Goodpasture syndrome is a rare, organ-specific autoimmune disease (Gell and Coombs classification type II). It is mediated by anti-glomerular basement membrane (anti-GBM) antibodies [1]. The disease was first described by Dr Ernest Goodpasture in 1919 [2], and the glomerular basement membrane was subsequently identified as the target antigen in the 1950s. More than a decade later, researchers demonstrated the association between antibodies derived from affected kidneys and nephritis [1].

The disorder is characterized by autoantibodies directed against the NC1 domain of the α3 chain of type IV collagen (α3(IV)NC1) in the glomerular and alveolar basement membranes, leading to activation of the complement cascade and subsequent tissue injury [1, 3]. In addition to α3(IV)NC1, other components of the glomerular basement membrane, such as peroxidasin and laminin-521, have recently been identified as target antigens [4]. The exclusive presence of this α3 subunit in basement membranes of the lungs and kidneys accounts for the selective involvement of these two organs in GPS [1]. This distinct immunopathology underlies the entity historically referred to as GPS. The term GPS was historically used to describe pulmonary-renal involvement in the presence of anti-GBM antibodies [5]. However, the preferred term today is anti-GBM disease, as atypical forms have since been described [5]. Typical cases involve IgG autoantibodies against the α3(IV)NC1 domain, usually resulting in a positive ELISA and rapidly progressive glomerulonephritis with or without pulmonary hemorrhage [5]. Atypical variants may be seronegative in standard ELISAs and involve other immunoglobulin subclasses such as IgA or IgG4; these forms often show milder or incomplete clinical manifestations – such as isolated renal or pulmonary disease – while retaining similar histological features to classic anti-GBM disease [5].

The etiology and triggering factors for anti-GBM production remain unknown. Because patients with specific human leukocyte antigen (HLA) types are more susceptible, an HLA-associated genetic predisposition appears likely [1, 6]. However, because this strongly associated allele is relatively common, additional behavioural or environmental factors are believed to influence immune response and disease expression.  These may include respiratory infections (e.g., influenza A2), exposition to hydrocarbon fumes, organic solvents, metallic dust, tobacco smoke, certain drugs (e.g., rifampicin, allopurinol, cocaine), as well as physical damage to basement membrane (e.g., lithotripsy or membranous glomerulonephritis) or lymphocyte-depletion therapy (such as alemtuzumab), although conclusive evidence is lacking [1, 3, 6, 7]. 

The incidence is estimated at approximately 0.5 to 2 cases per million population per year in European Caucasoid and Asian groups [1, 8, 9]. Unusually for an autoimmune disease, GPS affects more males than females among Caucasians and is even more prevalent in the Maori people of New Zealand [8]. It accounts for acute renal failure in approximately 10-20 % of cases of rapidly progressive or crescentic glomerulonephritis. The age distribution shows two peaks – one between 20 and 30 years (often with more pronounced hemorrhagic features) and another between 60 and 70 years. In the younger group, men are more frequently affected, whereas in the older age group, women predominate [1, 6]. Furthermore, older patients more often present with isolated renal involvement [10].

GPS typically presents as acute renal failure caused by a rapidly progressive glomerulonephritis, often accompanied by pulmonary hemorrhage that can be life-threatening without prompt diagnosis and treatment [1, 3]. Symptoms may develop gradually or progress rapidly within a few days [11]. Systemic and nonspecific initial symptoms such as fatigue, weakness, lethargy, nausea, vomiting, diarrhea, pruritus, loss of appetite, and weight loss are common. Patients may also experience malaise, chills, fever, headache, arthralgias, pallor, general discomfort, or, in rare cases, seizures [1, 6, 12-14]. 

About 60-80 % of patients present with both renal and pulmonary involvement, whereas 20-40 % exhibit renal disease alone, and fewer than 10 % have isolated pulmonary involvement [1, 6, 8]. Pulmonary symptoms include hemoptysis, dry cough, shortness of breath, inspiratory crackles over lung bases, chest pain, cyanosis, dyspnea, tachypnea, which may progress to respiratory failure [1]. In children, pulmonary findings rarely occur before puberty [15]. 

