[Cardiorenal syndromes: historical aspects and current challenges].

The article describes major milestones in acknowledgment of pathophysiological relationship between heart and kidneys since Ancient Egypt till our time and history of term "cardiorenal syndrome" (CRS). First references about kidney and heart functions could be dated to 13 BC when Hippocrates mentioned them. In the XIV century Gentile da Foligno proposed a hypothesis about functional interconnection between heart and kidneys. In the XVIII century Richard Bright described the link between myocardial hypertrophy and kidneys diseases. Frederic Justin Collet was the first one who used the term "cardiorenal" in his article in 1903. In Russia, I.I. Stolnikov conducted his experiments about myocardial hypertrophy and kidneys ischemia in 1880. Famous Russian internist, E.M. Tareev, devoted several paragraphs to cardiorenal interactions in his fundamental manuals "Anemia in Bright's disease" (1929) and "Hypertension" (1948). The research on this topic was continued by Tareev's followers: N.A. Mukhin, V.S. Moiseev, more recent successors - Zh.D. Kobalava, S.V. Moiseev, V.V. Fomin, S.V. Villevalde and others. Their contribution resulted in development of first Russian clinical guidelines on cardio and nephroprotection in CRS in 2014. In 2008 consensus of Acute Disease Quality Initiative summarized current experience on CRS. Today, research on controversial classification questions, biomarkers and other aspects of CRS continues.

[Study of urinary markers of different podocytopathies by proteomic analysis].

BACKGROUND: Focal segmental glomerulosclerosis (FSGS) is a primary podocytopathy characterized by primary podocyte detection and high proteinuria. The search for biomarkers and factors associated with the progression of this disease is an important task nowdays. AIM: To assess the proteomic profile of urine in patients with FSGS and to isolate urinary biomarkers of podocytopathies. MATERIALS AND METHODS: The study included 41 patients diagnosed with chronic glomerulonephritis, 27 men and 14 women. According to the morphological study, 28 patients were diagnosed with FSGS, 9 with steroid-sensitive nephrotic syndrome and 14 with steroid-resistant nephrotic syndrome. The comparison group included 13 patients with membranous nephropathy. The study of the urinary proteome was carried out by targeted liquid chromatography-mass spectrometry using multiple reaction monitoring with synthetic stable isotope labelled peptide standards. RESULTS: The main differences in the protein profile of urine were found in the subgroups of steroid-sensitive (SS) and steroid-resistant (SR) FSGS. In the FSGS SR group, at the onset of the disease, there was a high concentration of proteins reflecting damage to the glomerular filter (apo-lipoprotein A-IV, orosomucoid, cadherin, hemopexin, vitronectin), as well as proteins associated with tubulo-interstitial inflammation and accumulation of extracellular matrix (retinol- and vitamin D-binding proteins, kininogen-1, lumican and neurophilin-2). Compared with the membranous nephropathy group, FSGS patients had significantly higher urinary concentrations of carnosinase, orosomucoid, cadherin-13, tenascin X, osteopontin, and zinc-alpha-2-glycoprotein. CONCLUSION: Thus, in patients with SR FSGS, the proteomic profile of urine includes more proteins at elevated concentrations, which reflects severe damage to various parts of the nephron compared with patients with SS FSGS and membranous nephropathy.

Proactive anti-inflammatory therapy in the advanced stages of a new coronavirus infection. Main results of the inpatient phase of the COLORIT study (Colchicin vs. Ruxolitinib and secukinumab in an open, prospective, randomized trial in patients with novel coronavirus infection COVID-19).

