Extracapillary (rapidly progressive) glomerulonephritis

Extracapillary glomerulonephritis is the presence of extracapillary cellular or fibrocellular crescents in more than 50% of glomeruli, clinically manifested by rapidly progressive glomerulonephritis. Rapidly progressive glomerulonephritis is considered an urgent nephrological situation requiring urgent diagnostic and therapeutic measures. Rapidly progressive glomerulonephritis is clinically characterized by acute nephritic syndrome with rapidly progressive (over several weeks or months) renal failure. The incidence of rapidly progressive glomerulonephritis is 2-10% of all forms of glomerulonephritis registered in specialized nephrological hospitals.

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Pathogenesis

"Half moons" are a consequence of severe damage to the glomeruli with rupture of the capillary walls and penetration of plasma proteins and inflammatory cells into the space of the Shumlyansky-Bowman capsule. The cellular composition of the "half moons" is mainly represented by proliferating parietal epithelial cells and macrophages. The evolution of the half moons - reverse development or fibrosis - depends on the degree of accumulation of macrophages in the space of the Shumlyansky-Bowman capsule and its structural integrity. The predominance of macrophages in the cellular half moons is accompanied by rupture of the capsule, subsequent entry of fibroblasts and myofibroblasts from the interstitium, synthesis of matrix proteins by these cells: collagens of types I and III, fibronectin, which leads to irreversible fibrosis of the half moons.

An important role in regulating the processes of attraction and accumulation of macrophages in the crescents is given to chemokines - monocyte chemoattractant protein type 1 and macrophage inflammatory protein-la (MIP-1a). High expression of these chemokines in the places of formation of crescents with a high content of macrophages is detected in rapidly progressing glomerulonephritis with the most severe course and unfavorable prognosis.

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Symptoms extracapillary (rapidly progressive) glomerulonephritis

The symptoms of rapidly progressive glomerulonephritis include two components: acute nephritic syndrome (acute nephritis syndrome) and rapidly progressive renal failure, which, in terms of the rate of loss of renal function, occupies an intermediate position between acute and chronic renal failure, i.e. it implies the development of uremia within a year from the moment of the first signs of the disease.

This rate of progression corresponds to a doubling of serum creatinine levels every 3 months of illness. However, fatal loss of function often occurs in just a few (1-2) weeks, which meets the criteria for acute renal failure.

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Forms

Immunopathogenetic types of rapidly progressive glomerulonephritis

Depending on the leading mechanism of damage, clinical picture and laboratory parameters, three main immunopathogenic types of rapidly progressive glomerulonephritis are currently distinguished.

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Type I ("antibody", "anti-BMC nephritis")

Caused by the damaging effect of antibodies on the glomerular basement membrane. It exists as an isolated (idiopathic) kidney disease or as a disease with lung and kidney damage (Goodpasture's syndrome). It is characterized by a "linear" type of antibody glow in a renal biopsy and the presence of circulating antibodies to the glomerular basement membrane in the blood serum.

Type II ("immune complex")

Caused by immune complex deposits in various parts of the renal glomeruli (in the mesangium and capillary wall). A "granular" type of glow is detected in the renal biopsy; anti-GBM and ANCA are absent in the serum. Most typical for rapidly progressive glomerulonephritis associated with infections (poststreptococcal rapidly progressive glomerulonephritis), cryoglobulinemia, and systemic lupus erythematosus.

Type III ("poorly immune")

The damage is caused by cellular immune reactions, including neutrophils and monocytes activated by ANCA. Immune reactant luminescence (immunoglobulins, complement) in the biopsy is absent or insignificant (pauci-immune, "low-immune" glomerulonephritis), ANCA directed to proteinase-3 or myeloperoxidase are detected in the serum. This type of ECG is a manifestation of ANCA-associated vasculitis (microscopic polyangiitis, Wegener's granulomatosis) - its local renal or systemic variant.

Among all types of rapidly progressive glomerulonephritis, more than half (55%) is ANCA-associated rapidly progressive glomerulonephritis (type III), the other two types of rapidly progressive glomerulonephritis (I and II) are distributed approximately equally (20% and 25%).

