Differential Diagnosis of the Pulmonary-Renal Syndrome

The pulmonary-renal syndrome involves the combination of diffuse alveolar hemorrhage and a rapid progressive glomerulonephritis (RPGN). It is usually a systemic vasculitis that can led through a vast vasculitic process to life-threatening injury to the involved organs lung and kidney [Niles 1996, Salant 1987, Boyce 1986, Gallagher 2002 & De Groot 2005]. In the differential diagnosis other diseases of acute renal and lung injury with alveolar hemorrhage without RPGN have to be discussed.

evidence of a pathogenetic role of ANCA.Myeloperoxidase (MPO) and proteinase 3 (Pr3) are detected in the cytoplasm of non-stimulated neutrophils.It is assumed that cytokines (e.g.TNF, interleukins) raise the expression of Pr3 and MPO on the cell surface of granulocytes and thus a reaction of these antigens with ANCA is possible.This process leads to activation of granulocytes and release of adhesion molecules to the interaction of leukocytes with vascular endothelial cells.Finally cell necrosis and apoptosis contribute to vascular inflammation process [Bosch 2006].

Diagnosis 2.2.1 Basic steps
As with any systemic vasculitis the diagnosis of pulmonary-renal syndrome is made in three steps: 1. Adequate evaluation and networking of existing and past patient's symptoms.2. Establishing the diagnosis by laboratory, technical and biopsy examinations.3. Differential diagnosis of vasculitis.

Imaging
The value of imaging refers to the extent of pulmonary capillaritis resulting in diffuse alveolar hemorrhage: in a conventional X-ray or in a computer tomography of the chest confluent or mixed interstitial-alveolar infiltrates are found (Fig. 1).

Serology
Antibodies against the glomerular basement membrane (GBM) can be found typically in the rare Goodpasture's syndrome (Tab.1).The above briefly described heterogeneous pathogenesis of small vessels vasculitis results in the immunological classification considering serological / immunological parameters such as anti-neutrophil-cytoplasmic antibodies (ANCA) by immunfluorescence-optical findings (perinuclear or cytoplasmtic fluorescence) or ELISA against the target antigen proteinase 3 or myeloperoxidase (Tab. 1) [Bosch 2006].In addition, the eosinophils, IgE and the extended autoimmunserology: anti-nuclear factor (ANA), anti-ds-DNA, C3, C4 and cryoglobulins can be determined.

Disease
Proteinase The rapid availability of these antibodies has improved the time to establish an early diagnosis, which is prognostically relevant [Saxena 1995].

Renal biopsy
The diagnosis of RPGN is done by renal biopsy: in light microscopy there is a glomerulonephritis with crescent formation in the Bowman's capsule compartment (extracapillary proliferation) in more than 50% of the glomeruli.The further work is carried out by immunohistochemistry and electron microscopy.
In immunohistology, the type of immunoglobulins and the deposition pattern (capillary, mesangial, granular, linear along the glomerular basement membrane) differ.Only in Goodpasture syndrome, linear deposits are found along the glomerular basement membrane.In case of an ANCA triggered form immune deposits are missing (pauciimmune RPGN).In contrast, in immune-complex vaculitis there can be found a different picture, usually with granular deposition of IgG, IgM, IgA or complement.

Bronchoscopy
The diagnosis of diffuse alveolar hemorrhage includes the clinical picture and a brochoscopy with a bronchoalveolar lavage and the microscopic detection of siderophages.Especially in the case of diffuse infiltrates in imaging without hemopytsis a bronchoscopy can be helpful and a definite diagnosis can be established [Hauber 2007].

Differential diagnosis of the pulmonary-renal syndrome
As already stated the pulmonary-renal syndrome is usally caused by a systemic small vessels vasculitis (Tab.2), these can be categorized [Niles 1996, Salant 1987, De Groot 2005, Jennette 1994& Falk 1997]: morphological criteria (size of the infesting vessels, presence or absence of granulomas), -etiological criteria (idiopathic or secondary forms) and immunological criteria (ANCA-associated vasculitis, immune-complex vasculitis or caused by anti-basement antibodies).
Renal involvement is present in many systemic diseases, especially in the small vessel vasculitis -pointed out by Gallo in the New England Journal of Medicine: "The kidney is often a window on systemic disease" [Gallo 1991].
The suspicion of a pulmonary-renal syndrome in an ANCA-associated systemic vasculitis can often be taken from a careful history and thorough clinical examination with detection of other vasculitic signs (eye inflammation, intractable rhinitis / sinusitis, skin rashes, arthralgia, myalgia or polyneuropathy) (Fig. 2).
Fig. 2. General symptoms and signs of organ involvement in systemic small vessels vasculitis.Table 2.The most important differential diagnoses of pulmonary-renal syndrome with clinical features, laboratory and histological findings.

Wegener's granulomatosis
Wegener's granulomatosis is a necrotizing vasculitis of the small and medium-sized vessels, associated with granulomas inflammation of the upper and lower respiratory tract and the frequent finding of glomerulonephritis.In active disease in about 90% of cases c-ANCA are directed against proteinase 3 (Tab.1 and 2). Figure 3 shows the predominant symptoms in image and Figure 4 in number (at onset and during disease) [Hoffmann 1992].

Microscopic polyangiitis
Microscopic polyangiitis is characterized by a necrotizing vasculitis of small vessels with minimal or missing immune deposits and an inflammation of the pulmonary capillaries.Typically, there are p-ANCA directed against myeloperoxidase (Tab. 1 and 2) [Jennette 1994& Falk 1997].Wegener`s granulomatosis and Microscopic polyangiitis shows comparable organ involvement, but the symptoms of the upper respiratory tract are usally milder in Microscopic polyangiitis, because there is no granulomatous inflammation.Compared to Wegener's granulomatosis disease recurrence is rare in patients with Microscopic polyangiitis.