Focal segmental glomerulosclerosis

Focal segmental glomerulosclerosis is a very rare variant of glomerulonephritis, observed in 5-10% of adult patients with chronic glomerulonephritis (over the past 20 years - in 6%).

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Causes focal segmental glomerulosclerosis.

As with minimal glomerular changes, in focal segmental glomerulosclerosis the main pathology is epithelial cell (podocyte) damage, detectable only by electron microscopy, and a possible role of the same factors responsible for both vascular permeability and "podocytosis" is discussed. However, in focal segmental glomerulosclerosis, podocyte changes that are incapable of replication gradually lead to the development of sclerosis. The possible role of a circulating pathological factor is supported by the description of a woman with steroid-resistant focal segmental glomerulosclerosis who gave birth to two children with proteinuria and hypoalbuminemia: in both children, proteinuria and nephrotic syndrome disappeared, respectively, 2 and 3 weeks after birth.

Despite moderate morphological changes, the course of the disease is progressive, complete remissions are rare. The prognosis is serious, especially in nephrotic syndrome; this is one of the most unfavorable variants of glomerulonephritis, rarely responding to active immunosuppressive therapy. Spontaneous remissions are extremely rare. In adults, 5-year survival is 70-73%.

If in general this is a very rare variant of nephritis in adults, then among patients with terminal renal failure its share increases significantly. Thus, according to the USRDS (registry of patients with terminal renal failure in the USA), published in 1998, among 12,970 patients with a known morphological form of glomerulonephritis who received renal replacement therapy in 1992-1996, 6497 (50%) had focal segmental glomerulosclerosis.

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Symptoms focal segmental glomerulosclerosis.

Symptoms of focal segmental glomerulosclerosis are characterized by nephrotic syndrome (67% of cases) or persistent proteinuria, in most patients combined with hematuria (although macrohematuria is rare), in half - with arterial hypertension.

It is observed in 15-20% of patients with nephrotic syndrome, more often in children, in whom focal segmental glomerulosclerosis is the most common cause of steroid-resistant nephrotic syndrome.

Morphologically, it is characterized by segmental glomerulosclerosis (individual segments of the glomeruli become sclerotic) of part of the glomeruli (focal changes); the remaining glomeruli are intact at the onset of the disease.

Immunohistochemical examination reveals IgM. Often this morphological type of changes is difficult to distinguish from "minimal changes" of the glomerulus; the possibility of the transition of "minimal changes" to focal segmental glomerulosclerosis (FSGS) is discussed. There is an opinion, not shared by all authors, that these are variants of varying severity or different stages of the same disease, united by the term "idiopathic nephrotic syndrome".

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Treatment focal segmental glomerulosclerosis.

Patients with focal segmental glomerulosclerosis without nephrotic syndrome with a clinical picture of latent or hypertensive nephritis have a relatively favorable prognosis (10-year renal survival >80%). Active immunosuppressive therapy is usually not indicated for these patients (except for cases when the increase in activity is manifested by other signs - acute nephritic syndrome). In focal segmental glomerulosclerosis without nephrotic syndrome, antihypertensive drugs are indicated, primarily ACE inhibitors, which have an antiproteinuric effect and slow the development and progression of chronic renal failure, while the target blood pressure level should be 120-125/80 mm Hg.

In patients with focal segmental glomerulosclerosis with nephrotic syndrome, the prognosis is serious: terminal renal failure (TRF) occurs after 6-8 years, and with proteinuria >14 g/24 h - after 2-3 years.

The development of remission of nephrotic syndrome significantly improves the prognosis. Thus, among patients who responded to treatment with complete or partial remission, the frequency of terminal renal failure over 5.5 years of observation was 28% compared to 60% in resistant patients. The prognosis also depends on the stability of remission: relapse of nephrotic syndrome makes the prognosis as bad as in primarily resistant patients. However, at the onset of the disease, there are no reliable clinical or morphological signs that can predict the results of treatment of focal segmental glomerulosclerosis. The best indicator of prognosis in patients with focal segmental glomerulosclerosis with nephrotic syndrome is the very fact of response to treatment of focal segmental glomerulosclerosis - the development of remission of nephrotic syndrome.

