Goodpasture's syndrome N08.-

Goodpasture Ernest, 1919

Goodpasture's syndrome is a very rare, idiopathic autoimmune disease clinically defined by the simultaneous occurrence (in about 70% of cases) of antibasal membrane glomerulonephritis (GN) from the group of "rapid progressive GN" and diffuse alveolar hemorrhage (Greco A et al. 2015; McAdoo SP et al. 2017).

Rare disease; new disease rate is 0.5-1.0 million people/year (Hellmark T et al. 2014); men are mainly affected.

Autoantibodies (mostly IgG1 and IgG4, in 1/3 of the cases also IgA and IgM) against the non-collagenous domain of the alpha-3 chain of collagen type 4 of the glomerular and alveolar basement membrane are detectable) which are linearly deposited on the basement membrane. This process leads to complement activation and the initiation of a cytotoxic reaction (Alenzi FQ et al. 2012). The pathogenetic connection is established by an antigenic relationship between the basement membranes in the kidney and in the pulmonary alveoli.

Ultimately, the exact cause of the immunological misreaction is not known. In the presence of a genetic disposition (HLA-DRB1; HLA-DR2; HLA-DR4- Hellmark T et al. 2014), demasking of the antigens by infections (viral infection), cigarette smoke and other noxae is being discussed. Connections with pulmonary tuberculosis have been described.

The disease can occur at any age; the peak of manifestation is between 20 and 40 years of age. Older people apparently have a milder course.

General symptoms: weakness, arthralgias, fever, chills, nausea, vomiting, weight loss.

Pulmonary: cough, dyspnea, nonpleural chest pain, recurrent pulmonary hemorrhage (pulmonary hemorrhage may manifest weeks to months before renal involvement) which may lead to fulminant hemoptysis and then severe anemia. About 4% of Good Pasture patients start monosymptomatic with pulmonary symptomatology (Huart A et al 2016).

Kidney: Onset of acute tubulointerstitial nephritis with proteinuria, haematuria (up to 40% of patients have macrohaematuria), oliguria (nephritic syndrome) and rapidly progressive renal failure. 30% of cases of Good-Pasture syndrome begin monosymptomatically with renal symptomatology (Huart A et al. 2016).

Characteristic clinic, imaging, laboratory (circulating glomerular anti-basement membrane antibodies).

• Inspiratory rales, possibly muffled tapping sound.
• Pulmonary function test: evidence of restrictive ventilation disorder. Arterial hypoxemia in hyperventilation with increase in CO transfer factor, due to binding to hemoglobin located in the alveoli (in the acute bleeding phase).

Imaging:

• Radiologically, characteristic coarse and confluent pulmonary infiltrates are found.

Laboratory:

• In mild forms, iron deficiency anemia; in severe, possibly rapid Hb drop.
• Detection of circulating glomerular anti-basement membrane antibodies in serum. About 1/3 of patients are also (additionally) pANCA positive(this clientele is characterized by a better response to immunosuppressive therapy).
• Urine: Evidence of micro/macrohematuria and proteinuria.
• Possibly: Bronchoalveolar lavage: With reddish brown discoloration of the lavage fluid.

Histology (alveolar/renal tissue biopsy):

• Detection of anti-basement membrane Ak. In direct immunofluorescence (DIF), detection of IgG-Ak linearly attached to the basement membrane and C3.

Idiopathic pulmonary hemorrhage,

Hemosiderosis

Wegener's granulomatosis (granulomatosis with polyangiitis)

Systemic lupus erythematosus

Behcet's disease

Other variants of the Rapid progressive GN (RPGN)

Massive blood loss due to the lung bleeding; hypertensive crisis, kidney failure

In early stages of the disease, immediate daily plasmapheresis (for 2-3 weeks) until the serum concentration of anti-GBM antibodies remains stably low.

Supplemental immunosuppressive therapy with glucocorticoids (initial 1g methylprednisolone for 3 days, followed by symptom-related reduction to 20 mg p.o./day for 6-12 months) + cyclophosphamide (2 mg/kg bw p.o. once daily for 6-12 months). If the clinical findings stabilize, cyclophosphamide can be replaced by the less toxic azathioprine. Total therapy duration: 6-9 months.

At a later stage, when the patient is already on dialysis and there is no lung involvement, neither plasmapheresis nor immunosuppressive therapy is indicated.

The indication for kidney transplantation can be given if the basement membrane ACT titre is no longer detectable.

Without therapy, Goodpasture's syndrome is always lethal. The prognosis is therefore strongly dependent on the time of diagnosis, as it is rapidly progressive. Preexisting chronic interstitial pneumonia worsens the prognosis significantly (Tashiro H et al. 2017). In larger studies the survival rate after 1 year is 86.9% (Huart A et al. 2016).

Haemoptysis can be a good prognostic sign as it leads to an earlier diagnosis!

1. Alenzi FQ et al (2012) Cellular and molecular aspects of Goodpasture syndrome. Iran J Kidney Dis 6:1-8.
2. Fox HL et al (2001) Goodpasture syndrome: pathophysiology, diagnosis, and management. Nephrol Nur J 28:305-310.
3. Greco A et al (2015) Goodpasture's syndrome: a clinical update. Autoimmune Rev 14:246-253.
4. Hellmark T et al (2014) Diagnosis and classification of Goodpasture's disease (anti-GBM). J Autoimmune 48-49:108-112.
5. Huart A et al (2016) French Society of Hemapheresis. Outcomes of patients with Goodpasture's syndrome: A nationwide cohort-based study from the French Society of Hemapheresis. J Autoimmune 73:24-29.
6. McAdoo SP et al (2017) Anti-Glomerular Basement Membrane Disease. Clin J Am Soc Nephrol 12:1162-1172.
7. Tashiro H et al (2017) Pre-existing chronic interstitial pneumonia is a poor prognostic factor of Goodpasture's syndrome: a case report and review of the literature. J Med Case Rep 11:102.