Nephrology for Family Doctors - O.I. Bakaliuk 2003

Modern approaches to the treatment of specific pathological conditions associated with kidney damage
Treatment of nephrotic syndrome

The Treatment of Nephrotic Syndrome (NS) involves hospitalizing the patient in a specialized nephrology department. Its effectiveness depends on numerous factors, including the promptness and comprehensiveness of drug therapy, the patient's age, and The Nature and clinical course of the underlying disease.

Drug therapy is combined with a semi-bed rest regimen and a salt-restricted diet providing 1 g of protein per kg of body weight per day. Neither low-protein nor high-protein diets have proven beneficial. There are fairly well-reasoned attempts to prescribe a fasting and thirst regimen for the first 2–3 days of NS, or a short (4–7 day) course of controlled therapeutic fasting (O.I. Bakaliuk, 1998).

When prescribing medications, the potential decrease in albumin transport function resulting from hypoalbuminemia must be taken into consideration. This necessitates higher doses of drugs (1.5–2 times greater), administration 4–6 times a day, and, preferably, the parenteral route.

A turning point in the treatment of NS was the Introduction of glucocorticoids into clinical practice. However, a certain amount of disillusionment soon followed. It was observed that patients with mesangiocapillary GN, focal segmental glomerulosclerosis-hyalinosis, and a significant portion of patients with mesangioproliferative GN were resistant to this therapy. Steroid therapy is largely ineffective in cases of relentless relapsing NS and its hypervolemic variant. Glucocorticoids are strictly contraindicated in NS caused by Renal Amyloidosis, diabetic nephropathy, or malignancies.

It is generally accepted that Adrenal Cortex Hormones at doses of 1–2 mg/kg of body weight per day are the drugs of choice for NS in children, as well as in adults without arterial Hypertension or hypoalbuminemia. A lack of therapeutic response after 1 month warrants discontinuation. When a response is achieved, corticosteroid therapy is continued for an extended period (up to 1–2 years) with a gradual tapering of the dose and The Use of maintenance doses (10–15 mg/day).

The administration of cytostatic agents (either instead of corticosteroids or, more commonly, in various combinations with them) achieves the desired outcome in a significant number of cases.

Cytostatic agents are prescribed for NS patients who have contraindications to glucocorticoids, are intolerant to them, or fail to respond. Preference is given to cyclophosphamide (100 mg/day) daily for 10–15 days, followed by long-term oral administration of azathioprine (50–100 mg/day) or chlorambucil (2.5–5 mg/day). At the same time, it is recognized that alkylating agents (cyclophosphamide, leukeran) are more effective, yet also more hazardous, than antimetabolites (azathioprine).

In a specialized inpatient Setting, cytostatic pulse therapy is recommended—the intravenous administration of 800–1200 mg of cyclophosphamide once a month for 5–6 courses, sometimes more. Studies have shown that adverse effects with cyclophosphamide pulse therapy occur three times less frequently than with the conventional treatment regimen, while maintaining equal efficacy (T.N. Krasnova et al., 1998).

Recently, increasing attention in the treatment of NS has been given to the selective immunosuppressant sandimmun (cyclosporine A) (M.O. Kolesnyk et al., 1995).

Cyclosporine A was first identified in 1972 by scientists at Sandoz as a compound produced by the fungus Tolypocladium inflatum. Since then, over 25 natural cyclosporines have been isolated, yet only a few—specifically cyclosporines A, B, C, and F—exhibit pronounced in vivo immunosuppressive effects; cyclosporine H (immunologically inactive) and cyclosporine D (immunologically weakly active) are also distinguished. The mean elimination half-life of the drug is 7.3 hours in children and 10–27 hours in adults.

Sandimmun is capable of selectively altering lymphocyte function by suppressing The production of lymphokines (interleukins) by T Cells, as well as cytokines (catechin, lymphotoxin, gamma-interferon), their secretion, and binding to specific receptors. As a result, the differentiation and proliferation of cytotoxic T cells are inhibited, accompanied by the selective accumulation and preservation of T lymphocytes with suppressor properties.

