Steroid- and cyclophosphamide-resistant nephrotic syndrome

Steroid- and cyclophosphamide-resistant nephrotic syndrome

Steroid-resistant nephrotic syndrome (SRNS) is one of the most severe conditions in nephrology, which is determined by the high incidence of chronic renal failure (CRF), observed in more than 50% of patients within 5–10 years [1]. According to international registers, SRNS accounts for 15–29% of the structure of terminal chronic renal failure in children, being the leading acquired kidney disease [2].

Achieving remission of SRNS induced by immunosuppressive therapy is a predictor of favorable renal outcome of the disease [3]. The effectiveness of various types of immunosuppressive therapy for SRNS, including pulsed intravenous administration of cyclophosphamide (CPA), cyclosporine A (CsA), mycophenolate mofetil, according to various authors, varies widely from 33.3% to 70–80% [1, 4–6 ]. Despite the lack of response to therapy using oral CPA in children with SRNS shown in the ISKDC (International Study of Kidney Disease in Children) study [7], a number of studies have demonstrated the effectiveness of pulsed intravenous injections of CPA in 40–60% of patients [4, 8 ]. The data obtained require confirmation in prospective randomized controlled studies of the effectiveness of pulsed intravenous injections of CPA in children with SRNS.

CsA therapy is accompanied by the development of remission of SRNS in a larger number of patients (70–80%) and requires a longer course with monitoring of potential nephrotoxicity [9, 10]. According to the KDIGO (Kidney Disease Improving Global Outcomes) practice guidelines, the use of a calcineurin inhibitor, CsA, in combination with low-dose steroid regimens is recommended as initial first-line immunosuppressive therapy in children with SRNS [11].

In recent years, there have been reports of the successful use of another calcineurin inhibitor, tacrolimus, in the treatment of SRNS in both children and adult patients [12–14]. Tacrolimus is a macrolide antibiotic with a relatively selective inhibitory effect on the CD4 fraction of T-helper lymphocytes. The immunosuppressive effect of tacrolimus is the intracellular inhibition of calcineurin, a regulatory protein that dephosphorylates and activates the nuclear factor of stimulated T cells, which leads to the suppression of the activation and proliferation of CD4 T helper lymphocytes and the synthesis of the cytokine interleukin-2. Tacrolimus inhibits cytotoxic cell proliferation and suppresses the activation of NO synthase and B lymphocytes in vitro, and also has a steroid-potentiating effect, but does not increase the level of Transforming growth factor beta (TGF-β), an endogenous promoter of fibrogenesis [12 , 15].

Studies in kidney transplant recipients have shown that tacrolimus has a more pronounced immunosuppressive effect and is less likely to have potential nephrotoxic effects compared with CsA, which is associated with a lesser effect of tacrolimus on renal hemodynamics [16–18]. Treatment with tacrolimus compared with CsA was less often accompanied by the appearance of arterial hypertension and dyslipidemia, but an increased risk of developing diabetes mellitus was noted [19].

In 1990, tacrolimus was first used to treat SRNS with focal segmental glomerulosclerosis (FSGS) in a child [20]. Since that time, the results of several foreign single-center studies of the effectiveness of tacrolimus therapy have been published in the world literature, which contributed to the achievement of complete remission of SRNS in 40–86% of children with a heterogeneous composition of morphological variants of the pathology [21–23].

We present a joint case study demonstrating the effectiveness of tacrolimus in a patient with SRNS resistant to immunosuppressive therapy with CFA.

