Extracapillary (fast-progressive) glomerulonephritis

Extracapillary glomerulonephritis is the presence of more than 50% of the glomeruli of extra-capillary cellular or fibro-cellular crescents, clinically manifested by rapidly progressive glomerulonephritis. Rapidly progressive glomerulonephritis is regarded as an urgent nephrological situation requiring urgent diagnostic and therapeutic measures. Rapidly progressive glomerulonephritis is clinically characterized by an acute cold syndrome with fast-progressive (within a few weeks or months) renal failure. The frequency of fast-progressive glomerulonephritis is 2-10% of all forms of glomerulonephritis, registered in specialized nephrological hospitals.

[1], [2], [3], [4],

Pathogenesis

"Semi-moon" is a consequence of pronounced damage to the glomeruli with a rupture of the capillary walls and the penetration of plasma proteins and inflammatory cells into the space of the Shumlyansky-Bowman capsule. The cellular composition of "semilunium" is represented mainly by proliferating parietal epithelial cells and macrophages. The evolution of the semilunas - the 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-moon is accompanied by the rupture of the capsule, the subsequent entry of fibroblasts and myofibroblasts from the interstitium, the synthesis of matrix proteins such as collagen types I and III, fibronectin, leading to irreversible semibound fibrosis.

Important role in the regulation of the processes of attracting and accumulating macrophages in semilunas is given to chemokines - monocyte chemoattractant protein type 1 and macrophage inflammatory protein-la (MIP-1a). High expression of these chemokines in places of formation of semilunums with a high content of macrophages is detected with rapidly progressive glomerulonephritis with the most severe course and unfavorable prognosis.

[5], [6], [7]

Symptoms of the extracapillary (fast-progressive) glomerulonephritis

Symptoms of fast-progressing glomerulonephritis  include two components: acute nephritis syndrome (acute nephritis syndrome) and fast-progressive renal failure, which by the rate of loss of kidney function occupies an intermediate position between acute and chronic renal failure, i.e. Implies the development of uremia within a year from the first signs of the disease.

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

[8], [9], [10], [11], [12], [13], [14]

Forms

Immunopathogenetic types of fast-progressive glomerulonephritis

Depending on the leading mechanism of damage, clinical picture and laboratory indicators, three main immunopathogenetet type fast-progressive glomerulonephritis have been identified.

[15], [16], [17], [18], [19]

Type I ("anti", "anti-BMC-jade")

Due to the damaging effect of antibodies on the basal membrane of the glomeruli. There is either an isolated (idiopathic) kidney disease or a disease with lung and kidney damage (Goodpasture's syndrome). Characterized by the "linear" type of luminescence of antibodies in the renal biopsy and the presence of circulating antibodies to the basal membrane of glomeruli in the blood serum.

Type II ("immunocomplex")

Called by deposits of immune complexes in various departments of renal glomeruli (in mesangium and capillary wall). In the kidney biopsy, the "granular" type of luminescence is revealed, in the serum anti-BMC and ANCA are absent. The most typical for the rapidly progressive glomerulonephritis associated with infections (post-streptococcal fast-progressive glomerulonephritis), cryoglobulinemia, systemic lupus erythematosus.

Type III ("low immunity")

Damage is due to cellular immune responses, including neutrophils and monocytes activated by the ANCA. The glow of immune reactants (immunoglobulins, complement) in the biopsy is absent or insignificant (pauci-immune, "low immunity" glomerulonephritis), in the serum ANCA are detected, directed toward proteinase-3 or myeloperoxidase. This type of ECGH is a manifestation of ANCA-associated vasculitis (microscopic polyangiitis, Wegener's granulomatosis) - its locally-renal or systemic variant.

Among all types of fast-progressing glomerulonephritis, more than half (55%) account for ANCA-associated fast-progressive glomerulonephritis (type III), two other types of rapidly progressing glomerulonephritis (I and II) are distributed roughly equally (20% and 25%).

By the presence of these or other serological markers (and their combination), one can assume the type of luminescence in the renal biopsy and, accordingly, the mechanism of damage - the pathogenetic type of rapidly progressing glomerulonephritis, which is important to consider when choosing a treatment program.

Diagnostics of the extracapillary (fast-progressive) glomerulonephritis

Diagnosis of rapidly progressing glomerulonephritis requires the exclusion of conditions that outwardly resemble (simulate) the rapidly progressive glomerulonephritis, but are of a different nature and therefore require a different therapeutic approach. There are three groups of diseases:

• nephritis - acute post-infectious and acute interstitial; as a rule, with a favorable prognosis, in which immunosuppressants are used only in some cases;
• acute tubular necrosis with its own regularities of course and treatment;
• group of vascular diseases of the kidneys, combining the defeat of vessels of different caliber and of different nature (thrombosis and embolism of large vessels of the kidneys, scleroderma kidney,  thrombotic microangiopathies ). In most cases, these conditions can be excluded clinically. On the other hand, features of extrarenal symptoms may indicate the presence of a disease in which rapidly progressing glomerulonephritis ( systemic lupus erythematosus, systemic vasculitis, drug reaction) often develops .

