Treatment of glomerulonephritis

Treatment of glomerulonephritis has the following objectives:

• to assess how great the activity and probability of progression of nephritis are and whether they justify the risk of using certain therapeutic interventions;
• achieve reversal of kidney damage (ideally, complete recovery);
• stop the progression of nephritis or at least slow down the rate of increase in renal failure.

Etiological treatment of glomerulonephritis

Reversal of renal damage can be achieved primarily by an etiologic approach to treatment, but such treatment of glomerulonephritis is possible only in a few patients. Etiologic treatment is the use of antibiotics for poststreptococcal nephritis and nephritis associated with subacute infective endocarditis; antiviral drugs for virus-associated glomerulonephritis; specific treatment of syphilitic and malarial, paratuberculous nephritis with release from immune complexes and complete cure; tumor removal in paraneoplastic nephrotic syndrome; discontinuation of the corresponding drug that caused drug-induced nephritis; persistent abstinence in alcoholic nephritis, exclusion of allergenic factors in atopic nephritis.

The possibility of reverse development with 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, etc.

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Pathogenetic treatment of glomerulonephritis

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

Most of the means of pathogenetic therapy of nephritis ( glucocorticoids, cytostatics, including selective ones, heparin, plasmapheresis) have a wide range of action, interfere with homeostatic processes, often cause severe complications, which allows them to be called methods of "active" or "aggressive" therapy of nephritis. The appointment of active therapy is indicated at those stages of nephritis when the role of immune-inflammatory processes or intravascular coagulation processes in the progression of the disease is obvious.

A comprehensive assessment of clinical manifestations and the morphological picture of the disease is the optimal approach to determining the degree of activity of the process and the severity of nephrosclerosis.

Treatment of glomerulonephritis is as follows:

• in case of high activity of glomerulonephritis, especially glomerulonephritis with nephrotic syndrome, immunosuppressive therapy is necessary. Only in the presence of contraindications to active therapy or the impossibility of its implementation for some reason is symptomatic treatment limited, as well as the prescription of ACE inhibitors and statins;
• in the case of newly developed nephrotic syndrome, especially without hematuria and hypertension, treatment of glomerulonephritis with glucocorticoids is indicated. In subsequent relapses, treatment begins with glucocorticoids (if the first episode of glucocorticoid treatment was effective), then cytostatics or cyclosporine are prescribed;
• in progressive forms of nephritis (with a rapid increase in creatinine levels), large doses of glucocorticoids and cytostatics are prescribed orally and/or in the form of pulses;
• in latent nephritis with proteinuria > 1 g/day, ACE inhibitors are indicated;
• There is no single tactic for hematuric forms (see “Treatment of IgA nephropathy”).

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

Glucocorticoids and treatment of glomerulonephritis

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

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 inflammatory factors, and on the other hand, with the immune response, more so with the cellular than the humoral.

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

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

Effect on the inflammatory response

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

Glucocorticoids disrupt the adhesion of neutrophils to the capillary endothelium, 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 certain proteolytic enzymes by macrophages (collagenase, elastase, plasminogen activator); at the same time, glucocorticoids inhibit the antitumor and antimicrobial activity of macrophages.

In addition, when administered intravenously in high doses, glucocorticoids alter the chemical structure of the glomerular basement membrane, resulting in a decrease in proteinuria.

Impact on the immune response

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

Unlike T cells, B cells are less sensitive to glucocorticoids. The effect of glucocorticoids on antibody production depends on the dose: low doses do not affect it, while high doses can reduce the level of immunoglobulins (due to the suppression of T helper activity).

When administered intravenously in high doses, glucocorticoids have a more pronounced effect on T cells: suppression of the production of a number of cytokines that increase the permeability of the glomerular basement membrane; reduction of vascular permeability caused by immune complexes.

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

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Indications for the use of glucocorticoids in nephritis

General indications for the administration of glucocorticoids for nephritis are:

• pronounced activity of the renal process;
• the presence of nephrotic syndrome without pronounced hypertension and hematuria (morphologically - minimal changes in the glomeruli, mesangioproliferative and membranous nephritis).

Treatment is less promising in focal segmental glomerulosclerosis, mesangiocapillary glomerulonephritis and diffuse glomerulosclerosis resulting from any variant of glomerulonephritis.

Specific indications for individual clinical and morphological variants of glomerulonephritis will be discussed below.

