Treatment of glomerulonephritis

Treatment of glomerulonephritis sets itself the following tasks:

• to assess how great the activity and the probability of the progression of jade and whether they justify the risk of applying certain therapeutic effects;
• achieve reverse development of kidney damage (ideally - complete recovery);
• stop the progression of jade or at least slow the rate of increase in renal failure.

Etiological treatment of glomerulonephritis

The reverse development of renal damage can be achieved primarily through an etiological approach to treatment, but this treatment of glomerulonephritis is possible only in a few patients. Etiological treatment is the use of antibiotics in post-streptococcal nephritis and nephritis associated with subacute infective endocarditis; antiviral drugs for virus-associated glomerulonephritis; specific treatment of syphilitic and malarial, paratuberculous nephritis with the release of immune complexes and complete cure; removal of the tumor in paraneoplastic nephrotic syndrome; discontinuation of taking the appropriate drug that caused the drug nephritis; persistent abstinence in alcoholic nephritis, the exclusion of allergic factors in atopic nephritis.

The possibility of reverse development with the timely elimination of the etiological factor is quite real, as evidenced by our observations of patients with nephritis caused by subacute infective endocarditis, paraneoplastic nephritis, paratuberculous IgA-nephritis, and others.

[1], [2], [3], [4], [5], [6]

Pathogenetic treatment of glomerulonephritis

To lead to the reverse development of glomerulonephritis, to stop or slow down its progressing can pathogenetic treatment of glomerulonephritis, aimed at these or other links of pathogenesis: immune processes, inflammation, intravascular coagulation. To a certain extent, antihypertensive therapy also applies to pathogenetic therapy, and in some cases also diuretic therapy.

The most part of the pathogenetic therapy of nephritis ( glucocorticoids, cytostatics, including selective ones, heparin, plasmapheresis) has a wide range of action, interferes with homeostatic processes, often causes severe complications, which allows calling them "active" or "aggressive" therapy of nephritis. The purpose of active therapy is indicated in those stages of nephritis, when the role of immunoinflammatory processes or intravascular coagulation processes in the progression of the disease is evident.

Complex evaluation of clinical manifestations and morphological picture of the disease is an optimal approach to determining the degree of activity of the process and the severity of nephrosclerosis.

Treatment of glomerulonephritis is as follows:

• with a high activity glomerulonephritis, especially glomerulonephritis with nephrotic syndrome, immunosuppressive therapy is necessary. Only in the presence of contraindications to active therapy or the impossibility of conducting it for any reason is limited to symptomatic treatment, as well as the appointment of ACE inhibitors and statins;
• with the first arising nephrotic syndrome, especially without hematuria and hypertension, treatment of glomerulonephritis with glucocorticoids is indicated. At subsequent relapses, treatment starts with glucocorticoids (if the first episode of treatment with glucocorticoids was effective), then cytostatics or cyclosporine are prescribed;
• with progressive forms of nephritis (with a rapid increase in the level of creatinine), large doses of glucocorticoids and cytostatics are administered inside and / or in the form of pulses;
• for latent nephritis with proteinuria> 1 g / day ACE inhibitors are indicated;
• there are no uniform tactics for hematuric forms (see "Treatment of IgA Nephropathy").

Currently, the following groups of drugs are used to treat nephritis: glucocorticoids, cytotoxic drugs, ACE inhibitors, anticoagulants, antiaggregants, lipid-lowering drugs; in some situations, the method of "mechanical" immunosuppression - plasmapheresis - is of great importance.

Glucocorticoids and treatment of glomerulonephritis

Glucocorticoids for several decades remain one of the main means of pathogenetic therapy of nephritis.

Mechanisms of action

Glucocorticoids have both anti-inflammatory and immunosuppressive effects, interfering, on the one hand, with the function of all inflammatory cells and the formation of humoral factors of inflammation, and on the other - in the immune response, and more in the cellular than in the humoral.

The main mechanisms of action of glucocorticoids, leading to suppression of the inflammatory response and immune response, are:

• the redistribution of inflammatory cells and the immune system from the bloodstream to other organs of the immune system, which reduces their entry into the inflammatory focus and thereby inhibits the development of the inflammatory reaction;
• suppression of the production of many mediators involved in the realization and persistence of the immune response and inflammation (cytokines, arachidonic acid metabolites, active oxygen radicals, proteolytic enzymes, etc.), and a decrease in the sensitivity to these mediators of inflammatory and immune cells (suppression of membrane receptor synthesis for cytokines, increasing the production of receptor antagonists, etc.).