For a long time, it was believed that the treatment of focal segmental glomerulosclerosis with nephrotic syndrome with immunosuppressants was futile. It has now been shown that complete or partial remission may occur in some patients with long-term treatment. An increase in the frequency of remissions is associated with an increase in the duration of initial glucocorticoid therapy. In studies that achieved a high frequency of remissions, the initial dose of prednisolone [usually 1 mg/kg/day) up to 80 mg/day] was maintained for 2-3 months and then gradually reduced during subsequent treatment.

Among adult patients responding to glucocorticoid treatment of focal segmental glomerulosclerosis, less than 1/3 develop complete remissions within 2 months, and most within 6 months from the start of therapy. The time required to develop complete remission is on average 3-4 months. Based on this, it is currently proposed to define steroid resistance in adult patients with primary focal segmental glomerulosclerosis as persistence of nephrotic syndrome after 4 months of treatment with prednisolone at a dose of 1 mg/kg x day).

Corticosteroid treatment of focal segmental glomerulosclerosis with primary focal segmental glomerulosclerosis is indicated in the presence of nephrotic syndrome; relatively preserved renal function (creatinine no more than 3 mg%); absence of absolute contraindications for corticosteroid therapy.

When nephrotic syndrome occurs for the first time, the following is prescribed:

• prednisolone at a dose of 1-1.2 mg/kg/day) for 3-4 months;
• if complete or partial remission develops, the dose is reduced to 0.5 mg/kg/day (or 60 mg every other day) and treatment of focal segmental glomerulosclerosis continues for another 2 months, after which prednisolone is gradually (over 2 months) discontinued;
• in patients who do not respond to the initial course, the dose of prednisolone can be reduced more quickly - within 4-6 weeks;
• for patients over 60 years of age, prednisolone is prescribed every other day (1-2 mg/kg for 48 hours, maximum 120 mg for 48 hours) - the results are comparable to the effect in young patients receiving prednisolone every day. This can be explained by an age-related decrease in the clearance of corticosteroids, which prolongs their immunosuppressive effect;
• Cytostatics in combination with glucocorticoids as initial therapy do not increase the frequency of remissions compared with glucocorticoids alone. However, in the future, patients receiving cytostatics have fewer relapses than those receiving only corticosteroids (18% compared with 55%), i.e. remissions are more stable. If remission lasts more than 10 years, the probability of relapses is low.

Treatment of relapses in patients responding to glucocorticoid treatment

• In adult patients with steroid-sensitive focal segmental glomerulosclerosis, relapses are observed less frequently compared to children, and in most cases (>75%), remission of nephrotic syndrome can be achieved again with repeated treatment.
• In late relapses (6 months or more after discontinuation of corticosteroids), a repeated course of glucocorticoids is sufficient to achieve remission.
• In case of frequent exacerbations (2 or more relapses within 6 months or 3-4 relapses within 1 year), as well as in case of steroid dependence or undesirability of high doses of glucocorticoids, cytostatic drugs or cyclosporine A are indicated.
• Cytostatic therapy allows repeated remissions to be achieved in 70% of steroid-sensitive patients. Cyclophosphamide (2 mg/kg) or chlorbutin (0.1-0.2 mg/kg) for 8-12 weeks is often combined with a short course of prednisolone [1 mg/kg x day) for 1 month with subsequent withdrawal].
• Cyclosporine [5-6 mg/(kg x day) in 2 doses] is also highly effective in steroid-sensitive patients: most achieve remission within 1 month. However, maintaining remission usually requires continuous use of the drug: dose reduction or discontinuation results in relapse in 75% of cases.

Treatment of steroid-resistant focal segmental glomerulosclerosis

This is the most difficult problem. Two approaches are used - treatment with cytostatics or cyclosporine A.

• Cyclophosphamide or chlorbutin, regardless of duration (from 2-3 to 18 months), causes remission in less than 20% of steroid-resistant patients. In our observations, remission developed in 25% of them after 8-12 courses of pulse therapy with cyclophosphamide.
• Cyclosporine, especially in combination with low doses of prednisolone, causes remissions with almost the same frequency (25% of patients); if remission does not develop within 4-6 months, further treatment of focal segmental glomerulosclerosis with cyclosporine is futile. In our observations, cyclosporine caused remission in 7 out of 10 patients with focal segmental glomerulosclerosis with steroid-dependent or resistant nephrotic syndrome.