Unlike cyclophosphamide, azathioprine, and leukeran, sandimmun lacks myelotoxic effects, does not increase the risk of infectious complications, and does not impair natural resistance (H.N. Drannik et al., 1994). The clinical efficacy of sandimmun has been proven in forms of NS that are resistant to glucocorticoids and other cytostatics, including focal segmental glomerulosclerosis/hyalinosis (A. Magrier et al., 1997).

However, the nephrotoxicity of this drug must be noted.

The greatest toxicity toward renal structures is exhibited by cyclosporine A itself. Its nephrotoxicity is caused by its impact on the cellular mitochondrial apparatus, where, at immunosuppressive doses, it impairs calcium-induced membrane permeability and The rate of ADP phosphorylation. It can also cause a significant increase in calcium content within renal Tissues, predominantly in the medulla, as well as vasoconstriction, which is partly explained by The stimulation of the sympathoadrenal system and an imbalance between prostacyclin and thromboxane production. Constriction of the afferent glomerular arterioles leads to a reduction in renal Blood flow and Glomerular Filtration rate, along with increased reabsorption of sodium, Water, and urea. Notably, cyclosporine A also stimulates The Development of interstitial fibrosis, and the narrow margin between the therapeutic and toxic doses of the drug necessitates continuous and precise monitoring of its blood concentration. Hypomagnesemia, which develops during prolonged cyclosporine A use—particularly in Kidney transplant recipients—also requires constant monitoring and correction (C. Barton et al., 1997).

Following discontinuation, high concentrations of cyclosporine A in certain Organs (Liver, Kidneys, Adrenal Glands, Pancreas) can still be detected for several months. This is attributed to the elevated content of a specific protein (cyclophilin) in these organs, through which its immunosuppressive activity is mediated in the body and which exhibits high affinity for the structures of these organs. In recent years, data have emerged indicating that human cyclophilin activity varies considerably; consequently, the outcomes of cyclosporine conversion in the body, its efficacy, and its adverse effects may differ significantly (B. Killinger et al., 1989).

Strong arguments for the use of heparin in the treatment of NS include the multifaceted nature of its action: reduction of proteinuria, blockade of aldosterone synthesis, direct inactivation of antidiuretic hormone, inhibition of catecholamines and decreased vascular receptor sensitivity to them, a reduction in the progression rate of renal failure, as well as natriuretic, diuretic, and hypotensive effects (E.N. Amosova et al., 1998).

Heparin is a direct anticoagulant that, in a complex with the serum protein antithrombin III, directly inhibits The activity of factors II, VII, IX, X, XI, and XII and indirectly (by blocking thrombinogenesis) factors V and XIII. In addition, heparin increases the negative charge of the vascular intima, decreases the procoagulant activity of platelet Phospholipids, and inhibits platelet aggregation.

Heparin monotherapy for NS is rarely used; as a rule, it is employed in combination with antiplatelet agents or as part of a component therapy regimen.

In this context, mini-doses (10,000–15,000 IU/day) or even micro-doses (1,000–2,000 IU/day) are more frequently prescribed to enhance the anticoagulant effect of endogenous antithrombin III, prevent thrombinogenesis and its consequences by blocking the blood clotting cascade at the activated factor X stage. The use of such heparin doses does not require special laboratory monitoring tests of the Blood Coagulation SYSTEM.

Heparin in doses exceeding 30,000–40,000 IU/day, accompanied by appropriate laboratory monitoring, is used in cases where NS patients exhibit local vascular hypercoagulation, disseminated intravascular coagulation (DIC) syndrome, or thromboembolic complications. In these instances, monitoring heparin therapy is mandatory.

A rather approximate and imprecise control test is the determination of whole blood clotting time—the heparin dose is considered sufficient if, 45 hours after administration, the blood clotting time increases by two to three times compared to baseline.

A more informative indicator is considered to be the Determination of the clotting time of decalcified blood or plasma after adding a calcium chloride solution—the resulting value should exceed control values by 1.5–2.5 times.

Precise indicators of heparin therapy efficacy include determining the recalcification time of platelet-poor plasma and the Thrombin time (an increase of 1.5–2.5 times), the activated partial thromboplastin time (an increase of 1.5–2 times), and the thromboelastographic value r + k (an increase of at least 1.5 times). Upon completing heparin treatment (2–3 weeks), it is recommended to prescribe indirect-acting anticoagulants (dicumarol, neodicumarol, phenindione, warfarin) for 2–3 months.