Patient 19 years old, student, fell ill at the age of 15.5 years, nephrotic syndrome developed: peripheral edema of the legs and face, proteinuria up to 2.5 g/day with microhematuria (30–40 red blood cells in the field of view), blood albumin - 20 g /l, total blood protein - 40 g/l, arterial hypertension up to 180/100 mm Hg. Art., creatinine in the blood - 98 µmol/l. At the place of residence, the teenager was prescribed prednisolone at a dose of 80 mg/day, and was given antihypertensive therapy with losartan at a dose of 100 mg/day. Due to the lack of response to treatment with prednisolone within 8 weeks, SRNS was diagnosed, and the patient was transferred to the department of hereditary and acquired kidney diseases of the Moscow Research Institute of Pediatrics and Pediatric Surgery. A morphological study of renal tissue performed 3 months after the manifestation of the disease revealed mesangioproliferative glomerulonephritis. An immunohistochemical study of nephrobiopsy specimen revealed focal fixation of IgG, IgA, IgM and C3 on the glomerular basement membrane. The patient was prescribed immunosuppressive therapy with intravenous administration of ultra-high doses of CFA at the rate of 10–12 mg/kg per administration once every 3–4 weeks until the cumulative dose of the drug was reached 200 mg/kg (total received 10 g of CFA) in combination with prednisolone per os 60 mg every other day with gradual withdrawal of steroids. After completing the course of CFA therapy, nephrotic syndrome persisted: proteinuria - 2.9 g/day, blood albumin - 28 g/l, total blood protein - 56 g/l, arterial hypertension up to 160/100 mm Hg. Art. (while taking Cozaar 100 mg/day), kidney function is normal (creatinine - 79 µmol/l). Due to the continued activity of SRNS and the lack of effect of CFA therapy, 21 months after the onset of the disease, tacrolimus was prescribed at a dose of 3.5 mg 2 times a day (at the rate of 0.1 mg/kg/day) under the control of drug concentration in the blood (up to 6 .9 ng/ml). A rapid positive effect was noted: nephrotic syndrome was relieved by the end of the first month of tacrolimus therapy, and remission of glomerulonephritis was achieved over the next 9 months. From the age of 18 years, the patient is observed in the Clinic of Nephrology, Internal and Occupational Diseases named after. E. M. Tareeva. The persistence of clinical and laboratory remission of SRNS was noted during 12 months of tacrolimus therapy. We did not record an increase in hypertension, cosmetic side effects, hyperlipidemia or increased serum glucose. The only side effect was a short-term episode of diarrhea at the start of treatment, which resolved on its own. In connection with the achievement of stable remission of SRNS (proteinuria does not exceed 0.2 g/day, serum protein levels and kidney function indicators are within normal values: creatinine - 0.8 mg/dl, glomerular filtration rate (in the Rehberg test) - 80 ml/min/1.73 m2) the drug was discontinued.

6 months after discontinuation of tacrolimus therapy, the patient maintained clinical and laboratory remission of SRNS. Arterial hypertension is corrected by a combination of two antihypertensive drugs: losartan 100 mg/day, Isoptin — 120 mg/day.

Recent studies have provided limited information on the effectiveness and safety of tacrolimus therapy for SRNS [14, 24].

The starting dose of tacrolimus in children and adults is 0.1 mg/kg/day, followed by titration of the drug dose to achieve a therapeutic concentration in the blood of patients in the range of 5–10 ng/ml and avoid potential nephrotoxic effects. According to the Moscow Research Institute of Pediatrics and Pediatric Surgery, the time to achieve remission of SRNS when prescribed tacrolimus was quite short and ranged from 1 to 4 months (on average 2.5 months) [25]. In adult patients with FSGS, monotherapy with tacrolimus at a dose of 2 mg/day contributed to the development of remission of the disease for 6.5 ± 5.9 months [13].

A feature of our observation is the effective use of tacrolimus in a teenager with SRNS and mesangioproliferative glomerulonephritis, resistant to immunosuppressive pulse therapy with CFA.

The superior efficacy of tacrolimus compared with pulsed intravenous injections of CPA was shown in a multicenter randomized controlled trial in 131 children with SRNS [27]. Complete and partial clinical and laboratory remission of the disease was achieved after 6 months of therapy with tacrolimus and intravenous CFA in 82.5% and 45.9% of patients. 6 months after discontinuation of therapy, continued remission of SRNS was observed in 73.1% of patients after tacrolimus therapy and only in 42.9% after completion of the CPA course. Persistent and reversible nephrotoxic effects were observed with the use of tacrolimus in 3.3% and 10.6% of children, respectively. Severe infectious complications were noted more often when using CFA compared to tacrolimus: 6.1% and 24.6% of patients, respectively.