Renal involvement may result in hematuria, foamy urine, peripheral swelling, high blood pressure, edema, uremia, oliguria, anuria, and flank pain [1, 6, 7]. Autoimmune inner ear disease (AIED) may also occur, presenting with vertigo, tinnitus (ringing, hissing or roaring) and sudden hearing loss in one ear, progressing rapidly to the other within weeks or months [1]. More than 90 % of the patients with GPS have circulating serum anti-GBM antibodies [16]. 

A definitive diagnosis is established by percutaneous kidney biopsy showing the characteristic linear IgG deposition along the glomerular basement membrane (preferred over lung biopsy) and confirmed by immunofluorescence and enzyme-linked immunosorbent assay (ELISA) testing for pathognomonic circulating anti-GBM antibodies [1]. Chemiluminescence immunoassay (ChLIA) offers a highly sensitive alternative for anti-GBM antibody detection [5]. Atypical variants, including IgA- or IgG4-dominant forms may present with milder or incomplete clinical courses, occasionally resulting in false-negative ELISA findings and diagnostic uncertainty [5].

Differential diagnosis include Granulomatosis with polyangiitis (formerly Wegener’s granulomatosis), systemic lupus erythematosus, microscopic polyangiitis, other forms of systemic vasculitides (e.g., Churg-Strauss syndrome, essential mixed cryoglobulinaemia, Henoch-Schönlein purpura, microscopic polyarteritis, drug-induced vasculitis), pulmonary embolism, and other inflammatory or infectious disorders such as Pneumocystis carinii pneumonia or rheumatoid arthritis [1, 6, 8].

Because of the rarity of the disorder, systematic data and controlled therapeutic trials are lacking. Nevertheless, rapid recognition and treatment are crucial in GPS. The three key therapeutic principles are: (1) rapid removal of circulating antibodies, primarily by plasmapheresis; immunoadsorption represents an alternative to plasma exchange with comparable efficacy (2) inhibition of further antibody production through immunosuppressive therapy (high-dose corticosteroids and cyclophosphamide are standard, though other agents as azathioprine or rituximab may be used); and (3) elimination of potential triggering agents that may have initiated antibody formation [1, 17]. Imlifidase, an IgG-cleaving enzyme, is currently being investigated as a new therapeutic approach, among others, for GPS [17, 18]. Atypical forms (IgA-dominant, seronegative, or isolated pulmonary) require individualized treatment [17].

Renal replacement therapy (RRT) or kidney transplantation may be required to restore renal function. Most centers recommend at least six months of sustained negative anti-GBM antibody testing before undertaking transplantation [19]. Several case reports describe the use of extracorporeal membrane oxygenation (ECMO) for refractory hypoxemic respiratory failure in patients with severe pulmonary hemorrhage due to GPS [7, 11, 15, 20, 21]. 

GPS carries a poor prognosis, which largely depends on the timing of diagnosis and initiation of treatment for this rapidly progressive disease. If left untreated, mortality ranges from 77-96% [7]. With the triple therapeutic regimen comprising corticosteroids, immunosuppressive agents, and plasmapheresis, one-year survival rates of 70-90% and five-year survival up to 80 % have been reported [1, 6]. Among patients with RRT for end-stage renal disease in New Zealand and Australia, the median survival was nearly six years [9]. In addition to age, a history of pulmonary hemorrhage is associated with an increased risk of mortality while on RRT [9, 21]. Patients who are dialysis-dependant at presentation rarely achieve full recovery of renal function. However, recent population-based data suggest a 5.8 % one-year recovery rate of kidney function among dialysis-dependent patients with anti-GBM disease [22]. Those requiring only temporary RRT may regain satisfactory renal function, and fewer than 30 % of surviving patients remain dependant on long-term dialysis [1, 6, 21, 23]. 

Double positivity for serum antineutrophil cytoplasmic antibodies (ANCAs) and anti-GBM is another indicator of poorer renal prognosis and higher mortality [6]. Pulmonary involvement, by contrast, often resolves completely with prompt and adequate treatment [8, 20]. Low serum C3 complement levels have also been associated with a poorer overall and renal prognosis in GPS [24]. Long-term outcomes in children with GPS may be more favorable than in adults [15].