The efficacy of the 4-hydroxycoumadin derivative warfarin has been studied in the greatest detail in nephrological practice; its MECHANISM OF ACTION is associated with the inhibition of hepatic synthesis of K-dependent blood clotting factors (I.I. Lapchynska, 2001).

Recently, low-molecular-weight heparins (calciparine, clexane, fragmin, enoxaparin, clivarine, fraxiparine) have been successfully used instead of heparin, particularly in hemorrhagic vasculitis, NS, hypercoagulation syndrome, and when there are contraindications to glucocorticoids and/or cytostatics.

All of them differ significantly from heparin in their pharmacodynamics and mechanism of action, while offering A number of advantages. First and foremost, these include a longer duration of antithrombotic activity and nearly 100% bioavailability following subcutaneous administration. In addition, the clearance of low-molecular-weight heparins is slower and more uniform, and they exhibit a lower degree of binding to blood Proteins (platelet factor IV, Fibronectin, and von Willebrand factor), which neutralize their antithrombotic activity. A lower incidence of thrombocytopenia, increased vascular wall permeability, Osteoporosis, and hemorrhagic complications is also considered an important benefit (E.N. Amosova et al., 1998; H. Wolf, 1994).

Fraxiparine is administered subcutaneously at a dose of 0.3–0.6 ml once daily in the abdominal area for 10–14 days.

The potential use of other generations of thrombolytic agents in NS is also being investigated, such as two-chain urokinase-type plasminogen activator (urokinase) and tissue plasminogen activator (tPA). Alongside experimental data demonstrating the efficacy of these drugs, there are isolated reports of their successful clinical application (M. Segasothy, 1998).

Antiplatelet agents (Persantin, pentoxifylline [synonyms: Trental, pentoxifylline-Hormosan, Agapurin, pentomer, Pentilin], Ticlid, aspirin) continue to hold an important place in the treatment of NS. This is due to their antiplatelet, antithrombotic, and hypotensive effects. By inducing the synthesis of prostacyclins, interferon, and arachidonic acid, they improve microcirculation in the kidneys, particularly when baseline GFR is reduced.

The issue of prescribing NSAIDs for NS remains unresolved, despite clinical evidence of their anti-inflammatory, antiplatelet, and membrane-stabilizing actions, their normalizing effect on hyperfiltration, and even their ability to slow the progression rate of mesangiocapillary GN (A. Tejani, 1997). However, due to their potential nephrotoxic effects (decreased GFR, effective renal plasma flow, sodium excretion, and diuretic efficacy, as well as elevated blood pressure, increased serum creatinine levels, and the development of hyporeninemic hypoaldosteronism), this Class of drugs should be prescribed with caution in patients with NS. Currently, indomethacin, as the most widely used NSAID, is rarely employed in cases of pronounced PU. At the same time, high doses of indomethacin used as a "therapeutic nephrectomy" (I.E. Tareyeva, 1999) are sometimes prescribed for NS refractory to other interventions.

According to I.E. Tareyeva (1995), NSAIDs should be prescribed under conditions of preserved renal function, moderately severe NS, an absence of indications for Pathogenetic Therapy, and the presence of uremic pericarditis. With good tolerance and careful monitoring to prevent complications, their long-term use (up to 6 years) is possible.

NSAIDs capable of selectively inhibiting COX-2 (meloxicam, celecoxib, rofecoxib) are considered promising for the treatment of NS (A. Vane et al., 2000).

There are also reports in the literature regarding the usefulness of membrane stabilizers (ketotifen, Intal, dimephosphon) in the treatment of NS, particularly in pediatric practice (M.S. Ignatova et al., 1991).

Symptomatic therapy for NS plays a crucial role. Its objectives are the elimination of edema and the Prevention and treatment of complications. Management of edema takes into account the patient's general condition and renal function. For instance, in cases of renal failure and pronounced PU, aggressive diuretic therapy may lead to a further drop in circulating blood volume (CBV), potentially resulting in hypovolemic Shock.