At the same time, there are few studies in the literature on the use of tacrolimus for mesangioproliferative glomerulonephritis. In a study by Li X. et al. included 5 patients with mesangioproliferative glomerulonephritis (3 men and 2 women) aged 32.2 ± 11.1 years with SRNS, resistant to intravenous CFA therapy [24]. After administration of tacrolimus at a dose of 0.05 mg/kg/day for 5.2 ± 2.3 weeks, all patients achieved disease remission: 3 complete and 2 partial; therapy lasted 6 months. However, after discontinuation of a 6-month course of tacrolimus therapy, 2 patients experienced relapses of SRNS (after 46 and 64 months), while one of them developed secondary resistance to tacrolimus.

A prospective multicenter study of the effectiveness of tacrolimus therapy included 8 adult patients with SRNS with mesangioproliferative glomerulonephritis, 6 of them achieved disease remission after 12 months of treatment, and one patient experienced a relapse within 6 months after discontinuation of the drug [26].

A comparative analysis of the effectiveness of tacrolimus and CsA in children with SRNS and various morphological forms of glomerulonephritis (minimal change disease, FSGS, mesangioproliferative glomerulonephritis) was carried out in a randomized controlled trial by Choundhry et al. [23]. Therapy with tacrolimus and CsA contributed to the development of remission (complete or partial) of the disease in a similar proportion of patients: after 6 months - in 85.7% and 80% of patients, respectively; after 12 months - in 80.5% and 85% of patients. Moreover, the number of relapses of SRNS observed after discontinuation of immunosuppressive therapy in patients receiving CsA was significantly higher (50%) than in patients treated with tacrolimus (11.1%).

Moreover, in a study by Segarra A. et al. the effectiveness of tacrolimus in CsA-resistant or dependent FSGS was demonstrated in 25 adult patients [14]. Treatment was carried out for 12 months in combination with prednisolone per os at a dose of 1 mg/kg/day with an alternating course for two months, followed by a decrease to 6 months. After 6 months of treatment with tacrolimus, 40% of patients achieved complete remission, 8% had partial remission, and 20% had a decrease in proteinuria of less than 3 g/day. However, when tacrolimus was discontinued after 6 months, 76% of patients experienced a relapse of the disease, which required resumption of the drug for another year. At the same time, remission (complete or partial) of the pathology was achieved in 69.2% of patients, a decrease in proteinuria of less than 3 g/day was observed in 16% of patients. After discontinuation of the drug, stable remission of SRNS (for two years) persisted in 48% of patients. It should be noted that in 75% of patients with steroid- and CsA-resistant nephrotic syndrome, a response to tacrolimus was obtained in the case of secondary resistance. However, a positive effect when prescribing tacrolimus was achieved in 15.3% of patients with primary resistance to CsA.

Currently, the reasons for some differences in the clinical effects of CsA and tacrolimus remain the subject of widespread debate among researchers around the world. It is believed that the stronger immunosuppressive effect of tacrolimus is due to greater affinity for the FK-binding protein calcineurin, and the effectiveness of tacrolimus in patients resistant to CsA can apparently be explained by the presence of other mechanisms of action/points of action for tacrolimus than CsA.

Acute drug nephrotoxicity with an increase in blood creatinine levels by 25–30% of the initial level, according to various authors, ranges from 25% to 40% and occurs, as a rule, when the dose is selected in the first week of tacrolimus administration and the concentration of the drug in the blood serum is exceeded ( more than 10 ng/ml). The decrease in renal function is usually moderate and is reversible when the dose of tacrolimus is discontinued or reduced by 50% [14, 24]. The risk group for developing nephrotoxicity includes patients with underlying renal impairment; in this case, the dose of the drug should not exceed 0.06 mg/kg/day, and the concentration of the drug in the serum should not exceed 10 ng/ml [14]. Cases of the development of diabetes mellitus, hepatotoxicity and neurotoxicity of tacrolimus in SRNS are rare [13, 14, 22–24].