Influence on inflammatory reaction

Glucocorticoids interfere in all stages of the inflammatory response. The degree of anti-inflammatory activity of glucocorticoids is related to their concentration in inflammation sites, and therefore depends on the dose and route of administration.

Glucocorticoids disrupt the adhesion of neutrophils to the endothelium of capillaries, inhibit the influx of macrophages, affect their function, block the release of cytokines (IL-1, IL-6, TNF-a, etc.), and also suppress the production of macrophages by certain proteolytic enzymes (collagenase, elastase, activator of plasminogen); at the same time, glucocorticoids inhibit the antitumor and antimicrobial activity of macrophages.

In addition, when administered intravenously at high doses, glucocorticoids change the chemical structure of the basal membrane of the glomeruli with a subsequent decrease in proteinuria.

Effect on the immune response

In humans, glucocorticoids cause transient lymphopenia, suppress the presentation of macrophages by antigens to T cells, activation of T-lymphocytes (due to decreased production of IL-2) - helper, suppressor and cytotoxic subpopulations.

In contrast to T cells, B cells are less sensitive to glucocorticoids. The effect of glucocorticoids on the production of antibodies depends on the dose: low do not affect it, while high ones can reduce the level of immunoglobulins (by suppressing the activity of T-helpers).

When administered intravenously at high doses, glucocorticoids exert a more pronounced effect on T cells: suppressing the production of a number of cytokines that increase the permeability of the basal membrane of the glomeruli; reduction of vascular permeability caused by immune complexes.

From the clinical standpoint, it is important to remember that lower doses of glucocorticoids are required to suppress migration of leukocytes to inflammation sites and a cellular immune response, and higher doses of glucocorticoids are required to suppress the functional activity of leukocytes and humoral immunity.

[7], [8], [9], [10], [11], [12], [13], [14]

Indications for the appointment of glucocorticoids in nephritis

Common indications for the appointment of glucocorticoids in nephritis are:

• marked renal activity;
• presence of nephrotic syndrome without severe hypertension and hematuria (morphologically - minimal glomerular changes, mesangioproliferative and membranous nephritis).

Treatment is less promising for focal segmental glomerulosclerosis, mesangiocapillary glomerulonephritis and diffuse glomerulosclerosis in the outcome of any variant of glomerulonephritis.

Particular indications for individual clinico-morphological variants of glomerulonephritis will be considered below.

Methods (schemes) of glucocorticoid therapy in nephritis

There are different ways (modes) of glucocorticoid use for glomerulonephritis. To achieve effective concentrations of glucocorticoids in the areas of immune inflammation and edema in the renal tissue, where the blood flow is significantly reduced, two methods of administration of glucocorticoids are effective: prolonged daily administration of high and moderately high doses of glucocorticoids (prednisolone), and intravenous administration of ultrahigh doses (the so-called pulses) of glucocorticoids (methylprednisolone or prednisolone).

Daily intake of high doses of prednisolone

Depending on the severity of glomerulonephritis, prednisolone in high doses [1-2 mg / kghsut] for 1-2 months] can be given orally in 2-3 doses (the main part in the morning hours) or once in the morning. In the first case, with fractional administration of prednisolone, better control of renal inflammation is achieved, but more immediate side effects are more likely to develop and more pronounced. Therefore, some authors recommend at the first opportunity (clinical signs of improvement) to transfer the patient from a fractional one to a one-time admission. Then, when the positive effect is achieved, the daily dose is slowly reduced to the lowest possible support level.

[15], [16], [17], [18], [19], [20], [21]

Taking high doses of prednisolone every other day

When taking glucocorticoids in a day is much less than with daily intake, the function of the hypothalamic-pituitary-adrenal system is suppressed. In this case, the dose of prednisolone, which the patient takes every other day every morning, is equivalent to a double daily dose of daily intake. This method is used most often in pediatric practice, less often in adults. Efficacy is close to the conventional scheme, but the side effects are less common, the children do not have any growth retardation. Such an alternating regimen is especially indicated for maintenance therapy.

