Vol 93, No 6 (2021)

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Kidney injury associated with antitumor therapy: focus on the adverse events of modern immuno-oncological drugs

Kamyshova E.S., Bobkova I.N., Sekacheva M.I.


Immune checkpoint inhibitors (ICIs), including cytotoxic T-lymphocyte associated antigen 4 (CTLA-4) and programmed death protein 1 (PD-1) or its ligand (PD-L1), are a new generation of immuno-oncological drugs that to date have demonstrated efficacy in a number of malignancies. The mechanism of ICT inhibitors action consist in the potentiation of the immune response by eliminating the tumor cells inhibitory effect on the T-lymphocytes activation. However, excessive immune system activation can cause the development of a special class of immune-related adverse events (irAEs) involved a wide variety of organs and systems, including the kidneys. Despite the fact that immuno-mediated kidney injury caused by ICI therapy develops quite rarely, it can be serious and determine the patient's prognosis, which necessitates early diagnosis and timely start of treatment. In this regard, awareness of the manifestations of ICI-associated renal irAEs is particularly relevant not only for oncologists and for nephrologists, but for doctors of other specialties. In this review, we elucidated the main variants of immuno-mediated kidney injury caused by ICI therapy, discussed possible predictors and mechanisms of their development, and considers the general principles of diagnosis and management of patients according to the severity of irAEs.

Terapevticheskii arkhiv. 2021;93(6):649-660
pages 649-660 views

Original articles

Clinical and laboratory signs and risk factors for nephrotoxicity, associated with antiangiogenic drugs

Grechukhina K.S., Chebotareva N.V., Zhukova L.G., Krasnova T.N.


Background. Anti-angiogenic anticancer drugs that block the vascular endothelial growth factor signaling pathway can cause renal damage. Assessment of the risk of nephrotoxicity allows developing optimal treatment approaches and ensuring the relative safety of therapy.

Aim. To assess early clinical and laboratory manifestations and risk factors for nephrotoxicity of antiangiogenic drugs.

Materials and methods. The study included 50 patients who received antiangiogenic drugs in different regimens of chemotherapy. Demographic factors, body mass index, blood pressure levels, type of antiangiogenic drug, and concomitant therapy were assessed. Before treatment and over a period of 8 weeks, the levels of hemoglobin, number of platelets and schistocytes, D-dimer levels, serum lactate dehydrogenase (LDH) levels, as well as daily proteinuria and serum creatinine and eGFRCKD-EPI were assessed. Linear regression analysis was performed to assess risk factors for nephrotoxicity and arterial hypertension (AH).

Results. The median age of patients was 46 [34–57] years, 22 (44%) men and 28 (56%) women. AH developed in 52%, a decrease in eGFR – in 42%, along with a decrease in hemoglobin levels and an increase in LDH levels – at 2 weeks of therapy. The numbers of schistocytes and platelets significantly decreased by 8 weeks of therapy. Risk factors for impaired renal function during treatment with antiangiogenic drugs were an initial decrease in GFR less than 80 ml/min/1.73 m2, an increase in D-dimer levels, and a decrease in hemoglobin levels by 8 weeks of treatment. The risk factors for AH during therapy were the initial decrease in eGFR less than 80 ml/min/1.73 m2 and no prophylactic anticoagulant therapy.

Conclusion. Early signs of nephrotoxicity of antiangiogenic anticancer drugs were a decrease in eGFR and AH. The independent risk factors for nephrotoxicity were the initial decrease in eGFR, an increase in D-dimer levels, and a decrease in hemoglobin levels at 8 weeks of treatment, while the prophylactic use of anticoagulant therapy reduced this risk in our study.

Terapevticheskii arkhiv. 2021;93(6):661-666
pages 661-666 views

Assessment of the influence of different factors on the risk of the development of a new coronavirus infection in patients with contrast induced acute kidney injury

Isaev G.O., Mironova O.I., Fomin V.V.


Aim. The main aim of our study was to assess the role of risk factors in patients with previous contrast induced acute kidney injury (CI-AKI) on a probability of a development of the new coronavirus infection.

Materials and methods. Our study includes 65 patients with the history of CI-AKI after coronary angiography from 2013 to 2017 years; 10 of them had a new coronavirus infection, which had developed before November 2020. CI-AKI was defined as an increase of 25% or more, or an absolute increase of 0.5 mg/dl or more in serum creatinine from baseline value, assessed at 48 hours following the administration of the contrast. The primary endpoint was the development of a new coronavirus infection.