In our observation, there were no changes in biochemical blood parameters (glucose, transaminases, lipids, potassium), coagulogram, or manifestations of acute nephrotoxicity when taking the drug. Assessing the degree of tubulointerstitial fibrosis as a manifestation of chronic nephrotoxicity in our patient with complete remission of chronic glomerulonephritis is difficult, since it requires a kidney biopsy. The patient is recommended to undergo further observation by a nephrologist, control of arterial hypertension, study of kidney function indicators, as well as nephroprotective therapy with angiotensin-converting enzyme inhibitors.

According to the literature, repeat kidney biopsies were performed in children who received long-term (more than 12 months - average 24 (14–56) months) tacrolimus for SRNS. In 2 out of 7 children, an increase in the index of tubulointerstitial fibrosis was detected; in the rest (5 out of 7), a morphological study showed no changes in the size of the tubulointerstitium, an increase in tubular atrophy, or accumulation of TGF-beta in various structures of the kidney tissue; arteriolohyalinosis [22].

Thus, the presented clinical observation confirms the literature data indicating that the administration of tacrolimus for SRNS may be an alternative to CsA, including for mesangioproliferative glomerulonephritis, given the lower frequency of relapses of nephrotic syndrome and better tolerability.

Further multicenter studies of the effectiveness and safety of the use of tacrolimus in children and adults with SRNS with various morphological variants are needed in order to determine the optimal duration of therapy, clarify the profile of potential side effects, including the incidence of chronic nephrotoxicity, and also establish the order of priority for prescribing the drug from the standpoint of evidence-based medicine .

The experience of continuous management of a patient with SRNS and cyclophosphamide-resistant nephrotic syndrome in pediatric and adult nephrology clinics is shown, with a discussion of the tactics of tacrolimus therapy. The need for joint monitoring of patients with chronic kidney disease when transferring from a pediatric to an adult clinic is clearly demonstrated in the Agreement approved by the International Society of Nephrology and the International Association of Pediatric Nephrologists [28].

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N. V. Chebotareva*, Candidate of Medical Sciences L. S. Prikhodina**, Doctor of Medical Sciences E. M. Shilov***, Doctor of Medical Sciences, Professor

*Research Institute of Uronephrology of the First Moscow State Medical University named after. I. M. Sechenova, ** Federal State Budgetary Institution "Moscow Research Institute of Pediatrics and Pediatric Surgery" of the Ministry of Health of the Russian Federation, *** State Educational Institution of Higher Professional Education of the First Moscow State Medical University named after. I. M. Sechenova Ministry of Health of the Russian Federation, Moscow

Contact information for authors for correspondence

• Magazine archive /
• 2021 /

Possibility and prospects for the use of drugs from the group of cytostatics in patients with COVID-19 using the example of cyclophosphamide

DOI: https://dx.doi.org/10.18565/pharmateca.2021.1.10-13

V.M. Tsvetov (1), I.S. Burashnikova (2), D.A. Sychev (3), I.V. Poddubnaya (4)

1) Federal Center for Cardiovascular Surgery, Chelyabinsk, Russia, https://orcid.org/0000-0003-4810-2295; 2) Kazan State Medical Academy - branch of the Federal State Budgetary Educational Institution of Further Professional Education RMANPO of the Ministry of Health of Russia, Kazan, Russia, https://orcid.org/0000-0002-8511-5696; 3) Russian Medical Academy of Continuing Professional Education, Moscow, Russia, https://orcid.org/0000-0002-4496-3680; 4) Russian Medical Academy of Continuing Professional Education, Moscow, Russia, https://orcid.org/0000-0002-0995-1801

There is currently no evidence-based evidence to recommend the use of cyclophosphamide as a treatment for patients with COVID-19. The use of this drug may adversely affect the course of infection caused by SARS-CoV-2, including the occurrence of adverse side effects. Clinical trials are required to evaluate the effectiveness and safety of cytostatics, including cyclophosphamide, for patients with COVID-19.

Key words: COVID-19, cytostatics, cyclophosphamide

The full text of the article is available in the Doctor's Library

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Instructions for use CYCLOPHOSPHAN

In patients receiving Cyclophosphamide, depending on the dosage, the following adverse reactions may occur, which in most cases are reversible.