Pulse therapy with methylprednisolone

To quickly achieve very high concentrations of glucocorticoids in blood plasma, intravenous pulses of methylprednisolone have been used for many years to treat rejection crises of the renal allograft. The number of complications, as a rule, was small. A similar approach is used to treat rapidly progressive glomerulonephritis with semilunium and other severe forms of glomerulonephritis, which occur without the formation of a semilunium (for example, diffuse proliferative glomerulonephritis in patients with systemic lupus erythematosus). The procedure consists in intravenous drip for 20-40 minutes 0.5-1.5 g of methylprednisolone (or prednisolone, somewhat less effective in this situation), which is repeated 2 more times in the following days to achieve a total dose of 3-4 g of the drug . With nearly 30 years of experience using this method of introducing glucocorticoids (since 1977), we consider it to be a relatively safe way to quickly achieve control of severe inflammation of the glomeruli. The method is contraindicated in patients with severe hypertension, as well as with myocarditis or severe cardiomyopathy.

Supportive therapy

After a course of treatment with high doses (most often within 2 months), the dose is reduced (usually within the same period, and with systemic diseases more slowly) to the maintenance dose (10-20 mg / day). The timing of maintenance therapy is determined empirically, usually 2 months, sometimes (especially with glomerulonephritis associated with systemic diseases), longer maintenance therapy is required, even for several years, with the administration of the drug every other day causing fewer side effects than daily glucocorticoid therapy, in including when the dose of glucocorticoids for alternating therapy is 2-3 times higher than with daily intake. In this regard, the best tactic of maintenance therapy for glucocorticoids is to reduce the daily dose to the lowest possible level, and then switch to an alternating regimen using a 2-fold dose of daily intake.

If suppressing the activity of glomerulonephritis or maintaining normal kidney function requires unacceptably high doses of glucocorticoids, if side effects of glucocorticoid therapy quickly appear, it is advisable to prescribe cytotoxic drugs. This allows the use of smaller doses of glucocorticoids and thus reduce the risk of side effects.

Side effects of glucocorticoids

The undesirable effects of glucocorticoids can occur quickly (euphoria, depression, insomnia, increased appetite, corticosteroid psychosis, fluid retention, decreased glucose tolerance) and some time after the start of treatment (obesity, myopathy, striae, skin atrophy, hirsutism, cataracts, growth retardation , steroid diabetes, osteoporosis, aseptic necrosis and bone fractures, acne and opportunistic infections). The first disappear after the abolition of glucocorticoid therapy, the latter can persist for a long time.

The abrupt elimination of glucocorticoids after their long reception leads to a life-threatening adrenal crisis. Signs of an upcoming adrenal crisis include malaise, fever, muscle and headache, sweating and hypotonia with warm limbs due to dilatation of peripheral vessels.

Cytostatic (cytotoxic) drugs and treatment of glomerulonephritis

[22], [23], [24], [25]

Alkylating agents (cyclophosphamide and chlorobutin)

Cyclophosphamide (CFA) and chlorbutin are alkylating compounds that are absorbed into the intestine when ingested, and then converted into active metabolites in the liver. The main mechanism of action of these metabolites is the cross-linking of nucleic acids, which disrupts the process of information transcription necessary for protein synthesis and, accordingly, cell division.

[26], [27]

Cyclophosphamide

The half-life of cyclophosphamide is 6 hours, and it lengthens with simultaneous reception of allopurinol. In very high doses, cyclophosphamide inhibits the division of all cells in the body, and clinically the most important consequences of bone marrow suppression. When ingested at doses that lower the level of white blood cells to 3000 cells / mm3 (the number of neutrophils is 1500 cells / μl), the immune response to new antigens (mediated by both T and B cells) is suppressed. In these doses, cyclophosphamide has less effect on inflammation, can suppress proliferation of fibroblasts and thereby the development of fibrosis, but its main effect is the suppression of the immune system.

[28], [29], [30], [31], [32], [33], [34], [35],

Taking cyclophosphamide inside

Cyclophosphamide is taken orally usually at a dose of 2-2.5 mg / (kilogram). With severe damage to the kidneys (by the type of rapidly progressive glomerulonephritis) with systemic vasculitis can begin with a dose of 3.5-4 mg / kghsut). It is assumed that the number of leukocytes in the peripheral blood is reduced to about 3500 cells / μl (but not less than 3000 cells / μl), while the neutrophil count should be 1000-1500 cells / μl. The number of white blood cells decreases within a few days or weeks. During this period of induction of immunosuppression, it is very important to check the number of leukocytes in peripheral blood at least every other day so that if the number of white blood cells decreases below the acceptable level, the dose of the drug may be reduced or canceled.