Aim      To evaluate clinical efficacy of the proactive anti-inflammatory therapy in patients hospitalized for COVID-19 with pneumonia and a risk of "cytokine storm".Material and methods  The COLORIT study was a comparative study with randomization into 4 groups: colchicine (n=21) 1 mg for the first 3 days followed by 0.5 mg/day through day 12 or discharge from the hospital; secukinumab 300 mg/day, s.c., as a single dose (n=20); ruxolitinib 5 mg, twice a day (n=10); and a control group with no anti-inflammatory therapy (n=22). The effect was evaluated after 12±2 days of inpatient treatment or upon discharge, what comes first. For ethical reasons, completely randomized recruitment to the control group was not possible. Thus, for data analysis, 17 patients who did not receive any anti-inflammatory therapy for various reasons not related with inclusion into the study were added to the control group of 5 randomized patients. Inclusion criteria: presence of coronavirus pneumonia (positive PCR test for SARS-CoV-2 RNA or specific clinical presentation of pneumonia; IDC-10 codes U07.1 and U07.2); C-reactive protein (CRP) concentration >60 mg/l or its threefold increase from baseline; at least 2 of 4 symptoms (fever >37.5 °C, persistent cough, shortness of breath with inspiratory rate >20 per min or blood saturation with oxygen <94 % by the 7th-9th day of disease. The study primary endpoint was changes in COVID Clinical Condition Scale (CCS-COVID) score. The secondary endpoints were the dynamics of CRP and changes in the area of lung lesion according to data of computed tomography (CT) of the lungs from the date of randomization to 12±2 days.Results All three drugs significantly reduced inflammation, improved the clinical course of the disease, and decreased the disease severity as evaluated by the CCS score: in the ruxolitinib group, by 5.5 (p=0.004); in the secukinumab group, by 4 (p=0.096); in the colchicine group, by 4 (p=0.017), and in the control group, by 2 (р=0.329). In all three groups, the CCS-COVID score was 2-3 by the end of observation period, which corresponded to a mild process, while in the control group, the score was 7 (р=0.005). Time-related changes in CRP were significant in all three anti-inflammatory treatment groups with no statistical difference between the groups. By the end of the study, changes in CT of the lungs were nonsignificant.Conclusion      In severe СOVID-19 with a risk of "cytokine storm", the proactive therapy with ruxolitinib, colchicine, and secukinumab significantly reduces the inflammation severity, prevents the disease progression, and results in clinical improvement.

[Urinary biomarkers of kidney injury in patients treated with anti-VEGF drugs].

BACKGROUND: Antiangiogenic drugs are widely used in oncological practice and are aimed at inhibiting angiogenesis. Despite the high antitumor efficacy, their use may be limited by nephrotoxicity, and therefore the search for early biomarkers of kidney damage remains relevant, which will preserve a favorable safety profile of therapy. AIM: To determine urinary biomarkers of tubular and podocyte damage in patients receiving treatment with antiangiogenic drugs. MATERIALS AND METHODS: The study included patients (n=50) who received intravenous anti-VEGF drugs (aflibercept, bevacizumab, ramucirumab) in various chemotherapy regimens. Concentrations of tubular damage markers KIM-1 (Kidney Injury Molecule-1) and NGAL (Neutrophil Gelatinase-Associated Lipocalin), hypoxia marker HIF-1 (Hypoxia-Inducible Factor 1-alpha) in urine samples were determined by enzyme-linked immunosorbent assay (ELISA) before treatment, and during 8 weeks of treatment. To assess the risk factors for kidney damage, a logistic regression analysis was performed with the inclusion of the main clinical and laboratory parameters. RESULTS: A decrease in the calculated GFR of CKD-EPI (Chronic Kidney Disease Epidemiology Collaboration Formula) of less than 60 ml/min per 1.73 m2 at week 8 of treatment was noted in 42% of patients. An increase in NGAL, KIM-1, HIF-1 and nephrin in urine during the first two weeks of therapy predicted the development of renal damage by the 8th week of follow-up. When constructing ROC-curves, the high sensitivity and specificity of these urinary indicators as prognostic markers were established. Among the clinical and laboratory indicators, independent unfavorable prognostic factors of nephrotoxicity were an initial decrease in eGFR, a history of hypertension, an increase in the concentration of KIM-1 and HIF-1 in urine during the first two weeks of therapy. CONCLUSION: The predictors of renal damage in the treatment with antiangiogenic drugs were previously an increase in NGAL, KIM-1 and HIF-1 in urine during the first two weeks after the start of therapy.

Proactive anti-inflammatory therapy with colchicine in the treatment of advanced stages of new coronavirus infection. The first results of the COLORIT study.