The presence of certain serological markers (and their combinations) can be used to suggest the type of luminescence in a renal biopsy and, accordingly, the mechanism of damage - the pathogenetic type of rapidly progressive glomerulonephritis, which is important to consider when choosing a treatment program.

Diagnostics extracapillary (rapidly progressive) glomerulonephritis

Diagnosis of rapidly progressive glomerulonephritis requires exclusion of conditions that outwardly resemble (imitate) rapidly progressive glomerulonephritis, but have a different nature and therefore require a different therapeutic approach. Three groups of diseases are distinguished:

• nephritis - acute post-infectious and acute interstitial; as a rule, with a favorable prognosis, in which only in some cases are immunosuppressants used;
• acute tubular necrosis with its own patterns of progression and treatment;
• a group of vascular diseases of the kidneys that combine damage to vessels of different calibers and different natures (thrombosis and embolism of large renal vessels, scleroderma kidney, thrombotic microangiopathy ). In most cases, these conditions can be excluded clinically. On the other hand, the characteristics of extrarenal symptoms may indicate the presence of a disease in which rapidly progressive glomerulonephritis often develops ( systemic lupus erythematosus, systemic vasculitis, drug reaction).

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Treatment extracapillary (rapidly progressive) glomerulonephritis

Extracapillary glomerulonephritis (its clinical equivalent is rapidly progressive glomerulonephritis) occurs more often as a manifestation of a systemic disease (systemic lupus erythematosus, systemic vasculitis, essential mixed cryoglobulinemia, etc.), less often as an idiopathic disease, however, the treatment of extracapillary (rapidly progressive) glomerulonephritis is the same.

The prognosis of patients with rapidly progressive glomerulonephritis is primarily determined by the severity (extent) of the lesion - the number of glomeruli with crescents. With extensive lesions (crescents in 50% of glomeruli or more), rapidly progressive glomerulonephritis rarely undergoes spontaneous remission, and in the absence of special therapy, renal survival does not exceed 6-12 months.

With a small degree of damage (30% of glomeruli or less), especially if the crescents are superimposed on previously existing glomerulonephritis (eg, IgA nephritis, poststreptococcal nephritis), impaired renal function can spontaneously recover, sometimes even to the original level.

With moderate damage (30-50% of glomeruli), the loss of renal function occurs more slowly, but without treatment of extracapillary (rapidly progressing) glomerulonephritis, terminal renal failure still develops, so immunosuppressive therapy is indicated for all patients with rapidly progressing glomerulonephritis with extensive crescents (with damage to 50% of glomeruli or more), unless clinical and morphological prognostic factors indicate irreversibility of the process even with “aggressive” treatment and if immunosuppressive therapy is not associated with a high risk of complications.

If a biopsy cannot be performed (which is an all too common situation), the treatment approaches are the same.

Principles of treatment of rapidly progressive glomerulonephritis (extracapillary glomerulonephritis)

• To prevent irreversible catastrophic loss of renal function, it is necessary to urgently begin treatment immediately after establishing a clinical diagnosis of rapidly progressive glomerulonephritis (acute nephritic syndrome in combination with rapidly progressive renal failure with normal kidney size and exclusion of other causes of acute renal failure). A delay in treatment for several days may worsen its effectiveness; if anuria develops, treatment is almost always unsuccessful. This is the only form of glomerulonephritis for which active therapy should be chosen with less concern about the possibility of side effects, since the toxicity of treatment in patients cannot be more severe than the natural outcome.
• An urgent serum test for anti-GBM-AT and ANCA is necessary (if possible); biopsy is desirable for diagnosis (detection of rapidly progressive glomerulonephritis and the type of antibody glow - linear, granular, "low-immune") and, to a greater extent, for assessing the prognosis and confirming the need for aggressive therapy.
• Treatment should be started without delay, even before receiving the results of diagnostic tests (serological, morphological) with pulse therapy with methylprednisolone, which is currently considered an international standard. Doctors' experience shows that such tactics are fully justified, including due to the impossibility of performing a biopsy in many patients. Alkylating drugs (preferably cyclophosphamide in ultra-high doses) are a necessary additional component of therapy to glucocorticoids, especially in patients with vasculitis (local renal or systemic) and circulating ANCA.
• Intensive plasmapheresis in combination with immunosuppressants is valuable:
  • in anti-GBM nephritis, provided that treatment is started early, before the need for hemodialysis arises;
  • in patients with non-anti-GBM nephritis who already require hemodialysis but do not have morphological signs of irreversibility of the disease;
  • may also be useful in other situations - before administering cyclophosphamide "pulses".
• The long-term prognosis depends on the severity of the initial kidney damage, the frequency of relapses, and the presence of a systemic disease. An important task of further therapy is the prevention and treatment of exacerbations (timely increase in the dose of immunosuppressants) and the impact on non-immune mechanisms of glomerulonephritis progression (ACE inhibitors).