Methods (schemes) of glucocorticoid therapy for nephritis

There are various ways (modes) of using glucocorticoids in glomerulonephritis. To achieve effective concentrations of glucocorticoids in areas of immune inflammation and edema in renal tissue, where blood flow is significantly reduced, 2 ways of administering glucocorticoids are effective - long-term daily administration of high and moderately high doses of glucocorticoids (prednisolone) orally and intravenous administration of ultra-high doses (so-called pulses) of glucocorticoids (methylprednisolone or prednisolone).

Taking high doses of prednisolone orally every day

Depending on the severity of glomerulonephritis, high doses of prednisolone [1-2 mg/kg/day) for 1-2 months] can be given orally in 2-3 doses (the main part in the morning) or once in the morning. In the first case, with fractional administration of prednisolone, better control of renal inflammation is achieved, but immediate side effects develop more often and are more pronounced. Therefore, some authors recommend switching the patient from fractional to single administration at the first opportunity (clinical signs of improvement). Then, upon achieving a positive effect, the daily dose is slowly reduced to the minimum possible maintenance dose.

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Taking high doses of prednisolone every other day

When glucocorticoids are taken every other day, the hypothalamic-pituitary-adrenal system function is suppressed to a much lesser extent than when taken daily. In this case, the dose of prednisolone that the patient takes every other day once in the morning is equivalent to a double daily dose of daily intake. This method is used most often in pediatric practice, less often in adults. The effectiveness is close to the generally accepted scheme, but side effects are observed less often, and growth retardation is not observed in children. Such an alternating regimen is especially indicated for maintenance therapy.

Methylprednisolone pulse therapy

In order to rapidly achieve very high plasma glucocorticoid concentrations, intravenous methylprednisolone pulses have been used for many years to treat renal allograft rejection crises. Complication rates have generally been low. A similar approach is used to treat rapidly progressive crescentic glomerulonephritis and other severe forms of glomerulonephritis with or without crescent formation (eg, diffuse proliferative glomerulonephritis in patients with systemic lupus erythematosus). The procedure involves intravenous drip infusion of 0.5-1.5 g methylprednisolone (or prednisolone, which is somewhat less effective in this situation) over 20-40 min, repeated twice more on subsequent days to achieve a total dose of 3-4 g. With almost 30 years of experience using this method of glucocorticoid administration (since 1977), we consider it a relatively safe method for rapidly achieving control over severe glomerular inflammation. The method is contraindicated in patients with severe hypertension, as well as myocarditis or severe cardiomyopathy.

Supportive therapy

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

If unacceptably high doses of glucocorticoids are required to suppress the activity of glomerulonephritis or maintain normal renal function, if side effects of glucocorticoid therapy quickly appear, it is advisable to prescribe cytostatic drugs. This allows using smaller doses of glucocorticoids and thus reduce the risk of side effects.

Side effects of glucocorticoids

Adverse effects of glucocorticoids may occur rapidly (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 former disappear after discontinuation of glucocorticoid therapy, the latter may persist for a long time.

Abrupt withdrawal of glucocorticoids after long-term use leads to life-threatening adrenal crisis. Signs of an impending adrenal crisis include malaise, fever, muscle and headache pain, sweating, and hypotension with warm extremities due to dilation of peripheral vessels.

Cytostatic (cytotoxic) drugs and treatment of glomerulonephritis

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Alkylating agents (cyclophosphamide and chlorbutin)

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

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Cyclophosphamide

The half-life of cyclophosphamide is 6 hours, and it is prolonged by concomitant administration of allopurinol. In very high doses, cyclophosphamide suppresses the division of all cells in the body, with the effects of bone marrow suppression being clinically most important. When taken orally in doses that reduce the white blood cell count to 3,000 cells/µl (neutrophil count 1,500 cells/µl), the immune response to new antigens (mediated by both T and B cells) is suppressed. At these doses, cyclophosphamide has less effect on inflammation, may suppress fibroblast proliferation and thereby the development of fibrosis, but its main effect is suppression of the immune system.

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Taking cyclophosphamide orally

Cyclophosphamide is usually taken orally at a dose of 2-2.5 mg / (kg x day). In severe kidney damage (such as rapidly progressive glomerulonephritis) in systemic vasculitis, a dose of 3.5-4 mg / kg x day can be started). A decrease in the number of leukocytes in the peripheral blood is expected to approximately 3500 cells / μl (but not less than 3000 cells / μl), while the neutrophil content should be 1000-1500 cells / μl. The number of leukocytes decreases over several days or weeks. During this period of induction of immunosuppression, it is very important to check the number of leukocytes in the peripheral blood at least every other day, so that if the number of leukocytes decreases below the permissible level, the dose of the drug can be reduced or canceled.