Infections and infestations:

• Usually, severe bone marrow suppression can lead to agranulocytic fever and secondary infections such as pneumonia, which can progress to sepsis (life-threatening infections), which in some cases can be fatal.

From the immune system:

rarely, hypersensitivity reactions may occur, accompanied by rash, chills, fever, tachycardia, bronchospasm, shortness of breath, edema, blood flow and decreased blood pressure. In rare cases, anaphylactoid reactions can progress to anaphylactic shock.

From the blood and lymphatic system:

Depending on the dosage, various forms of bone marrow suppression may occur, such as leukopenia, neutropenia, thrombocytopenia with an increased risk of bleeding, and anemia. It should be borne in mind that severe bone marrow suppression can lead to agranulocytic fever and the development of secondary (sometimes life-threatening) infections. The minimum number of leukocytes and platelets is usually observed during the 1st and 2nd weeks of treatment. The bone marrow recovers relatively quickly, and the blood picture returns to normal, usually 20 days after the start of treatment. Anemia may usually develop only after several cycles of treatment. The most severe suppression of bone marrow function should be expected in patients who have previously been treated with chemotherapy and/or radiation therapy, as well as in patients with renal failure.

Simultaneous treatment with other substances that inhibit hematopoiesis requires dose adjustment. You should use the appropriate dose adjustment tables for cytotoxicity of drugs based on the quantitative composition of the blood at the beginning of the treatment cycle and adjust the dosage with low levels of cytostatic substances.

From the nervous system:

in rare cases, neurotoxic reactions such as paresthesia, peripheral neuropathy, polyneuropathy, as well as neuropathic pain, taste disturbances and convulsions have been reported.

From the digestive tract:

Adverse reactions such as nausea and vomiting are very common and dose dependent. Moderate and severe forms of their manifestations are observed in approximately 50% of patients. Anorexia, diarrhea, constipation and inflammation of the mucous membranes from stomatitis to ulceration are observed with less frequency. In isolated cases, hemorrhagic colitis and acute pancreatitis were reported. Gastrointestinal bleeding has been reported in isolated cases. In cases of nausea and vomiting, dehydration can sometimes develop. Isolated cases of abdominal pain due to gastrointestinal disorders have been reported.

From the digestive system:

Rarely reported liver dysfunction (increased levels of serum transaminases, gammaglutamyl transpeptidase transpeptidase, alkaline phosphatase, bilirubin).

Obliterative endophlebitis of the hepatic veins has been reported in approximately 15-50% of patients receiving high-dose cyclophosphamide in combination with busulfan or whole body irradiation for allogeneic bone marrow transplantation. But on the contrary, this complication was observed in patients with aplastic anemia who received only high doses of Cyclophosphamide. The syndrome usually develops 1-3 weeks after transplantation and is characterized by sudden weight gain, hepatomegaly, ascites and hyperbilirubinemia and portal hypertension. Very rarely, hepatic encephalopathy may develop. Known risk factors that contribute to the development of hepatic vein occlusive endophlebitis in a patient are the presence of impaired liver function, therapy with hepatotoxic drugs in combination with high-dose chemotherapy, and especially if an element of the co-induced therapy is the alkylating compound busulfan.

From the kidneys and urinary system:

Once excreted in the urine, cyclophosphamide metabolites cause changes in the urinary system, namely the bladder. Hemorrhagic cystitis, microhematuria and macrohematuria are the most common dose-dependent complications during treatment with Cyclophosphamide and require discontinuation of therapy. Cystitis develops very often, at first they are sterile, but secondary infection can occur. Swelling of the bladder walls, bleeding from the cell layer, interstitial inflammation with fibrosis, and sometimes sclerosis of the bladder were also noted. Renal dysfunction (especially in cases with a history of renal impairment) is an uncommon adverse reaction when used in high doses. Treatment with uromitexane or drinking plenty of fluids may reduce the frequency and severity of urotoxic adverse reactions. In isolated cases, hemorrhagic cystitis with fatal outcome has been reported. Acute or chronic renal failure and toxic nephropathy may occur, especially in patients with a history of reduced renal function.