S. Ponticelli et al. (1993) reported 50% remissions (21% complete and 29% partial) in cyclosporine treatment of steroid-resistant adults with nephrotic syndrome and focal segmental glomerulosclerosis. However, the authors defined steroid resistance as the absence of a response after 6 weeks of treatment with prednisolone 1 mg / (kg x day), which does not meet modern criteria (4 months of unsuccessful treatment of focal segmental glomerulosclerosis). After drug withdrawal, the relapse rate was high, but the number of cases of terminal renal failure was 3 times less than in patients receiving placebo. In some patients, in whom remission was maintained by cyclosporine for a long time (at least a year), it became possible to slowly discontinue the drug without relapse.

Thus, although none of the approaches is sufficiently effective in patients with steroid resistance, cyclosporine appears to have some advantage over cytostatics.

Cyclosporine should be used with caution in patients with focal segmental glomerulosclerosis with pre-existing renal failure and tubulointerstitial changes. In patients requiring continued treatment with cyclosporine for more than 12 months, a repeat kidney biopsy is necessary to assess the degree of nephrotoxicity (severity of interstitial sclerosis).

Non-immune treatments for focal segmental glomerulosclerosis

In focal segmental glomerulosclerosis, ACE inhibitors are most effective; some success can also be achieved with lipid-lowering therapy.

Thus, when treating patients with focal segmental glomerulosclerosis, it is necessary to be guided by the following provisions:

• a conclusion about steroid resistance in patients with focal segmental glomerulosclerosis and nephrotic syndrome can be made only after 3-4 months of treatment with corticosteroids;
• cytostatics and cyclosporine A are more effective in patients with steroid-sensitive nephrotic syndrome (indicated for frequent relapses or steroid dependence), but can lead to remission in 20-25% of steroid-resistant cases;
• If immunosuppressive therapy is ineffective or impossible, ACE inhibitors and lipid-lowering drugs are indicated.

Forecast

The prognosis of focal segmental glomerulosclerosis is worsened by the following factors:

• presence of nephrotic syndrome;
• severe hematuria;
• arterial hypertension;
• severe hypercholesterolemia;
• lack of response to therapy.

The 10-year survival rate of patients with focal segmental glomerulosclerosis with nephrotic syndrome (91) was 50%, and without nephrotic syndrome (44) - 90%. According to the literature, terminal renal failure develops after 5 years in 55% of patients who did not respond to therapy at first admission and only in 3% of those who responded. Among the morphological signs of a poor prognosis are the development of sclerosis in the region of the glomerular handle, severe changes in the tubules, interstitium and vessels, as well as glomerular hypertrophy. The size of the glomeruli is a good predictor of renal survival and response to steroids.

A special morphological form of focal segmental glomerulosclerosis with an extremely unfavorable prognosis is also distinguished - collapsing glomerulopathy, in which collapse of glomerular capillaries is observed, as well as pronounced hypertrophy and hyperplasia of epithelial cells, microcysts of tubules, dystrophy of tubular epithelium, and interstitial edema. The same picture is described in HIV infection and heroin abuse. The clinical picture is characterized by severe nephrotic syndrome, early increase in serum creatinine.

Malaise and fever are sometimes observed, leading to discussion of the possibility of a viral etiology.

Focal segmental glomerulosclerosis quite often recurs in the transplant - in about 1/4 of patients, more often in children. Familial cases of focal segmental glomerulosclerosis have been described, which are characterized by a progressive course, resistance to steroid therapy and relapses of focal segmental glomerulosclerosis after transplantation.

The problem of focal segmental glomerulosclerosis is complicated by the fact that the same morphological changes are possible in other pathological conditions - in reflux nephropathy, a decrease in the mass of the renal parenchyma (for example, in a remnant kidney - after the removal of 5/6 of the functioning parenchyma in an experiment), pathological obesity, genetic, metabolic (lipids, glucose) disorders, the action of hemodynamic factors (arterial hypertension, ischemia, hyperfiltration), etc.

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