Focal-segmental glomerulosclerosis

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

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

Causes of the focal segmental glomerulosclerosis

As with minimal glomerular changes, with focal segmental glomerulosclerosis, the main pathology is the involvement of epithelial cells (podocytes), which is detected only by electron microscopy, and the possible role of the same factors responsible for vascular permeability and "subcytosis" is discussed. However, with focal segmental glomerulosclerosis, changes in podocytes that are not capable of replication gradually lead to the development of sclerosis. The description of a woman with steroid-resistant focal segmental glomerulosclerosis, which gave birth to two children with proteinuria and hypoalbuminemia, confirms the possible role of the circulating pathological factor: in both children, proteinuria and nephrotic syndrome disappeared respectively at 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 with nephrotic syndrome; this is one of the most unfavorable variants of glomerulonephritis, which rarely responds to active immunosuppressive therapy. Spontaneous remissions are extremely rare. In adults, the 5-year survival rate is 70-73%.

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

[5], [6], [7], [8], [9], [10]

Symptoms of the focal segmental glomerulosclerosis

Symptoms of focal segmental glomerulosclerosis are characterized by a nephrotic syndrome (67% of cases) or persistent proteinuria, in most patients it is combined with hematuria (although the hematuria is rare), and 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 (certain segments of the glomeruli are sclerized) of part of the glomeruli (focal changes); the remaining glomeruli at the beginning of the disease are intact.

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

[11], [12], [13], [14], [15], [16]

Treatment of the focal segmental glomerulosclerosis

Patients with focal segmental glomerulosclerosis without a nephrotic syndrome with a clinical picture of latent or hypertonic nephritis have a relatively favorable prognosis (10-year renal survival> 80%). These patients usually have no active immunosuppressive therapy (except for cases when the increase in activity is manifested by other signs - acute cold syndrome). With focal segmental glomerulosclerosis without nephrotic syndrome, antihypertensive drugs are shown, primarily ACE inhibitors that have antiproteinuric action and slow the development and progression of chronic renal failure, with the target blood pressure level being 120-125 / 80 mmHg.

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

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

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

Among adult patients responding to the treatment of focal segmental glomerulosclerosis with glucocorticoids, less than one-third of the total remissions develop after 2 months, and in most patients 6 months after the start of therapy. The time required before the development of complete remission is on average 3-4 months. Proceeding from this, it is now proposed to determine the steroid resistance in adult patients with primary focal segmental glomerulosclerosis as the preservation of the nephrotic syndrome after 4 months of treatment with prednisolone at a dose of 1 mg / kghs.

Corticosteroid treatment of focal segmental glomerulosclerosis with primary focal segmental glomerulosclerosis is indicated in the presence of nephrotic syndrome; relative to the preserved function of the kidneys (creatinine not more than 3 mg%); Absence of absolute contraindications for corticosteroid therapy.

With the first arising nephrotic syndrome appoint:

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

Treatment of relapses in patients responding to treatment with glucocorticoids

• In adult patients with steroid-sensitive focal segmental glomerulosclerosis, relapses are less frequent than in children, and in most cases (> 75%) with repeated treatment, a remission of the nephrotic syndrome can be obtained again. 
• At late relapses (after 6 months and more after the abolition of corticosteroids), a repeated course of glucocorticoids is sufficient to obtain remission.
• With frequent exacerbations (2 relapses and more within 6 months or 3-4 relapses within 1 year), as well as with steroid dependence or undesirability of high doses of glucocorticoids, cytotoxic drugs or cyclosporin A are indicated.
• Cytostatic therapy allows you to repeatedly receive remission 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 / kghsut) for 1 month with subsequent cancellation].
• Cyclosporine [5-6 mg / (kghsut) in 2 doses] is also highly effective in steroid-sensitive patients: the majority of remission occurs within 1 month. However, usually for the maintenance of remission, a constant intake of the drug is necessary: a dose reduction or abolition in 75% of cases ends in a relapse.

Treatment of focal segmental glomerulosclerosis, resistant to steroids

This is the most difficult problem. Use 2 approaches - treatment with cytostatics or cyclosporin A.

• Cyclophosphamide or chlorbutin, regardless of duration (from 2 to 3 months to 18 months), causes remission in less than 20% of steroid-resistant patients. In our observations, 25% of them developed remission 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 the remission does not develop within 4-6 months, further treatment of focal segmental glomerulosclerosis with cyclosporine is unpromising. In our observations, cyclosporine caused remission in 7 out of 10 patients with focal segmental glomerulosclerosis with a steroid-dependent or resistant nephrotic syndrome.

S. Ponticelli et al. (1993) reported 50% of remissions (21% complete and 29% partial) in the treatment of steroid-resistant adults with nephrotic syndrome and focal segmental glomerulosclerosis with cyclosporine. However, the authors determined steroid resistance as a lack of response after 6 weeks of treatment with prednisolone 1 mg / kggsut, which does not meet modern criteria (4 months of unsuccessful treatment of focal segmental glomerulosclerosis). After the withdrawal of drugs, the frequency of recurrence was high, but the number of cases of terminal renal failure was 3 times less than in patients receiving placebo. A part of patients, whose remission was supported by cyclosporine for a long time (at least a year), it became possible to slowly cancel the drug without the development of relapse.

Thus, although in patients with steroid resistance none of the approaches are effective enough, cyclosporine apparently has some advantage over cytotoxic drugs.

Cyclosporin in patients with focal segmental glomerulosclerosis with already existing renal failure and tubulointerstitial changes should be used with caution. Patients who need to continue treatment with cyclosporine for more than 12 months need a repeated kidney biopsy to assess the degree of nephrotoxicity (severity of interstitial sclerosis).

Non-immune methods of treatment of focal segmental glomerulosclerosis

With focal segmental glomerulosclerosis, ACE inhibitors are most effective; a certain success can be achieved and lipid-lowering therapy.

Thus, when treating patients with focal segmental glomerulosclerosis, the following guidelines should be followed:

• the conclusion about steroid resistance of patients with focal segmental glomerulosclerosis and nephrotic syndrome can be done only after 3-4 months of treatment with corticosteroids;
• cytostatics and cyclosporin A are more effective in patients with steroid-sensitive nephrotic syndrome (shown with frequent recurrence or steroid dependence), but can lead to remission in 20-25% of steroid-resistant cases;
• with ineffectiveness or inability to conduct immunosuppressive therapy, ACE inhibitors and hypolipidemic drugs are indicated.

Forecast

The following factors worsen the prognosis of focal segmental glomerulosclerosis:

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

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

Isolate and a special morphological form of focal segmental glomerulosclerosis with an extremely unfavorable prognosis - collapsing glomerulopathy, in which glomerular capillaries collapse (collapse), as well as marked hypertrophy and hyperplasia of epithelial cells, microtubules of tubules, dystrophy of tubular epithelium, edema of interstitium. The same picture is described for HIV infection and heroin abuse. The clinic is characterized by a severe nephrotic syndrome, an early increase in serum creatinine.

Sometimes malaise and fever are noted, and therefore the possibility of viral etiology is discussed.

Focal segmental glomerulosclerosis quite often recurs in the transplant - approximately in 1/4 of patients, more often in children. Family cases of focal segmental glomerulosclerosis are described, for which progressive course, resistance to steroid therapy and relapses of focal segmental glomerulosclerosis after transplantation are characteristic.

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

[17], [18]