Actuality The course of the novel coronavirus disease (COVID-19) is unpredictable. It manifests in some cases as increasing inflammation to even the onset of a cytokine storm and irreversible progression of acute respiratory syndrome, which is associated with the risk of death in patients. Thus, proactive anti-inflammatory therapy remains an open serious question in patients with COVID-19 and pneumonia, who still have signs of inflammation on days 7-9 of the disease: elevated C-reactive protein (CRP)>60 mg/dL and at least two of the four clinical signs: fever >37.5°C; persistent cough; dyspnea (RR >20 brpm) and/or reduced oxygen blood saturation <94% when breathing atmospheric air. We designed the randomized trial: COLchicine versus Ruxolitinib and Secukinumab in Open-label Prospective Randomized Trial in Patients with COVID-19 (COLORIT). We present here data comparing patients who received colchicine with those who did not receive specific anti-inflammatory therapy. Results of the comparison of colchicine, ruxolitinib, and secukinumab will be presented later.Objective Compare efficacy and safety of colchicine compared to the management of patients with COVID-19 without specific anti-inflammatory therapy.Material and Methods Initially, 20 people were expected to be randomized in the control group. However, enrollment to the control group was discontinued subsequently after the inclusion of 5 patients due to the risk of severe deterioration in the absence of anti-inflammatory treatment. Therefore, 17 patients, who had not received anti-inflammatory therapy when treated in the MSU Medical Research and Educational Center before the study, were also included in the control group. The effects were assessed on day 12 after the inclusion or at discharge if it occurred earlier than on day 12. The primary endpoint was the changes in the SHOCS-COVID score, which includes the assessment of the patient's clinical condition, CT score of the lung tissue damage, the severity of systemic inflammation (CRP changes), and the risk of thrombotic complications (D-dimer) [1].Results The median SHOCS score decreased from 8 to 2 (p = 0.017), i.e., from moderate to mild degree, in the colchicine group. The change in the SHOCS-COVID score was minimal and statistically insignificant in the control group. In patients with COVID-19 treated with colchicine, the CRP levels decreased rapidly and normalized (from 99.4 to 4.2 mg/dL, p<0.001). In the control group, the CRP levels decreased moderately and statistically insignificantly and achieved 22.8 mg/dL by the end of the follow-up period, which was still more than four times higher than normal. The most informative criterion for inflammation lymphocyte-to-C-reactive protein ratio (LCR) increased in the colchicine group by 393 versus 54 in the control group (p = 0.003). After treatment, it was 60.8 in the control group, which was less than 100 considered safe in terms of systemic inflammation progression. The difference from 427 in the colchicine group was highly significant (p = 0.003).The marked and rapid decrease in the inflammation factors was accompanied in the colchicine group by the reduced need for oxygen support from 14 (66.7%) to 2 (9.5%). In the control group, the number of patients without anti-inflammatory therapy requiring oxygen support remained unchanged at 50%. There was a trend to shorter hospital stays in the group of specific anti-inflammatory therapy up to 13 days compared to 17.5 days in the control group (p = 0.079). Moreover, two patients died in the control group, and there were no fatal cases in the colchicine group. In the colchicine group, one patient had deep vein thrombosis with D-dimer elevated to 5.99 µg/mL, which resolved before discharge.Conclusions Colchicine 1 mg for 1-3 days followed by 0.5 mg/day for 14 days is effective as a proactive anti-inflammatory therapy in hospitalized patients with COVID-19 and viral pneumonia. The management of such patients without proactive anti-inflammatory therapy is likely to be unreasonable and may worsen the course of COVID-19. However, the findings should be treated with caution, given the small size of the trial.

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

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 [3457] 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.

[Steroid pulse -therapy in patients With coronAvirus Pneumonia (COVID-19), sYstemic inFlammation And Risk of vEnous thRombosis and thromboembolism (WAYFARER Study)].

Introduction Coronavirus pneumonia not only severely affects the lung tissue but is also associated with systemic autoimmune inflammation, rapid overactivation of cytokines and chemokines known as "cytokine storm", and a high risk of thrombosis and thromboembolism. Since there is no specific therapy for this new coronavirus infection (COVID-19), searching for an effective and safe anti-inflammatory therapy is critical.Materials and methods This study evaluated efficacy and safety of pulse therapy with high doses of glucocorticosteroids (GCS), methylprednisolone 1,000 mg for 3 days plus dexamethasone 8 mg for another 3-5 days, in 17 patients with severe coronavirus pneumonia as a part of retrospective comparative analysis (17 patients in control group). The study primary endpoint was the aggregate dynamics of patients' condition as evaluated by an original CCS-COVID scale, which included, in addition to the clinical status, assessments of changes in the inflammation marker, C-reactive protein (CRP); the thrombus formation marker, D-dimer; and the extent of lung injury evaluated by computed tomography (CT). Patients had signs of lung injury (53.2 % and 25.6 %), increases in CRP 27 and 19 times, and a more than doubled level of D-dimer (to 1.41 µg/ml and 1.15 µg/ml) in the active therapy and the control groups, respectively. The GCS treatment group had a more severe condition at baseline.Results The GCS pulse therapy proved effective and significantly decreased the CCS-COVID scores. Median score difference was 5.00 compared to the control group (р=0.011). Shortness of breath considerably decreased; oxygen saturation increased, and the NEWS-2 clinical status scale scores decreased. In the GCS group, concentration of CRP significantly decreased from 134 mg/dl to 41.8 mg/dl (р=0.009) but at the same time, D-dimer level significantly increased from 1.41 µg/ml to 1.98 µg/ml (р=0.044). In the control group, the changes were nonsignificant. The dynamics of lung injury by CT was better in the treatment group but the difference did not reach a statistical significance (р=0.062). Following the GCS treatment, neutrophilia increased (р=0.0001) with persisting lymphopenia, and the neutrophil/lymphocyte (N/L) ratio, a marker of chronic inflammation, increased 2.5 times (р=0.006). The changes in the N/L ratio and D-dimer were found to correlate in the GCS pulse therapy group (r =0.49, p=0.04), which underlined the relationship of chronic autoimmune inflammation with thrombus formation in COVID-19. No significant changes were observed in the control group. In result, four patients developed venous thromboembolic complications (two of them had pulmonary artery thromboembolism) after the GCS pulse therapy despite the concomitant antiplatelet treatment at therapeutic doses. Recovery was slower in the hormone treatment group (median stay in the hospital was 26 days vs 18 days in the control group, р=0.001).Conclusion Pulse therapy with high doses of GCS exerted a rapid anti-inflammatory effect but at the same time, increased the N/L ratio and the D-dimer level, which increased the risk of thromboembolism.