Since the stabilization of the level of leukocytes, their content should be monitored no less than once in 2 weeks. Over time, the dose of cyclophosphamide, necessary to maintain leukocytes at the proper level, has to be reduced. If prednisolone is prescribed concomitantly with cyclophosphamide (which protects the bone marrow from suppression), then with a decrease in the dose of prednisolone, a dose of cyclophosphamide should be reduced.

Side effects of cyclophosphamide treatment

Side effects of cyclophosphamide treatment may be short-term, disappearing after discontinuation of treatment (nausea, vomiting, diarrhea, alopecia and infections developing during the period of leukopenia), and long-term (gonadal insufficiency with the probability of subsequent infertility, which should be warned, hemorrhagic cystitis, teratogenic effect, tumors and chronic infections). At a cumulative dose of up to 200 mg / kg, the incidence of severe adverse events is small, but it increases significantly with a cumulative dose above 700 mg / kg. In this regard, when deciding on the long-term treatment of cyclophosphamide patients (especially young men) it is necessary to inform them of possible complications. At very high doses, the development of the syndrome of inadequate ADH secretion is possible.

Intravenous pulse-therapy of cyclophosphamide

The group of nephrologists, led by J. Balow and A. Steinberg (National Institutes of Health, USA), proposed in the early 1980s for the treatment of patients with lupus glomerulonephritis a "pulse-therapy" of cyclophosphamide, which is currently considered highly effective and at the same time has fewer side effects than conventional cyclophosphamide ingestion. Doses of 0.5-2.0 g / m ^{2 of} the body surface were used, causing a drop in the white blood cell count to a maximum of 2000-3000 cells / mm3, which occurs between 8-12 days, then the white blood cells return to normal approximately at the 3rd week. Pulses were used every 3 months, the duration of treatment was 2 years or more. It was found that the frequency of complications from the bladder in this mode (1 pulse in 3 months) is significantly reduced. This is probably due to the fact that the duration of contact of toxic metabolites of cyclophosphamide with the wall of the bladder is reduced to about 36 hours every 3 months and the total dose of the drug during these 3 months also decreases. Infections, both severe and less severe (eg, herpes zoster), continued to be observed, especially in the period of the maximum decline in the number of leukocytes. Serious problem remained amenorrhea, although its frequency decreased slightly (45% instead of 71%, which is observed with prolonged oral therapy).

In the following years, new regimes for the use of cyclophosphamide were proposed in our center and in several other centers, in particular, an increase in the pulse rate up to 1 time per month in the initial phase of therapy in the treatment of lupus as well as chronic idiopathic glomerulonephritis. The effectiveness of treatment can be judged not earlier than 6 months. If there are signs of improvement, continue treatment with glomerulonephritis for another 3 months; in the future - if necessary to continue treatment, breaks between pulses should be increased to 2-3 months. The risk of developing side effects depends on the total dose of the drug.

When carrying out pulse therapy with cyclophosphamide, the following conditions must be met:

• to prevent severe bone marrow suppression, the dose of the drug should correspond to the level of GFR, since cyclophosphamide metabolites are excreted by the kidneys (the drug is administered intravenously in 150-200 ml of isotonic sodium chloride solution for 30-60 min):
  • at normal CF, 15 mg / kg body weight of the patient (or approximately 0.6-0.75 g / m ² body surface area);
  • with CF less than 30 ml / min - 10 mg / kg (or about 0.5 g / m ² ).
• strict control of leukocyte counts on the 10th and 14th days after pulse therapy is necessary: when the leukocyte count drops <2000 cells / μl, reduce the next dose by 25%, with a white blood cell count> 4000 cells / μL increase the next dose cyclophosphamide by 25% (up to 1 g / m ² );
• to prevent nausea and vomiting recommend antagonists of serotonin receptors: cerucal 10 mg 3 times a day, ondansetron 4-8 mg orally 3-4 times every 4 hours (alternatively - Navoban or Latran); can be combined with a single dose of 10 mg dexamethasone inside;
• To prevent the toxic effects of cyclophosphamide metabolites on the mucosa of the bladder: stimulation of frequent urination (increased intake of fluid inside) and the reception of mesna that binds toxic metabolites in the bladder (4 times every 3 hours, the total dose corresponds to 80% of the dose of cyclophosphamide).