From the reproductive system:

through its ankylation effect, cyclophosphamide can rarely cause impairment of spermatogenesis (sometimes irreversible) and lead to azoospermia and/or persistent oligospermia. Rarely, ovulation disturbances have been reported. In some cases, amenorrhea and decreased levels of female sex hormones have been reported.

From the cardiovascular system:

cardiotoxicity from minor changes in blood pressure, ECG changes, arrhythmias, to secondary cardiomyopathy with reduced left ventricular function and heart failure, which in some cases can cause death. Clinical symptoms of cardiotoxicity may include, for example, chest pain and angina. Ventricular supraventricular arrhythmia has occasionally been reported. Very rarely, atrial or ventricular fibrillation, as well as cardiac arrest, may occur during cyclophosphamide therapy. In very rare cases, myocarditis, pericarditis and myocardial infarction have been reported. Cardiotoxicity is especially enhanced after use of the drug in high doses (120-240 mg/kg body weight) and/or when combined with other cardiotoxic drugs, for example, anthracyclines or pentostatin. Increased cardiotoxicity may also occur after prior radiotherapy to the cardiac region.

From the respiratory system:

bronchospasm, shortness of breath or cough, which leads to hypoxia. Very rarely, obliterating endophlebitis of the lungs can develop, sometimes as a complication of pulmonary fibrosis. Toxic pulmonary edema, pulmonary hypertension, pulmonary embolism and pleural effusion have been reported very rarely. In some cases, pneumonitis and interstitial pneumonia may develop, progressing to chronic interstitial pulmonary fibrosis, and respiratory distress syndrome and respiratory failure with fatal outcome have also been reported.

Benign and malignant neoplasms (including cysts and polyps):

as always with cytostatic treatment, the use of Cyclophosphamide is accompanied by the risk of developing secondary tumors and their precursors as late complications. The risk of developing urinary tract cancer, as well as myelodysplastic changes, which can partially progress to acute leukemia, increases. Animal studies have shown that the threat of bladder cancer can be significantly reduced by appropriate use of uromitexane. In rare cases, tumor collapse syndrome has been reported due to the rapid response of large, chemotherapy-sensitive tumors.

Skin and its derivatives/allergic reactions:

alopecia areata, which is a common side effect (can progress to complete baldness), is usually reversible. Cases of changes in skin pigmentation of the palms, nails and fingers, as well as soles have been reported;

• dermatitis, expressed by inflammation of the skin and mucous membranes. Erythrodysesthia syndrome (tingling sensation in the palms and soles, to the point of severe pain). Very rarely, general irritation and erythema of the irradiated area (radiation dermatitis) have been reported after radiation therapy and subsequent treatment with cyclophosphamide. In isolated cases - Stevens-Johnson syndrome and toxic epidermal necrolysis, fever, shock.

From the musculoskeletal system and connective tissue:

muscle weakness, rhabdomyolysis.

From the endocrine system and metabolism:

very rarely - SSIAG (syndrome of inappropriate ADH secretion), Schwartz-Bartter syndrome with hyponatremia and fluid retention, as well as corresponding symptoms (confusion, convulsions). Anorexia has been reported in isolated cases, dehydration has rarely been reported, and fluid retention and hyponatremia have been reported very rarely.

From the organs of vision:

blurred vision. Symptoms such as conjunctivitis and swelling of the eyelids have been reported very rarely as a result of a hypersensitivity reaction.

Vascular disorders:

the underlying disease may cause certain very rare complications such as thromboembolism and peripheral ischemia, disseminated intravascular coagulation or hemolytic uremic syndrome, the incidence of these complications may increase with cyclophosphamide chemotherapy.

Common disorders:

Fever during treatment with cyclophosphamide is a very common adverse reaction in the setting of hypersensitivity and neutropenia (associated with infection). Asthenic conditions and malaise are common complications in cancer patients. Very rarely, as a result of extravasation, reactions may occur at the injection site in the form of erythema, inflammation or phlebitis.