Results. We found statistically significant difference in the prevalence of the allergic reaction to iodine (р=0.0178) between non-COVID and COVID-patients group. Also, there were statistically significant differences in the secondary endpoints: renal replacement therapy (р=0.0178) and repeated percutaneous coronary intervention in the last year (р=0.0112) were more common among patients with coronavirus. The difference in the prevalence of arterial hypertension was near to statistical significance (р=0.0882).

Conclusion. COVID-patients with CI-AKI had more allergic reactions to iodine than non-COVID patients. The trend of more common arterial hypertension between COVID-patients was found in our research. There were not any statistical significant differences in other risk factors. There were statistically significant difference in the secondary endpoints such as repeated percutaneous coronary intervention and renal replacement therapy. Other endpoints didn’t show a statistically significant difference.

Terapevticheskii arkhiv. 2021;93(6):667-671
pages 667-671 views

The analysis of secondary AA-amyloidosis current etiology and its influence on the approaches for diagnosis and treatment

Rameev V.V., Kozlovskaya L.V., Rameeva A.S., Novikov A.V., Barsuk M.V.


Aim. To investigate an influence of the currently changed etiologic structure of AA-amyloidosis on the diagnosis and treatment tactics.

Materials and methods. In 110 patients with АА-amyloidosis followed during full disease duration (1 month – 29 years) etiology, clinical manyfestations and approaches to diagnose and treatment of AA-amyloidosis were evaluated. With ELISA levels of amyloid precursor acute phase inflammation reactant SAA and neutrophil activity marker S100A12 were measured.

Results. Among the most common causes of AA-amyloidosis at the present stage, in addition to RA (40.3%), a significant place is occupied by a group of diseases with a predominantly autoinflammatory mechanism (53.73%). To confirm the autoinflammatory mechanism of the predisposing disease it is recommended to study a highly sensitive parameter serum protein S100A12. An effective marker of the risk of AA-amyloidosis progression, especially in patients with subclinical activity of inflammatory disease, is a high level of production of amyloidogenic protein-a precursor of SAA.

Terapevticheskii arkhiv. 2021;93(6):672-678
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Effect of vitamin D receptor activators on serum Klotho levels in 3b–4 stages chronic кidney disease patients: a prospective randomized study

Milovanova L.Y., Beketov V.D., Milovanova S.Y., Taranova M.V., Kozlov V.V., Pasechnik A.I., Reshetnikov V.A., Androsova T.V., Kalashnikov M.V.


Background. High risk of cardiovascular events is among leading problems in chronic kidney disease (CKD). Serum Klotho is supposed to be cardio- and nephroprotective; modification of its levels may be important in CKD.

Aim. To evaluate the impact of vitamin D receptor activators (VDRA) on Klotho serum levels in CKD 3b–4 stages patients.

Materials and methods. Study included 90 CKD 3b–4 stages patients who had elevated serum levels of parathyroid hormone (PTH). From them, 47 patients (group 1) started to treat with the selective VDRA (zemplar 1 mcg/day), and 43 patients (group 2) started to treat with non-selective VDRA (alfacalcidol 0.25 mcg/day). At baseline and after 12 months we conducted routine examination, serum Klotho measurement, and broad cardiovascular examination.

Results. The patients who managed to maintain a target serum PTH level, had higher Klotho serum level (p=0.037) at the end of the study. Patients who used selective VDRA significantly more often reached the target PTH level (p=0.032), had higher serum Klotho levels (p=0.037), and glomerular filtration rate (eGFR) level (p=0.048) than patients who used non-selective VDRA. In addition, patients treated with alfacalcidol more than 6 months, more often had hypercalcemia (p=0.047) and hyperphosphatemia (p=0.035). Group 2 showed higher: pulse wave velocity (p=0.051), left ventricular myocardial mass index (p=0.033), and more advanced heart valve calcification (p=0.038).

Conclusion. Successful parathyroid hormone level control with vitamin D receptor activators was associated with higher serum Klotho, selective agents having shown greater effect. Long-term treatment with selective vitamin D receptor activators may contribute to cardiovascular calcification prevention by modifying Klotho levels.

Terapevticheskii arkhiv. 2021;93(6):679-684
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Analysis of the course and outcomes of pregnancy in patients with advanced stages chronic kidney disease

Demyanova K.A., Kozlovskaya N.L., Korotchaeva Y.V., Apresyan S.V., Rylceva L.P., Usatenko G.V., Lugovoj A.O., Vorobyeva M.A., Bondarenko T.V., Bespalova A.V., Volkova O.A.