With the help of methods of mathematical modeling, prognostic signs were revealed that allow presupposing the sensitivity of the patient to therapy with ultra-high doses of cyclophosphamide, thereby avoiding the unjustified administration of immunosuppressants. The results of the analysis, conducted in 44 patients with glomerulonephritis, indicate that:

• treatment of glomerulonephritis with ultra-high doses of cyclophosphamide satisfactorily tolerate the majority (89%) of patients with chronic glomerulonephritis;
• at the end of treatment, a positive effect was recorded in almost 50% of patients previously resistant to oral immunosuppressive therapy;
• a good long-term result can be expected in patients with a normal creatinine level and duration of the disease no more than 2 years. The accuracy of the prognosis (especially with an increased level of creatinine and a prescription of the disease for more than 2 years) increases with kidney biopsy: a higher efficiency can be assumed for MN, MPGH and MCGN, lower for focal segmental glomerulosclerosis and sclerosing glomerulonephritis. However, the degree of activity of the immune-inflammatory process is crucial: for all morphological variants, the survival rate is higher with a high morphological activity index;
• to achieve the effect (in patients potentially sensitive to cyclophosphamide), long-term treatment with glomerulonephritis (at least 6.0 g of cyclophosphamide for 6 months or more) is necessary. Inadequate treatment sharply worsens the prognosis, especially with an elevated level of creatinine;
• positive response of the patient to the end of the course of treatment (complete or partial remission) - an indicator of a good long-range prognosis;
• the absence of an immediate answer makes a good forecast unlikely.

Chlorobutin

Assign a dose of 0.1-0.2 mg / kght). The half-life is 1 hour; it is completely metabolized. Chlorobutin acts more slowly than cyclophosphamide, and the associated bone marrow suppression develops less rapidly and is more often reversible. Side effects include gastrointestinal disorders and gonadal insufficiency. The more rare side effects are pulmonary fibrosis, convulsive seizures, dermatitis and toxic liver damage. Tumors develop less frequently than when treated with cyclophosphamide.

In young men, cyclophosphamide is preferred (less gonadotoxic than chlorbutin) at a dose of <2 mg / (kilogram); in women and elderly men - chlorbutin (the ovaries are less sensitive to the toxic effect of alkylating drugs) at a dose of 0.15 mg / (kilogram).

[36], [37]

Antimetabolites and treatment of glomerulonephritis

[38], [39], [40]

Azathioprine

Azathioprine, an analogue of the purine base of hypoxanthine, is a derivative of 6-mercaptopurine. Metabolites of azathioprine inhibit the enzymes required for DNA synthesis, so suppress any immune response that requires cell division. Azathioprine is taken in a dose of 1-3 mg / mg / kght), and the dose is selected in such a way as to maintain a number of leukocytes in the blood of not less than 5000 cells / μl. The main side effect is bone marrow suppression, especially neuropathy with the development of infections. Other complications include anemia, thrombocytopenia, hepatitis, dermatitis, stomatitis, alopecia, gastrointestinal disorders and an increased risk of developing tumors, especially skin cancer and lymphomas.

In general, in comparison with cyclophosphamide, azathioprine acts less actively on renal inflammation, but causes fewer serious complications. In patients with signs of renal failure, azathioprine is not recommended to be administered together with allopurinol, which blocks its inactivation.

[41], [42], [43], [44],

Selective immunosuppressants and treatment of glomerulonephritis

Cyclosporin A

Ciclosporin A - a cyclic polypeptide of fungal origin - was synthesized in 1980. It is eliminated from the body by the liver through the bile ducts. The effect of cyclosporin A on the immune response is due to the suppression of not only T-helper activity at the time of antigen presentation, but also the production of interleukin-2, the proliferation of cytotoxic T cells, and indirectly (through inhibition of T cells) activation of B cells. On the already developed antibody response, cyclosporine A has no effect.

The greatest experience with cyclosporine A has been accumulated in renal transplantation. In recent years, it has been used for the treatment of a steroid-resistant nephrotic syndrome, with lower doses prescribed to prevent nephrotoxic effects than with kidney transplantation. According to some data, unlike patients with a transplanted kidney, the effectiveness of cyclosporine A in patients with glomerulonephritis is not so clearly related to the concentration of the drug in the blood plasma.