[20], [21], [22], [23], [24]

Treatment of the extracapillary (fast-progressive) glomerulonephritis

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

The prognosis of patients with fast-progressive glomerulonephritis is primarily determined by the severity (prevalence) of the lesion-the number of glomeruli having a half moon. In case of extensive lesion (half-moon 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 the glomeruli or less), especially if the semilunum is layered on a pre-existing glomerulonephritis (eg, IgA-nephritis, post-streptococcal nephritis), the impaired renal function can spontaneously recover, sometimes even to the baseline level.

With moderate damage (30-50% of glomeruli), the loss of renal function is slower, but without treatment of extracapillary (fast-progressive) glomerulonephritis, terminal renal failure still develops, so immunosuppressive therapy is indicated for all patients with rapidly progressive glomerulonephritis with extensive half-moons (with a lesion of 50% of glomeruli and more ), unless the clinical and morphological prognostic factors speak of the irreversibility of the process even under "aggressive" treatment and if immunosupret sive therapy does not involve a high risk of complications.

If it is impossible to carry out a biopsy (which is an all too common situation), the approaches to treatment are the same.

Principles of treatment of fast-progressive glomerulonephritis (extracapillary glomerulonephritis)

• To prevent irreversible catastrophic loss of renal function, it is urgent to begin treatment immediately after the clinical diagnosis of a rapidly progressing glomerulonephritis (acute cold syndrome in combination with rapidly progressive renal failure with normal kidney size and exclusion of other causes of acute renal failure). Delayed treatment for several days can worsen its effectiveness, with the development of anuria treatment is almost always unsuccessful. This is the only form of glomerulonephritis, when choosing the means of active therapy, one should think less about the possibility of side effects, since the toxicity of treatment in patients can not be more severe than the natural outcome.
• It is necessary (if possible) an emergency study of serum for the presence of anti-BMP-AT and ANCA; biopsy is desirable for the diagnosis (detection of rapidly progressing glomerulonephritis and the type of luminescence of antibodies - linear, granular, "low immunity") and more to assess the prognosis and confirm the need for aggressive therapy.
• Treatment should begin without delay before the results of diagnostic studies (serological, morphological) with pulse therapy with methylprednisolone, which is now considered an international standard. The experience of doctors testifies that such tactics are fully justified, including because of the impossibility of carrying out a biopsy in many patients. Alkylating drugs (better cyclophosphamide in ultra-high doses) is a necessary additional component to glucocorticoids, especially in patients with vasculitis (locally renal or systemic) and circulating ANCA.
• Intensive plasmapheresis in combination with immunosuppressants is valuable:
  • with anti-BMP-nephritis provided that the treatment is started early, before the need for hemodialysis;
  • in patients with non-anti-BMP-nephritis who already need hemodialysis, but do not have morphological signs of the irreversibility of the disease;
  • can be useful in other situations - before carrying out "pulses" with cyclophosphamide.
• The long-term prognosis depends on the severity of the initial kidney damage, the frequency of relapse, the presence of a systemic disease. An important task of further therapy is the prevention and treatment of exacerbations (the timely increase in the dose of immunosuppressants) and the effect on non-immune mechanisms of the progression of glomerulonephritis (ACE inhibitors).

Recommendations for the treatment of certain forms of fast-progressive glomerulonephritis

Anti-BMP-nephritis (type I no Glassock, 1997), including Goodpasture's syndrome. For creatinine, <600 μmol / L (6.8 mg%) is prednisolone [60 mg / (kiloceut) orally], cyclophosphamide [2-3 mg / kghs]) and daily intensive plasmapheresis (10-14 sessions with removal per session up to 2 l of plasma). Upon stable improvement, the dose of prednisolone is gradually reduced over the next 12 weeks, and cyclophosphamide is completely eliminated after 10 weeks of treatment. Patients with stabilized moderate renal failure and proteinuria show a long-term intake of ACE inhibitors. With exacerbations, the same approaches are again used.

With a creatinine level> 600 μmol / l, aggressive therapy is ineffective. Patients in need of hemodialysis should be treated conservatively, except when the disease has started recently with rapid progression (within 1-2 weeks) and changes in the renal biopsy are potentially reversible (cell-type hemi-moon, tubular fibrosis absent or mild).

Immunocomplex fast-progressive glomerulonephritis (type II according to Glassock, 1997)

Treatment of extracapillary (fast-progressive) glomerulonephritis is the same, but without plasmapheresis. Most often begin with intravenous pulses of methylprednisolone (1000 mg for 3-5 days) with further intake of prednisolone by mouth [60 mg / kghsut]]. Not all people consider it necessary to add cytostatics (cyclophosphamide in the pulses or inside) with idiopathic rapidly progressive glomerulonephritis; cytotoxic drugs are certainly effective in systemic lupus erythematosus or cryoglobulinemia (after excluding hepatitis caused by HCV). HCV infection shows the addition of interferon alfa. The benefits of plasmapheresis have been proven only with rapidly progressive glomerulonephritis in patients with cryoglobulinemia. In case of response to initial therapy, long-term use of prednisolone is required, then azathioprine [2 mg / kghsut] can be switched to].

Maloimmune fast-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 only by the kidneys. The best results were obtained when treating with cyclophosphamide (inside or intravenously in the form of pulses) in combination with glucocorticoids (also inside or intravenously). Different modes of initial suppressive and maintenance therapy are proposed.

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