From the moment the leukocyte level stabilizes, their content should be monitored at least once every 2 weeks. Over time, the dose of cyclophosphamide required to maintain leukocytes at the proper level must be reduced. If prednisolone (which protects the bone marrow from suppression) is prescribed simultaneously with cyclophosphamide, then when the dose of prednisolone is reduced, the dose of cyclophosphamide must also be reduced.

Side effects of cyclophosphamide treatment

Side effects during treatment with cyclophosphamide 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 failure with the possibility of subsequent infertility, which patients should be warned about; hemorrhagic cystitis, teratogenic effect, tumors and chronic infections). With a cumulative dose of up to 200 mg/kg, the probability of severe side effects is low, but it increases significantly with a cumulative dose above 700 mg/kg. In this regard, when deciding on long-term treatment with cyclophosphamide, patients (especially young men) should be informed of possible complications. With very high doses, the syndrome of inappropriate ADH secretion may develop.

Intravenous cyclophosphamide pulse therapy

A group of nephrologists headed by J. Balow and A. Steinberg (National Institutes of Health, USA) proposed "pulse therapy" of cyclophosphamide for the treatment of patients with lupus glomerulonephritis in the early 1980s. It is currently considered to be highly effective and at the same time has fewer side effects than conventional oral cyclophosphamide. Doses of 0.5-2.0 g/m2 of body surface area were used ^, causing a drop in the leukocyte level to a maximum of 2000-3000 cells/μl, which occurs between the 8th and 12th days, then the leukocytes 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 urinary bladder with this regimen (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 bladder wall is reduced to approximately 36 h every 3 months and the total dose of the drug over these 3 months is also reduced. Infections, both severe and less severe (eg, herpes zoster), continued to be observed, especially during the period of maximum decline in the white blood cell count. Amenorrhea remained a serious problem, although its incidence was somewhat reduced (45% instead of 71%, which is observed with long-term oral therapy).

In subsequent years, our center and several other centers proposed new modes of using cyclophosphamide, in particular, increasing the pulse rate to once a month in the initial phase of therapy for lupus and chronic idiopathic glomerulonephritis. The effectiveness of treatment can be judged no earlier than after 6 months. If there are signs of improvement, continue treatment of glomerulonephritis for another 3 months; subsequently, if it is necessary to continue treatment, the intervals between pulses should be increased to 2-3 months. The risk of developing side effects depends on the total dose of the drug.

When administering 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 SCF, 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 minutes):
  • with normal CF - 15 mg/kg of the patient's body weight (or approximately 0.6-0.75 g/m2 ^of body surface);
  • with a CF of less than 30 ml/min - 10 mg/kg (or about 0.5 g/m2 ⁾.
• Strict monitoring of the leukocyte level is required on the 10th and 14th day after pulse therapy: if the leukocyte level drops to <2000 cells/μl, reduce the next dose by 25%; if the leukocyte level is >4000 cells/μl, increase the next dose of cyclophosphamide by 25% (up to 1 g/m2 ⁾;
• To prevent nausea and vomiting, serotonin receptor antagonists are recommended: cerucal 10 mg 3 times a day, ondansetron 4-8 mg orally 3-4 times every 4 hours (as an alternative - navoban or latran); can be combined with a single dose of 10 mg dexamethasone orally;
• to prevent the toxic effect of cyclophosphamide metabolites on the mucous membrane of the bladder: stimulation of frequent urination (increased fluid intake) and taking mesna, which binds toxic metabolites in the bladder (4 times every 3 hours, the total dose corresponds to 80% of the cyclophosphamide dose).