Among the four groups of Diuretics (thiazides, furosemide and ethacrynic acid, potassium-sparing agents, and osmotic diuretics), preference is given to furosemide (40–400 mg/day orally, 40–1000 mg intravenously) and ethacrynic acid (uregyt, 50–200 mg orally). In the absence of renal failure, thiazides (hydrochlorothiazide [25–100 mg/day], clopamide [20–80 mg/day]) are added to the treatment regimen.

It should be noted that when furosemide and thiazides are used in combination, furosemide is best administered during the peak diuresis induced by thiazides, rather than vice versa. Their action is also potentiated by aminophylline (2.4% - 10 ml), administered intravenously at the height of diuresis.

Among potassium-sparing agents, whose overall action is not characterized by an extreme diuretic effect, the administration of spironolactone (Veroshpiron, 25–300 mg/day) and competitive aldosterone antagonists (triamterene, 200–400 mg/day) is recommended, either alone or in combination (Triampur, furmil, furesis).

In the later hypoproteinemic phase of nephrotic edema, characterized by hypovolemia—which may occur either per se or be potentiated by the administration of diuretics—attempts to restore the colloid-osmotic balance of the blood are warranted.

To this end, intravenous administration of albumin (100–200 ml of a 5–10% solution 2–3 times a week) or rheopolyglucin (400–800 ml daily for 3–4 days) is employed; these agents may also be administered alternately.

In cases of refractory massive edema, to jump-start diuresis, oral intake of 100–150 ml of a 33% magnesium sulfate solution is recommended, or immersing the patient up to the neck for 2–4 hours in a sitting bath with a water Temperature of 34 °C (K. Miki et al., 1986; E.I. Taran, 2001).

Resistance of nephrotic edema is an indication for isolated ultrafiltration. According to P.V. Klepikov et al. (1989), performing this Procedure in patients with severe NS allows for a rapid reduction in the degree of hyperhydration; notably, the removal of 3 to 6 liters of ultrafiltrate is not accompanied by protein loss or electrolyte shifts and, most importantly, does not lead to a subsequent compensatory decrease in diuresis.

Any infectious complication in a patient with NS requires "aggressive" therapy with reserve Antibiotics for 10–14 days or longer.

The issue of correcting hyperlipidemia in NS remains relevant. While recognizing its necessity, most researchers note a significant number of side effects and toxic reactions associated with the use of lipid-lowering agents such as miscleron, nicotinic acid, and probucol.

Fibrates are used, particularly those of the latest generation, such as gemfibrozil and bezafibrate (M. Elisaf et al., 1993). Statins offer new possibilities for correcting nephrotic hyperlipidemia, especially in cases of pronounced hypercholesterolemia, due to their minimal side effects (C. Wanner et al., 1991; T. Gopler et al., 1997).

Some significance is attributed to dietary supplements in the form of omega-3 polyunsaturated Fatty acids—eicosapentaenoic and docosapentaenoic acids (De Fijter et al., 1995).

Managing a nephrotic crisis is a challenging task. Such patients require close monitoring and intensive care.

If There is a tendency toward arterial hypotension, salt supplementation in the diet or intravenous administration of sodium chloride is permitted. Repeated intravenous infusions of dextrans are indicated (rheopolyglucin administered as an IV drip from 400 to 800–1200 ml/day for 3 consecutive days or every other day, with the administration of 80–200 mg of Lasix at the end of the infusion in cases of massive edema), along with protein solutions (albumin) and plasma substitutes.

Glucocorticoids are administered intravenously (they are contraindicated in the presence of thrombotic complications). High doses (up to 1000–3000 mg/day for 2–3 days) combined with antihistamines (suprastin, tavegil, diazolin, Zyrtec, Claritin, Telfast) are preferred.

Graded trunk compression and water immersion—prolonged (12–24 hours), high-level (immersion of the patient up to the neck) sitting baths—are also utilized.

Upon the appearance of the first dangerous symptoms of a crisis (Skin rash, abdominal pain, development of ascites), high doses of antikinin (prodektin, parmidin) and antikallikrein (Contrical) drugs are administered.

Compresses with heparin and butadione (methindole) ointments are applied to the areas of erythema, supplemented by leg wrapping and an elevated position in bed.

In Conclusion, it should be noted that the complex of therapeutic measures for nephrotic syndrome also includes appropriate (basic and symptomatic) therapy for the underlying disease that caused its development, taking into account the nephrotoxicity of the agents used.