Cyclosporin A may be an alternative treatment for patients with glomerulonephritis with a steroid-resistant or steroid-dependent nephrotic syndrome. Mainly, these are patients with minimal changes (lipoid nephrosis) and focal-segmental glomerulosclerosis, in the pathogenesis of which plays the role of hyperproduction of lymphokines, suppressed by cyclosporin A.

The frequency of positive results of treatment is at a minimum changes of about 80%, with FSGS - 50%. In our observations, treatment with glomerulonephritis with cyclosporin A was accompanied by remission in 20 of 25 patients with a steroid-dependent and steroid-resistant nephrotic syndrome.

Before treatment, it is necessary to conduct a kidney biopsy : interstitial sclerosis, canal atrophy or vascular lesion interfere with the administration of cyclosporine A. In patients older than 60 years, the drug increases the risk of developing tumors.

The initial dose of cyclosporine A per day for adults is 2.5-5 mg / kg, for children - 6 mg / kg. Depending on the morphology of glomerulonephritis, a decrease in proteinuria is usually observed within 1-3 months. The level of cyclosporin A in the blood does not always correlate with the effectiveness of treatment, but it is useful for monitoring the clearness of taking the drug to patients and detecting the possible interaction of cyclosporin A with other drugs. Mandatory control of kidney function: increasing the level of creatinine by 30% in relation to the initial requires a reduction in the dose of cyclosporine A by 30-50%.

The most serious side effects are nephrotoxicity, which depends on the dose and is usually reversible, and the development of hypertension, which is associated with a spasm of afferent glomerular arterioles.

Other side effects are hypertrichosis, gingival hypertrophy (with azithromycin, and possibly metronidazole).

Nephrotoxicity of cyclosporine with its long-term administration is often difficult to assess clinically. Continuous administration of cyclosporine for 12-38 months is accompanied by a significant increase in tubulo-interstitial fibrosis, and its severity in repeated biopsies correlates with the number of glomeruli with segmental sclerosis in the first biopsy, the level of creatinine at the time of the first biopsy, and with a dose of cyclosporine exceeding 5 , 5 mg / kg per day. The development of nephrotoxicity can be clinically not noticeable, since there is no direct correlation between the severity of structural damage and the state of renal function. To prevent nephrotoxicity, adequate fluid intake and elimination, as far as possible, of other nephrotoxic drugs, especially NSAIDs, are necessary, since in patients with hypovolemia, blockade of prostaglandin production may dramatically worsen renal blood flow.

After the abolition of cyclosporine A, a relapse of the nephrotic syndrome and a steroid-dependent non-rhythmic syndrome can become a cyclosporin A-dependent. However, patients with complications of steroid therapy tolerate cyclosporin A fairly well.

[45], [46], [47], [48], [49], [50], [51], [52],

Tacrolimus (FK-506) and mycophenolate mofetil

Currently, attempts are being made to apply new immunosuppressants in nephrology - tacrolimus and mycophenolate mofetil.

Tacrolimus (FK-506) - a calcineurin inhibitor, by the mechanism of action is close to cyclosporin A, relatively selectively suppresses CD4 T-helpers; possibly, somewhat suppresses the release of cytokines; it is possible that the inhibitory effect on the production of the vascular permeability factor is not excluded. In the experiment, the introduction of FK-506 prevented the development of autoimmune nephritis in rats.

Tacrolimus has the same spectrum of numerous side effects as cyclosporin A: acute and chronic nephrotoxicity, neurotoxicity, hypertension, hyperlipidemia, increased potassium and uric acid levels.

Mofetil mycophenolate, a derivative of mycophenolic acid, an inhibitor of inosine monophosphate dehydrogenase, which depletes the reserves of guanidine nucleotides in cells, selectively inhibits the proliferation of T and B lymphocytes, the production of antibodies and the formation of cytotoxic T lymphocytes. In addition, it inhibits the glycosylation of adhesive molecules, which can affect the influx of lymphocytes into the foci of inflammation in rejected transplants. Applied primarily in transplantology. Suppress proliferation of rat and human mesangial cells in tissue culture without the development of cell necrosis or apoptosis.

Mofetil Mycophenolate causes a number of serious side effects from the gastrointestinal tract: nausea, vomiting, diarrhea - due to which it is necessary to reduce the dose of the drug or even to cancel the treatment of glomerulonephritis. Leukopenia develops with the same frequency as with the appointment of azathioprine. The risk of developing opportunistic infections is increasing.

