of therapy is anticoagulation 59.

In cases of Pulmonary–renal syndrome and thrombotic thrombocytopenic purpura, mortality exceeded 90% before the application of plasmapheresis. Today's response to treatment with plasmapheresis reaches 80%. While waiting for plasmapheresis treatment, plasma transfusions are indicated to make up for the inadequate von Willebrand factor cleavage protein 67.

Despite rigorous treatment, almost 66% of patients with small-vessel vasculitis and Pulmonary–renal syndrome will need renal transplantation within less than 4 years of initial presentation. The ICU physician will have to care for patients with end-stage renal disease due to Pulmonary–renal syndrome because of an increased rate of fluid and electrolyte abnormalities, cardiovascular disease, haematological and neurological abnormalities, and bacterial infections. In the post-transplant period, the ICU admission rates for these patients are high and their prognosis remains poor 118.