Rapid progressive glomerulonephritisN01.9

Severe, relatively rare, relapsing, extracapillary proliferating glomerulonephritis (RPGN, cf. Glomerulonephritides, overview ), a pathogenetic process leading to the histologic phenomenon of crescent formation in the glomeruli ("crescentic glomerulonephritis" or "glomerulonephritis with crescent formation") that, if left untreated, leads to rapid, progressive deterioration of renal function (50% drop in glomerulofiltrate within 3 months, terminal renal failure within 6 months) (Haubitz M 2019; Moroni G et al. 2014). Vasculitic skin changes can be observed in rare cases (Ryba M et al 2013).

RPGN occurs either

• primarily idiopathic

or

• secondary as a renal manifestation of systemic vasculitis.

Type1-RPGN, anti-basal membrane RPGN (≤ 10%)

Type 1 RPGN" is an autoimmune glomerulonephritis (GN) with serological detection of antibodies against the glomerular basement membrane (GMB-Ak). Diagnostic evidence is the histological finding with the extracapillary proliferating glomerulonephritis leading to the morphological finding of the glomerular "crescents" which in RPGN is detectable in >50% of the glomerula. The number of crescent formations is a prognostic factor (Piyaphanee N et al. 2017). For the type 1 RPGN, the immunohistological detection of linearly deposited antibodies on the glomerular and alveolar basement membrane (GN+ lung involvement = Goodpasture's syndrome) or only on the glomerular basement membrane (= RPGN without lung involvement) is also required. Detection is performed on kidney tissue by means of DIF (=direct immunofluorescence). The RPGN is probably generated when alveolar-capillary basement membrane collagen is unmasked by respiratory exposure (e.g. cigarette smoke, viral or bacterial infections) or another stimulus, whereby the formation of anti-collagen antibodies reaches a critical threshold. These alveolar basement membrane specific anti-collagen antibodies cross-react with collagen components of the glomerular basement membrane, and by fixing complement initially induce a neutrophil and later monocytic inflammatory response in the kidneys and/or lungs (see Goodpasture's syndrome below).

The type 1 RPGN is divided into:

• Type-1- RPGN with pulmonary hemorrhage (Goodpasture's syndrome). The term Goodpasture's syndrome refers to the combination of a rapid progressive GN + alveolar haemorrhage (up to pulmonary haemorrhages) and the serological and tissue-fixed presence of anti-GBM antibodies.
• Type 1- RPGN without pulmonary hemorrhage: A GN without alveolar hemorrhage in the presence of anti-GBM antibodies is called anti-GBM glomerulonephritis. It is rare. Immunofluorescence staining of the renal biopsy tissue shows linear IgG deposits on the glomerular basement membrane but no pulmonary symptoms. Note: Goodpasture's syndrome can also begin initially without pulmonary bleeding.

Type 2-RPGN (immune complex RPGN, ≤ 40%).

The "Type 2-RPGN" can occur complicatively as an immune complex disease in infectious and connective tissue diseases. It also occurs in other primary glomerulopathies. Diagnostically, the immunofluorescence staining (direct immunofluorescence) of the kidney biopsy with granular deposits of immune complexes on the glomerular basement membrane, partly stored in clusters (humps). Type 2 RPGN is probably caused by previous infections (streptococci or viral infections, e.g. infectious endocarditis, hepatitis B infections, sepsis). Furthermore, this manifestation form can occur as "lupus nephritis" in the context of systemic lupus erythematosus (serological detection of DNA antibodies), in cryoglobulinemia (detection of mixed IgG-/IgM-cryoglobulins).

Type 3 RPGN (Pauci-immune RPGN, ANCA-associated vasculitis; ≤ 50%).

In this form of manifestation, neither immunoglobulins nor complement are detected in kidney biopsies at the glomerular basement membrane. All patients show elevated antineutrophilic cytoplasmic antibodies (p-ANCAs/c-ANCAs) mostly antiproteinase 3-ANCAs (PR3-ANCAs), myeloperoxidase-ANCAs (MPO-ANCAs) or h-LAMP-2-Ak (antibodies against lysosome-associated membrane protein-2). There are signs of systemic vasculitis.

This disease group includes:

• Renal course of microscopic polyangitis (M30.0) - renal involvement in 70% of cases.
• Renal form of granulomatosis with polyangiitis (Wegener's granulomatosis - M31.3).

Rarer:

• Eosinophilic granulomatosis with polyangiitis (M0.1) also called Churg-Strauss syndrome. Renal involvement in 20% of cases
• IgA vasculitis (Purpura Schönlein-Henoch) (D69.0). Renal involvement in 30% of cases
• Cryoglobulinemic vasculitis (D89.1). Renal involvement in 50% of cases

Incidence: <1:1000,000 per year. The RPGN affects 10-15% of patients with glomerulonephritis (GN).

10, 60 years. In larger pediatric populations the mean age was 10.6 ± 3.0 years; m: w=1:1 (Piyaphanee N et al. 2017)

The clinical prodromes are usually nonspecific, insidious, with weakness, fatigue, fever, nausea, vomiting, anorexia, arthralgia and abdominal pain. Some patients present with sudden hematuria. Other patients present with sudden pulmonary hemorrhage (typical leading symptom of Good-Pasture syndrome). About 50% of patients suffer from acute edema and rapidly progressive renal failure after influenza-like prodromes. Nephrotic syndrome is present in 10-30%. Hypertension is uncommon and rarely severe.

The histological picture of the RPGN is varied, since the disease progresses in relapses (especially type 2 and type 3 RPGN) and thus older and fresh foci coexist. Characteristic for all RPGN types are focal proliferations of glomerular epithelial cells that form crescent-shaped cell clusters (crescent-shaped GN: crescent-shaped formation detectable in > 50% of glomeruli). Further detection of necroses within the glomerular cluster. The results of direct immunofluorescence microscopy (DIF) allow further typing.

Clinic (initially little specific, subacute, constitutional or non-specific symptoms such as fatigue, fever, anorexia, arthralgia, abdominal pain). Evidence of progressive renal failure over weeks to months accompanied by hematuria or pulmonary hemorrhage).

Laboratory: Urine sediment: dysmorphic erythrocytes or erythrocyte cylinders.Serum creatinine is almost always elevated. Blood count usually shows anemia and often leukocytosis. Serum complement level (initially decreased).

Serological clarification (DNA-Ak, p-ANCA, c-ANCA, GBM-Ak; antistreptolysin-O-antibodies; cryoglobulins (immune complex-RPGN)

Kidney biopsy (in case of doubt about the diagnosis) with histological/immunohistological work-up (note: immunohistological diagnosis is performed on unfixed tissue)

Since the RPGN is not a defined disease, but a group of diseases, the clinical course and prognosis depends on the respective form of manifestation (Moroni G et al. 2014). For all patients with RPGN, the principle of early therapy applies. Patients with focal ANCA-associated glomerulonephritis have the best prognosis. For Goodpasture's syndrome, vigorous early immunosuppressive therapy (corticosteroids + cyclophosphamide) is considered an important prognostic factor (see Goodpasture's syndrome below). Rituximab has a well-established status as a complementary therapy option in adults (Appel GB et al. 2018). In severe cases (creatinine >6mg/dl) plasmapheresis is indicated in addition to immunosuppression.

Patients with a high percentage of necrotic or scarred glomeruli are already in an advanced stage of the disease, the chance that they will respond to treatment decreases with the percentage of destroyed glomeruli. In paediatric populations, 1/3 of patients developed ESRD (end-stage renal disease) (Piyaphanee N et al. 2017).

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