Using mathematical modeling methods, prognostic features have been identified that allow one to predict in advance the patient's sensitivity to therapy with ultra-high doses of cyclophosphamide, thereby avoiding the unjustified prescription of immunosuppressants. The results of the analysis conducted in 44 patients with glomerulonephritis indicate that:

• treatment of glomerulonephritis with ultra-high doses of cyclophosphamide is tolerated satisfactorily by the majority (89%) of patients with chronic glomerulonephritis;
• by 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 normal creatinine levels and a disease duration of no more than 2 years. The accuracy of the prognosis (especially with elevated creatinine levels and a disease duration of more than 2 years) is increased by performing a kidney biopsy: higher efficiency can be assumed for MN, MPGN and MCGN, lower - for focal segmental glomerulosclerosis and sclerosing glomerulonephritis. However, the degree of activity of the immune-inflammatory process is of decisive importance: for all morphological variants, survival is higher with a high morphological activity index;
• to achieve the effect (in patients potentially sensitive to cyclophosphamide), long-term treatment of glomerulonephritis is necessary (at least 6.0 g of cyclophosphamide for 6 months or more). Insufficient treatment significantly worsens the prognosis, especially with elevated creatinine levels;
• a positive response from the patient at the end of the course of treatment (complete or partial remission) is an indicator of a good long-term prognosis;
• the lack of an immediate answer makes a good prognosis unlikely.

Chlorbutin

It is prescribed at a dose of 0.1-0.2 mg/kg x day). The half-life is 1 hour; it is completely metabolized. Chlorbutin acts more slowly than cyclophosphamide, and the associated bone marrow suppression develops less rapidly and is often reversible. Side effects include gastrointestinal disturbances and gonadal failure. Less common side effects include pulmonary fibrosis, seizures, dermatitis, and toxic liver damage. Tumors develop less frequently than with cyclophosphamide.

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

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Antimetabolites and treatment of glomerulonephritis

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Azathioprine

Azathioprine, an analogue of the purine base hypoxanthine, is a derivative of 6-mercaptopurine. Azathioprine metabolites inhibit enzymes required for DNA synthesis, thereby suppressing any immune response that requires cell division. Azathioprine is taken at a dose of 1-3 mg/mg/kg/day, with the dose selected in such a way as to maintain the white blood cell count at least 5000 cells/μl. The main side effect is bone marrow suppression, especially neugropenia with the development of infections. Other complications include anemia, thrombocytopenia, hepatitis, dermatitis, stomatitis, alopecia, gastrointestinal disorders, and an increased risk of tumors, especially skin cancer and lymphomas.

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

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Selective immunosuppressants and treatment of glomerulonephritis

Cyclosporine A

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

The greatest experience with the use of cyclosporine A has been accumulated in renal transplantation. In recent years, it has been used to treat steroid-resistant nephrotic syndrome, with lower doses prescribed to prevent nephrotoxicity than in renal transplantation. According to some data, in contrast to 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.

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

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

Before treatment, a kidney biopsy is mandatory: interstitial sclerosis, tubular atrophy or vascular damage prevent the administration of cyclosporine A. In patients over 60 years of age, the drug increases the risk of developing tumors.

The initial daily dose of cyclosporine A 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 cyclosporine A in the blood does not always correlate with the effectiveness of treatment, but is useful for monitoring the accuracy of drug intake by the patient and detecting possible interactions of cyclosporine A with other drugs. Monitoring of renal function is mandatory: an increase in creatinine by 30% relative to the initial level requires a decrease in the dose of cyclosporine A by 30-50%.

The most serious side effects are nephrotoxicity, which is dose-dependent and usually reversible, and the development of arterial hypertension, which is associated with spasm of the afferent glomerular arteriole.

Other side effects include hypertrichosis and gingival hypertrophy (azithromycin helps with the latter; metronidazole may also help).

The nephrotoxicity of cyclosporine during long-term administration is often difficult to assess clinically. Continuous administration of cyclosporine for 12-38 months is accompanied by a significant increase in tubulointerstitial fibrosis, and its severity in repeat biopsies correlates with the number of glomeruli with segmental sclerosis in the first biopsy, the creatinine level at the time of the first biopsy, and with a cyclosporine dose exceeding 5.5 mg/kg per day. The development of nephrotoxicity may not be clinically 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 exclusion, as far as possible, of other nephrotoxic drugs, especially NSAIDs, are necessary, since in patients with hypovolemia, blockade of prostaglandin production can sharply worsen renal blood flow.

After discontinuation of cyclosporine A, relapse of nephrotic syndrome is possible and steroid-dependent nephrotic syndrome may become cyclosporine A-dependent. However, patients with complications of steroid therapy tolerate cyclosporine A quite well.

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Tacrolimus (FK-506) and mycophenolate mofetil

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

Tacrolimus (FK-506) is a calcineurin inhibitor, similar in mechanism of action to cyclosporin A, relatively selectively suppresses CD4 T-helpers; possibly suppresses cytokine release somewhat more strongly; an inhibitory effect on the production of vascular permeability factor cannot be ruled out. In an experiment, the introduction of FK-506 prevented the development of autoimmune nephritis in rats.