Background. Pregnancy in patients with advanced chronic kidney disease (CKD) is associated with a high risk of adverse outcomes for the mother and the fetus, but data on the characteristics of the course of pregnancy in these women is limited.

Aim. To analyse of the course and outcomes of pregnancy in patients with CKD stages 3a–4.

Materials and methods. Thirty five pregnant women with CKD stages 3–4 were included: 3a – 12 (34.3%) patients, stage 3b – 10 (28.6%), stage 4 – 13 (37.1%).

Results. Proteinuria, serum creatinine, blood pressure in dynamics, the presence of a physiological response were investigated. Pregnancy management included blood pressure correction, antianemic, antiplatelet, anticoagulant therapy, prevention and treatment of urinary infection, correction of metabolic disorders. All pregnant women had proteinuria of varying severity, which increased towards the end of pregnancy. Seventeen (51.5%) patients had hypertension, successfully corrected with antihypertensive drugs. The average delivery term was 34.6 weeks. Preeclampsia developed in 14 (42.4%) cases, an inverse relationship was found between the presence of a physiological response and preeclampsia (p=0.009; rs=-0.463). All children were born alive and viable. After delivery in patients with CKD 3a creatinine values returned to the pre-gestational level, in patients with grade 3b and 4 progression of CKD was noted.

Conclusion. A favorable pregnancy outcome in women with late stages of CKD is possible with constant monitoring by a multidisciplinary team of doctors with mandatory monitoring of renal function, proteinuria, blood pressure, coagulation, markers of preeclampsia and indicators of fetal health. It was proposed to consider the physiological response of the kidneys to pregnancy as a predictor of a favorable outcome.

Terapevticheskii arkhiv. 2021;93(6):685-692
pages 685-692 views

The state of cytokine regulation and endothelial dysfunction in the combined course of vibration disease and arterial hypertension

Babanov S.A., Baraeva R.A., Strizhakov L.A., Moiseev S.V., Fomin V.V.


Background. The article presents data on the state of cytokine regulation, indicators of endothelial damage when exposed to industrial vibration (general, local) and in combination with arterial hypertension.

Aim. To improve the quality of early diagnosis and prevention of vibration disease in an isolated course and its combination with arterial hypertension based on a study of the cytokine profile, biomarkers of endothelial dysfunction in this pathology.

Materials and methods. A comprehensive survey of 84 patients with isolated vibration disease from the effects of local, general, first, second degree and 61 patients with a combined course of vibration disease from the effects of local, general second degree vibration and arterial hypertension, 30 people in the control group without contact with industrial vibration and found healthy by medical examination. The levels of pro-inflammatory (IL-1β, IL-8, TNF-α) and anti-inflammatory cytokines (IL-4), biomarkers of endothelial damage (EDN-1, TGF-β1, VEGF-A, PDGF-BB, fibronectin, Willebrand factor) were determined using the enzyme immunoassay method.

Results. The response of the immune system to the effects of industrial vibration is characterized by a cytokine imbalance – an increase in the level of pro-inflammatory cytokines (IL-1β, IL-8, TNF-α) and a decrease in the level of anti-inflammatory cytokine (IL-4). With a combined course of vibratory disease and arterial hypertension, the cytokine imbalance is characterized by an even more significant increase in serum IL-1β, IL-8, TNF-α and a decrease in serum IL-4 concentration. Endothelial dysfunction with WB from the action of both local and general vibration in combination with hypertension is characterized by a significant increase in serum EDN-1, TGF-β1, VEGF-A, PDGF-BB, fibronectin, Willebrand factor.

Conclusion. The study of the cytokine profile, biomarkers of damage to the vascular endothelium in this pathology will allow for the early diagnosis of vascular disorders and to optimize preventive measures for workers in vibration-hazardous industries.

Terapevticheskii arkhiv. 2021;93(6):693-698
pages 693-698 views

Diagnostic value of urinary biomarkers excretion in estimation of morphological lesions in patients with primary glomerulopathies

Saganova E.S., Zubina I.M., Bogdanova E.O., Galkina O.V., Sipovskii V.G., Smirnov A.V.


Aim. To investigate the diagnostic value of biomarkers in assessing the severity of sclerotic and atrophic lesions in primary glomerulopathies.

Materials and methods. One hundred patients were included in the study, according to the results of kidney biopsy in 9 (9%) cases minimal change disease was diagnosed, in 28 (28%) – focal segmental glomerulosclerosis, in 26 (26%) – membranous nephropathy and in 37 (37%) – IgA nephropathy. The clinical course of nephropathy was evaluated, standard laboratory tests were performed, and urinary excretions of cystatin C, α1-microglobulin, β2-microglobulin and NGAL were measured. The degree of glomerulosclerosis was assessed quantitatively, tubulointerstitial sclerosis and tubular atrophy – semiquantitatively.