[Nephrotoxicity of anti-angiogenesis drugs].

Neoangiogenesis is a basic factor for most physiological as well as pathological processes i.e. tumor metastases. The most important is vascular endothelium growth factor (VEGF) and its receptors (VEGFR1/2) in angiogenesis processes. Nowadays antiangiogenic agents (which inhibit VEGF like bevacizumab neither VEGFR2 like ramucirumab) are widely used in very different chemotherapeutic regimens in clinical oncology. The signalling pathway VEGF-VEGFR plays a crucial role in supporting of adequate kidney function. Appearance of antiangiogenic drugs led to adverse nephrotoxic effects: arterial hypertension, proteinuria, rarely nephrotic syndrome, and kidney dysfunction. Various hystological variants of nephropathy are described, however, in most cases, signs of thrombotic microangiopathy of the renal vessels are noted. This literature review discusses mechanisms, clinical and morphological aspects of nephropathy associated with antiangiogenic drugs.

The first experience of non-interferon therapy of HCV infection in patients with Wilson-Konovalov's disease.

In the article we present three clinical observations demonstrating that HCV infection in patients with remission of Wilson disease causes an recrudescence of the disease, in one of the observations - decompensation of liver cirrhosis. In this study we first describe on the successful treatment of HCV infection with direct antiviral drugs in patients with Wilson disease. Establishment of all factors of liver damage and successful treatment (elimination of the virus, adequate lifelong medical treatment) allow to expect a favorable prognosis in patients with a combination of Wilson disease and HCV infection.

[Role of neutrophil dysfunction in the pathogenesis of systemic lupus erythematosus]. / Rol' disfunktsii neitrofilov v patogeneze sistemnoi krasnoi volchanki.

Neutrophil dysfunction plays a considerable role.in systemic lupus erythematosus (SLE) The protective function of neutrophils is carried out through various mechanisms: isolation of granular antimicrobial peptides (gAMP), microbial phagocytosis with subsequent degradation via reactive oxygen species inside the phagolysosomes; as well as bactericidal action due to the release of networks from chromatin and gAMP, also called neutrophil extracellular traps (NECTs). The development of neutropenia in SLE has multiple causes, including the formation of antibodies directly to leukocytes; that of neutralizing autoantibodies to the growth factors of neutrophils and cells - myeloid precursors; bone marrow suppression; involvement of neutrophils in the processes of apoptosis and NETosis. Neutrophils in SLE are characterized by reduced phagocytic ability and pathological oxidative activity. In SLE, there is a decrease in the ability to remove the products of neutrophil apoptosis, which is correlated with disease activity. SLE patients are noted to have a higher expression level of the genes specific for low-density granulocytes, an abnormal immature neutrophil population. The impaired processes of formation of NECTs and removal NETosis products play a substantial role in the pathogenesis of SLE. It is shown that the abnormal formation of NECTs also causes endothelial injury and increases the risk of thromboses. The design of novel drugs that act on the specific parts of the formation of NECTs or contribute to their removal from the extracellular environment can propel therapy for SLE and other autoimmune diseases to new heights. There is evidence for further investigations of neutrophil-mediated pathogenetic processes in SLE in order to identify potential therapeutic targets and to understand the mechanisms of action of drugs used in clinical practice.

[Role of polymorphic markers for the genes of hemostasis and platelet receptors in liver fibrosis progression in patients with chronic hepatitis C]. / Rol' polimorfnykh markerov genov gemostaza i trombotsitarnykh retseptorov v progressirovanii fibroza pecheni u bol'nykh khronicheskim gepatitom S.