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

Mycophenolate mofetil, a derivative of mycophenolic acid, is an inhibitor of inosine monophosphate dehydrogenase that depletes guanidine nucleotides in cells, selectively inhibits the proliferation of T and B lymphocytes, antibody production, and the formation of cytotoxic T lymphocytes. In addition, it inhibits glycosylation of adhesion molecules, which can affect the influx of lymphocytes into inflammation sites in rejected transplants. It is used primarily in transplantology. It suppresses the proliferation of rat and human mesangial cells in tissue culture without the development of cellular necrosis or apoptosis.

Mycophenolate mofetil causes a number of serious gastrointestinal side effects: nausea, vomiting, diarrhea, which require a reduction in the dose of the drug or even discontinuation of treatment for glomerulonephritis. Leukopenia develops with the same frequency as when prescribing azathioprine. The risk of opportunistic infections increases.

The new form of the drug (Mayfortic), which is soluble only in the intestine, causes fewer gastrointestinal side effects and opens the way for wider use of this drug.

Clinical observations of glomerulonephritis are still few. Thus, F. Schweda et al. (1997) achieved remission during tacrolimus treatment of a young woman with minimal changes in the glomeruli and NS, resistant to glucocorticoids and cyclosporine A, for 20 months without visible side effects. M. Choi et al. (1997) used mycophenolate mofetil to treat 8 patients with steroid- or cyclosporine 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 mycophenolate mofetil was used as suppressive [Chan, 2000] or maintenance [Contreras, 2004] therapy. The main conclusion of these studies is that mycophenolate mofetil is as effective as cyclophosphamide in causing remission of nephritis, but increases the survival of patients due to a lower number of septic complications.

Combined regimens for the treatment of glomerulonephritis

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

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

A unique treatment regimen with alternating glucocorticoids and cytostatics was proposed by S. Ponticelli et al. (1984). During the first 3 days of the 1st month of treatment, methylprednisolone is administered intravenously (1000 mg), in the following 27 days, methylprednisolone is given orally daily at a dose of 0.4 mg/kg, i.e. 28 mg for a body weight of 70 kg; during the 2nd month of treatment, the patient takes only chlorbutin at a very high dose - 0.2 mg/kg x day), i.e. 14 mg for a body weight of 70 kg. This 2-month cycle is repeated 3 times; the total duration of treatment is 6 months.

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Six-month therapy with methylprednisolone and chlorbutin (PONTICELLI regimen)

A. Months 1st, 3rd, 5th

Methylprednisolone - 1000 mg intravenously for 3 days, followed by oral administration of prednisolone, 0.5 mg/kg/day) - for 27 days.

B. Months 2nd, 4th, 6th

Chlorbutin - 0.2 mg/kg/day) - for 30 days

Recommendations:

Intravenous methylprednisolone - the dose may be reduced to 500 mg per pulse in patients weighing less than 50 kg.

Chlorbutin - the dose should be reduced to 0.1 mg/kg/day) if the leukocyte level is less than 5000 cells/mm3 ^and completely discontinued if the level is less than 3000 cells/ ^mm3.

Possible modifications

Chlorbutin is indicated at a dose of 0.1 mg/kg per day:

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

In 1968, P. Kincaid-Smith proposed combining immunosuppressants (prednisolone and cytostatics) with anticoagulants (heparin followed by its replacement with warfarin) and antiplatelet agents (dipyridamole 400 mg/day) in the treatment of rapidly progressing glomerulonephritis. Later, such a combination was called a 4-component scheme. Similar schemes are also used, where chlorbutin is prescribed instead of cyclophosphamide. In addition, a modified scheme was proposed: prednisolone at a dose of 60 mg/day, azathioprine at 2 mg/kg x day), dipyridamole at 10 mg/kg x day), heparin at a dose causing a doubling of thrombin time are prescribed for 8 weeks. Then, for a year, treatment of glomerulonephritis is continued with azathioprine and dipyridamole in the same doses, and heparin is replaced with phenylin (in a dose that causes a doubling of prothrombin time). Similar regimens without prednisolone are recommended.

In some patients with slowly progressive renal failure, aggressive treatment with corticosteroids and/or cytostatics may improve renal function. However, patients with renal failure are more sensitive to the side effects of immunosuppressants. Therefore, treatment of glomerulonephritis should be used only if there is a real chance of improvement.