Results. According to the results of linear correlations and ROC-analysis, urinary excretion of cystatin C and α1-microglobulin had diagnostic value for early degree of tubulointerstitial sclerosis (cut-off value 319.9 and 10.94 mg/day, respectively). Urinary excretion of β2-microglobulin reflected the initial degree of tubalar atrophy (cut-off value of 0.224 mcg/day), as well as tubulointerstitial sclerosis of various degrees of severity (cut-off value 0.224 and 0.240 mkg/day). NGAL urinary excretion was the only marker of early degree of glomerulosclerosis with its excretion of more than 1445.4 ng/day and tubular atrophy, with a severity of 50% or more (cut-off value 4897.8 ng/day).

Conclusion. A comprehensive assessment of sclerotic and atrophic lesions in the renal parenchyma, can be performed using a panel of traditional (GFR, proteinuria) and specific biomarkers (α1-, β2-microglobulins, cystatin C, NGAL) to implement a comprehensive, personalized approach, as well as to assess the prognosis of nephropathy. In addition, the evaluation of the panel of different biomarkers can be used in those clinical situations where kidney biopsy can not be performed.

Terapevticheskii arkhiv. 2021;93(6):699-705
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A novel approach to rapid induction of remission in primary membranous nephropathy

Dobronravov V.A., Bystrova O.B., Kochoyan Z.S., Fomicheva E.N.


Aim. То evaluate the effectiveness of a novel multi-targeted treatment approach including rituximab (RTX), cyclophosphamide (CPH) and steroids (S) to the induction of remission in patients with primary membranous nephropathy (PMN) compared to standard immunosuppression (IST).

Materials and methods. An open-label prospective comparative study included 56 PMN patients (pts) with nephrotic syndrome (NS) and high serum level of antibodies to the phospholipase A2 receptor – anti-PLA2R (mean age 51±12 years, men – 70%). We recorded demographic and clinical parameters at the time of kidney biopsy, data from light-optical and immunomorphological studies. All pts were on stable doses of the renin-angiotensin systems blockers. We compared the effectiveness of different treatments in the inductions of clinical and immunological remissions in pts who received experimental treatment with RTX, CPH and S (RTX+CPH+S group, n=14) and two control groups: high-dose RTX therapy (group RTX, n=12), cyclosporine and steroids (group CsA+S, n=30).

Results. In the RTX+CPH+S group, remission was achieved in 100% of cases (of which complete remissions – CR in 21.4%). The median time-to-remission (2.5 [1.0; 3.5] months) was significantly lower compared to both control groups: RTX (8.7 [6.6; 14.0] months, p=0.005) and CsA+S (12.4 [6.5; 19.9] months, p<0.001). The cumulative incidence of clinical and immunological remissions was also significantly higher in the RTX+CPH+S group than in the control groups. These results were confirmed in comparative analyzes in the same treatment groups after propensity score matching. The cumulative incidence of clinical and immunological remissions in the RTX+CPH+S group was higher than in the combined group of patients who received other therapies (p<0.001). The incidence of serious adverse events was low and did not differ between groups.

Conclusion. The use of multi-targeted therapy with rituximab, cyclophosphamide, and steroids seems to be an effective approach for the rapid induction of PMN remission and prevention of NS complications.

Terapevticheskii arkhiv. 2021;93(6):706-712
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The dapagliflozin and prevention of adverse outcomes in chronic kidney disease: results of the DAPA-CKD study

Batyushin M.M.


Aim. The article presents the main results of a randomized, double-blind, parallel, placebo – controlled trial of DAPA-CKD.

Materials and methods. The study included patients with chronic kidney disease (CKD) and the possibility of using dapagliflozin at a dose of 10 mg once a day compared with placebo. The study involved 386 centers from 21 countries. A total of 4304 patients were included in the study, the average age was 61.8 years, men predominated, 2906 (67.5%) patients had an initial diagnosis of type 2 diabetes. Patients with diabetic and non-diabetic CKD were included with an estimated glomerular filtration rate (eGFR) of 25 to 75 ml/min/1.73 m2 and a urinary albumin/creatinine ratio of 200 to 5000 mg/g.