Recommendations for the treatment of individual forms of rapidly progressive glomerulonephritis

Anti-GBM nephritis (type I by Glassock, 1997), including Goodpasture's syndrome. With creatinine <600 μmol/l (6.8 mg%) - prednisolone [60 mg/(kg x day) orally], cyclophosphamide [2-3 mg/kg x day)] and daily intensive plasmapheresis (10-14 sessions with removal of up to 2 l of plasma per session). Upon achieving stable improvement, the dose of prednisolone is gradually reduced over the next 12 weeks, and cyclophosphamide is completely discontinued after 10 weeks of treatment. Patients with stabilized moderate renal failure and proteinuria are shown long-term use of ACE inhibitors. In case of exacerbations, the same approaches are used again.

At creatinine levels >600 μmol/l, aggressive therapy is of little use. Patients requiring hemodialysis should be treated conservatively, unless the disease has recently begun with rapid progression (within 1-2 weeks) and changes in the renal biopsy are potentially reversible (cell-type crescents, tubular fibrosis is absent or moderate).

Immune complex rapidly progressive glomerulonephritis (type II according to Glassock, 1997)

Treatment of extracapillary (rapidly progressive) glomerulonephritis is the same, but without plasmapheresis. Most often, they begin with intravenous methylprednisolone pulses (1000 mg for 3-5 days) followed by oral prednisolone [60 mg/kg x day]. Not everyone considers it necessary to add cytostatics (cyclophosphamide in pulses or orally) in idiopathic rapidly progressive glomerulonephritis; cytostatics are certainly effective in systemic lupus erythematosus or cryoglobulinemia (after excluding HCV-induced hepatitis). In HCV infection, the addition of interferon alpha is indicated. The benefit of plasmapheresis has been proven only in rapidly progressive glomerulonephritis in patients with cryoglobulinemia. In case of a response to initial therapy, long-term administration of prednisolone is necessary, and then a switch to azathioprine [2 mg/kg x day] is possible.

Pauci-immune rapidly progressive glomerulonephritis associated with ANCA (type III no Glassock, 1997)

Most often, these are patients with necrotizing vasculitis - systemic ( Wegener's granulomatosis or microscopic polyarteritis) or limited to the kidneys. The best results are obtained with treatment with cyclophosphamide (orally or intravenously in the form of pulses) in combination with glucocorticoids (also orally or intravenously). Various regimens of initial suppressive and maintenance therapy have been proposed.

Patients with Wegener's granulomatosis with rapidly progressive glomerulonephritis type III and antibodies to proteinase-3 are recommended to take cyclophosphamide for a long time both to suppress the activity of the process and for maintenance therapy. Patients with microscopic polyarteritis with rapidly progressive glomerulonephritis type III and antibodies to myeloperoxidase are recommended to take a shorter course of cyclophosphamide to suppress the activity and take azathioprine for a long time for maintenance therapy. Plasmapheresis is indicated in case of rapid development of renal failure and the presence of potentially reversible changes in the renal biopsy. 7-10 plasmapheresis sessions are prescribed for 2 weeks. If there is no positive effect during this time, plasmapheresis is canceled.