Rapidly progressive glomerulonephritis

Rapidly progressive glomerulonephritis (RPGN) is a syndrome of the kidney that, if left untreated, rapidly progresses into acute renal failure and death within months. In 50% of cases, RPGN is associated with an underlying disease such as Goodpasture syndrome, systemic lupus erythematosus, or Wegener granulomatosis; the remaining cases are idiopathic. Regardless of the underlying cause, RPGN involves severe injury to the kidney's glomeruli, with greater than 50% of the glomeruli containing characteristic crescent-shaped scars. Because of this microscopic feature, RPGN is also called crescentic glomerulonephritis.

Patients with RPGN have blood in the urine (hematuria), urinary protein (proteinuria), and occasionally high blood pressure (hypertension) and edema. The clinical picture is consistent with nephritic syndrome, although the degree of proteinuria may occasionally exceed 3 g/24 h, a range associated with nephrotic syndrome. Untreated disease may progress to decreased urinary volume (oliguria), which is associated with poor kidney function.

RPGN is classified into three types, all of which involve immune-mediated damage to the glomeruli. In type I RPGN, which accounts for approximately 20% of RPGN cases, injury is caused by antibodies directed against the glomerular basement membrane. Type II RPGN accounts for roughly 25% of RPGN cases and is characterized by the deposition of immune complexes in the glomerulus. The remainder of RPGN cases are type III, or pauci-immune RPGN, which features antibodies directed against neutrophils (anti-neutrophil cytoplasmic antibodies, ANCA).

Treatment depends on the underlying disease process. For example, plasmapheresis, corticosteroids, and cytotoxic drugs may promote recovery in Goodpasture syndrome, a cause of type I RPGN. Despite even early treatment, however, many patients with RPGN may ultimately require dialysis and possibly renal transplant.

Type I
Accounting for approximately 20% of RPGN, type I RPGN is characterized by the presence of autoantibodies directed against the glomerular basement membrane (GBM). It is also called anti-GBM glomerulonephritis. The antibodies are directed against a particular protein found in the GBM, type IV collagen, specifically the noncollagenous region of its α3 chain.

In addition to the anti-GBM antibodies, some cases of type I RPGN are also associated with antibodies directed against the basement membrane of lung alveoli, producing Goodpasture syndrome. The majority of type I disease, however, features anti-GBM antibodies alone; these cases are considered idiopathic.

Type II
RPGN caused by the deposition of immune complexes accounts for 25% of RPGN and is classified as type II. Thus any immune complex disease that involves the glomerulus may progress to RPGN if severe enough. These diseases include systemic lupus erythematosus, postinfectious glomerulonephritis, Henoch-Schönlein purpura, and IgA nephropathy.

Type III
Also known as pauci-immune RPGN, type III RPGN accounts for 55% of RPGN and features neither immune complex deposition nor anti-GBM antibodies. Instead, the glomeruli are damaged in an undefined manner, perhaps through the activation of neutrophils in response to anti-neutrophil cytoplasmic antibodies (ANCA). Type III RPGN may be isolated to the glomerulus (primary, or idiopathic) or associated with a systemic disease (secondary). In most cases of the latter, the systemic disease is an ANCA-associated vasculitis such as Wegener granulomatosis, microscopic polyangiitis, or Churg-Strauss syndrome.

Classification of type III RPGN into primary or secondary may be unnecessary, as primary type III RPGN and secondary type III RPGN may represent a spectrum of the same disease process.

Signs and symptoms
Most types of RPGN are characterized by severe and rapid loss of kidney function featuring severe hematuria (blood in the urine), red blood cell casts in the urine, and proteinuria (protein in the urine), sometimes exceeding 3 g protein/24 h, a range associated with nephrotic syndrome. Some patients also experience hypertension (high blood pressure) and edema. Severe disease is characterized by pronounced oliguria or anuria, which portends a poor prognosis.

When the cause of RPGN is Goodpasture syndrome or vasculitis that involves the lungs (such as Wegener granulomatosis), the lungs and upper airway may be involved. Patients with such underlying diseases may present with cough, hemoptysis, dyspnea, nasal bleeding, obstruction, or sinusitis.

Serum analysis often aids in the diagnosis of a specific underlying disease. The presence of anti-GBM antibodies suggests type I RPGN; antinuclear antibodies (ANA) may support a diagnosis of systemic lupus erythematosus and type II RPGN; and type III and idiopathic RPGN are frequently associated with ANCA-positive serum.

Crescent formation
Despite the wide variety of diseases that cause RPGN, all types of RPGN are characterized by glomeruluar injury and the formation of crescents. Severe injury and GBM rupture leads to the leakage of plasma proteins through the GBM. Of these proteins, fibrin is thought to contribute most strongly to crescent formation. Epithelial cells lining the Bowman capsule respond to the leaked fibrin and proliferate. Infiltrating white blood cells such as monocytes and macrophages may also proliferate. These proliferating cells surround and compress the glomerulus, forming a crescent-shaped scar that is readily visible on light microscopy of a renal biopsy.