Results. The primary composite endpoint (time to eGFR reduction of 50% or more compared to baseline, time to end-stage renal disease defined as eGFR<15 ml/min/1.73 m2, need for chronic dialysis or kidney transplantation, time to renal or cardiovascular death) was shown to occur in 9.2% of patients treated with dapagliflozin and in 14.5% of patients treated with placebo. Also, dapagliflozin therapy was less likely to have a secondary endpoint, such as a combination of a decrease in eGFR by 50% or more, end-stage kidney disease, or renal death. Less frequently, the dapagliflozin group experienced cardiovascular death or hospitalization for heart failure, as well as death from any cause.

Conclusion. Thus, dapagliflozin demonstrated the ability, in comparison with placebo, to reduce the primary composite point and a number of secondary composite points in patients with both diabetic and non-diabetic CKD.

Terapevticheskii arkhiv. 2021;93(6):713-723
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Role of the intestinal MALT in pathogenesis of the IgA-nephropathy

Guliaev S.V., Strizhakov L.A., Chebotareva N.V., Moiseev S.V.


Modern view on pathogenesis of immunoglobulin (Ig)A-nephropathy and possible relation to intestinal MALT-system activity is presented in the article. Aberrant glycosylation of IgA and increased association of IgA-nephropathy with intestinal diseases or abnormal intestinal permeability are discussed in details. Based on supposed entero-renal pathogenesis of the disease future treatment modalities are considered. Relevant world’s literature is cited.

Terapevticheskii arkhiv. 2021;93(6):724-728
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The value of a low-protein diet and ketoanalogues of essential amino acids in the сontrol of protein carbamylation and toxic effects of urea in chronic kidney disease

Mikhailova N.A.


Chronic kidney disease (CKD) is characterized by high mortality from cardiovascular diseases, the development of which is facilitated by traditional risk factors (typical for the general population) and by nontraditional ones (specific to patients with CKD) as well. These factors include also uremic toxins, for which a causal relationship has been established with specific pathological processes in patients with CKD, comprising the development of vascular dysfunction and accelerated progression of atherosclerosis. Urea has long been considered not as a uremic toxin, but as a marker of metabolic imbalance or dialysis efficiency (Kt/V) in CKD patients. In recent years, more and more publications have appeared on the study of the toxic effects of urea with the development of toxic-uremic complications and the phenotype of premature aging, common in CKD. It was found that an increase in urea levels in uremic syndrome causes damage to the intestinal epithelial barrier with translocation of bacterial toxins into the bloodstream and the development of systemic inflammation, provokes apoptosis of vascular smooth muscle cells, as well as endothelial dysfunction, which directly contributes to the development of cardiovascular complications. The indirect effects of increased urea levels are associated with carbamylation reactions, when isocyanic acid (a product of urea catabolism) changes the structure and function of proteins in the body. Carbamylation of proteins in CKD patients is associated with the development of renal fibrosis, atherosclerosis and anemia. Thus, urea is now regarded as an important negative agent in the pathogenesis of complications in CKD. Studies on a low-protein diet with using ketoanalogues of essential amino acids to minimize the accumulation of urea and other uremic toxins demonstrate the clinical benefit of such an intervention in slowing the progression of CKD and the development of cardiovascular complications.

Terapevticheskii arkhiv. 2021;93(6):729-735
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Treatment of thrombotic thrombocytopenic purpura

Galstyan G.M., Maschan A.A., Klebanova E.E., Kalinina I.I.


The review discusses approaches to treatment of acquired thrombotic thrombocytopenic purpuгa (aTTP). In patients with aTTP plasma exchanges, glucocorticosteroids allow to stop an acute attack of TTP, and use of rituximab allows to achieve remission. In recent years, caplacizumab has been used. Treatment options such as cyclosporin A, bortezomib, splenectomy, N-acetylcysteine, recombinant ADAMTS13 are also described. Separately discussed issues of management of patients with TTP during pregnancy, and pediatric patients with TTP.

Terapevticheskii arkhiv. 2021;93(6):736-745
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History of medicine

Scientific activity and the fate of print works of Professor G.A. Zakhar’in

Panferov A.S., Blagova O.V.


The meetings’ syllabuses and main works of the Physical and Medical Society established at the Imperial Moscow University during the period of membership of it prof. G.A. Zakhar’in are analyzed for the first time. A characteristic of Zakhar’in 's scientific activity is given, taking into account the subject of his public performances and publications found in the original sources. The information is given on European and American editions of his works, as well as on publications previously unknown and not mentioned in the literature about Gregory A. Zakhar’in.

Terapevticheskii arkhiv. 2021;93(6):746-749
pages 746-749 views

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