The new form of the drug (myfortic), soluble only in the intestine, causes fewer side effects on the part of the gastrointestinal tract and opens the way for a wider use of this drug.

Clinical observations with glomerulonephritis are still few. Thus, F. Schweda et al. (1997) achieved remission with tacrolimus treatment of a young woman with minimal changes of glomeruli and NS resistant to glucocorticoids and cyclosporin A for 20 months without visible side effects. M. Choi et al. (1997) used mycophenolate mofetil for treatment of 8 patients with a steroid or cyclosporin A-dependent nephrotic syndrome (with different morphological basis) - the condition improved in 6 patients. The greatest experience was obtained in controlled trials in patients with diffuse proliferative lupus nephritis, where mofetilamycophenolate was used as an overwhelming [Chan, 2000] or supporting [Contreras, 2004] therapy. The main conclusion of these studies: mycophenolate mofetil is as effective as cyclophosphamide, it causes remission of nephritis, but increases the survival rate of patients due to the lower number of septic complications.

Combined treatment of glomerulonephritis

Among the combined treatment regimens, the most common treatment regimens are glucocorticoids with cytostatics and the so-called 4-component regimen.

Glucocorticoids in combination with various cytostatics can be administered orally, as well as parenterally. For example, pulse-therapy with methylprednisolone followed by oral intake of prednisolone and cytostatics, pulse therapy with cyclophosphamide and methylprednisolone. The following combined pulse therapy schemes are used: on day 1, 800-1200 mg of cyclophosphamide and 1000 mg of methylprednisolone or prednisolone are intravenously injected, only methylprednisolone or prednisolone on the next two days.

A peculiar scheme of reception with alternation of glucocorticoids and cytostatics was suggested by S. Ponticelli et al. (1984). During the first 3 days of the first month of treatment, intravenous methylprednisolone (1000 mg) is injected intravenously, and methylprednisolone daily at a dose of 0.4 mg / kg for the next 27 days, i.e. 28 mg with a body weight of 70 kg; During the 2nd month of treatment, the patient takes chlorobutin only at a very high dose of 0.2 mg / kghs. 14 mg with a body weight of 70 kg. This 2-month cycle is repeated 3 times; the total duration of treatment is 6 months.

[53], [54]

Six-month therapy with methylprednisolone and chlorobutin ("PONTICELLI Scheme")

A. Months 1 st, 3 rd, 5 th

Methylprednisolone - 1000 mg intravenously for 3 days with the subsequent intake of prednisolone by mouth, 0.5 mg / kghs) - for 27 days.

B. Months 2 nd, 4 th, 6 th

Chlorbutin - 0.2 mg Dkgsut) - within 30 days

Recommendations:

Intravenous methylprednisolone - a dose can be reduced to 500 mg per pulse in patients with a body weight of less than 50 kg.

Chlorbutin - the dose should be reduced to 0.1 mg / kghs) with a white blood cell level of less than 5000 cells / mm ³ and completely eliminated at a level of less than 3000 cells / mm ³.

Possible modifications

Chlorbutin is shown in a dose of 0.1 mg / kg per day:

• in young men to prevent azoospermia;
• in patients who after 1 month of treatment developed leukopenia.

In 1968, P.Kincaid-Smith proposed to combine immunosuppressants (prednisolone and cytostatics) with anticoagulants (heparin with subsequent replacement with warfarin) and antiplatelet agents (dipyridamole 400 mg / day) in the treatment of rapidly progressive glomerulonephritis. Later, this combination was called the 4-component scheme. Similar schemes are also used, where chlorbutin is used instead of cyclophosphamide. In addition, a modified scheme is proposed: prednisolone at a dose of 60 mg / day, azathioprine at a dose of 2 mg / kghs for 10 weeks, dipyridamole at 10 mg / kghs), heparin at a dose that doubles the thrombin time. Then, during the year, treatment with glutamulonephritis is continued with azathioprine and dipyridamole in the same doses, and heparin is replaced with phenylamine (at a dose that causes a doubling of prothrombin time). Similar schemes are recommended without prednisolone.

In some patients with slowly progressive renal failure, aggressive treatment with corticosteroids and / or cytostatics can improve kidney function. At the same time, patients with renal insufficiency are more sensitive to the side effect of immunosuppressants. In this regard, treatment of glomerulonephritis should be used only with realistic chances of getting an improvement.