AIM: to estimate the clinical and prognostic value of the carriage of different allele variants of the gene polymorphisms of the coagulation system and platelet receptors in the progression of liver fibrosis (LF) in patient with chronic hepatitis C (CHC). SUBJECTS AND METHODS: The investigation enrolled 177 patients with CHC and liver cirrhosis at its outcome who were divided into 2 groups according to the rate of LF progression: 1) 89 patients with rapid (rapid fibrosis) and 2) 88 patients with slow (slow fibrosis) progression. The polymorphism of the study genes was studied using a real-time polymerase chain reaction and a melting curve analysis. RESULTS: In CHC patients, the FV 1691G/A genotype was more often in the rapid progressors than that in the slow progressors (10.11% vs 1.14%; p=0.011). The A allele of the 1691 G/A FV gene was more common in the rapid fibrosis group than that in the slow fibrosis group (1.7% vs 5.56%, odd ratio 9.787; p=0.139). In our investigation, the polymorphic marker GA in the FII 20210 G/A gene, as well as the 4G allele (5G4G + 4G4G genotypes) and the 4G allele of PAI-I -675 5G/4G were more often seen in the rapid fibrosis group than that in the slow fibrosis group; the detection rate was only at the trend level (p=0.118, p=0.112, and p=0.117 respectively). There were no significant differences between the groups in the spread of variant genotypes and alleles of other study genes. Integral model construction by coding «profibrogenic¼ genotypes (FV 1691 G/A, FII 20210 G/A, PAI-I -675 5G/4G) showed that the fibrosis progression rate expressed as fibrosis units annually also increased with higher total scores (p=0.039), indicating the combined effect of these genes. CONCLUSION: The carriage of mutant genotypes of FV 1691 G/A, FII 20210 G/A, and PAI-I -675 5G/4G genes is a prognostic factor for rapid CHC progression.

[Mathematic Model for Prediction of Liver Fibrosis Progression Rate in Patients with Chronic Hepatitis C Based on Combination of Genomic Markers].

AIM OF STUDY: To evaluate clinical significance of different combinations of gene polymorphisms IL-1b, IL-6, IL-10, TNF, HFE, TGF-b, ATR1, N0S3894, CYBA, AGT, MTHFR, FII, FV, FVII, FXIII, ITGA2, ITGB3, FBG, PAI and their prognostic value for prediction of liver fibrosis progression rate in patients with chronic hepatitis C (CHC). SUBJECTS AND METHODS: 118 patients with CHC were divided into "fast" and "slow" (fibrosis rate progression ≥ 0.13 and < 0.13 fibrosis units/yr; n = 64 and n = 54) fibrosis groups. Gene polymorphisms were determined. Statistical analysis was performed using Statistica 10. RESULTS: A allele (p = 0.012) and genotype AA (p = 0.024) of AGT G-6T gene, as well as T allele (p = 0.013) and MT+TT genotypes (p = 0.005) of AGT 235 M/T gene were significantly more common in "fast fibrosers" than in "slow fibrosers". Patients with genotype TT of CYBA 242 C/T had a higher fibrosis progression rate than patients with CC+CT genotype (p = 0.02). Our analysis showed a protective effect of TTgenotype of ITGA2 807 C/T on fibrosis progression rate (p = 0.03). There was a trend (p < 0.15) to higher fibrosis progression rate in patients with mutant alleles and genotypes of TGFb +915 G/C, FXIII 103 G/T, PAI-675 5G/4G genes. Other gene polymorphisms were not associated with enhanced liver fibrosis. To build a mathematical modelfor prediction of liverfibrosis progression rate we performed coding with scores for genotypes and virus genotype. Total score correlated with the fibrosis progression rate (R = 0.39, p = 0.000). CONCLUSION: Determination of genetic profile of the patient and virus genotype allows to predict the course of CHC.

[Prognostic value of renal resistance index in estimating the progression of chronic kidney disease].

AIM: To study a relationship between main renal and intraparenchymal renal arterial resistance indices (RIs) measured by Doppler ultrasonography and clinical and laboratory parameters and to determine their prognostic value in estimating the progression of chronic kidney disease (CKD). SUBJECTS AND METHODS: The investigation enrolled 53 CKD patients divided into groups: glomerular and interstitial diseases. Glomerular filtration rate (GFR) calculated using the CKD-EPI formula, proteinuria (PU) severity, kidney sizes, renal parenchyma thickness, parenchyma/collecting index, and main and intrarenal vessel RIs were determined at the first hospitalization. The mean follow-up was 14 ± 2.64 months. The rate of GFR decline was estimated at the rehospitalization. RESULTS: Main renal and intrarenal vessel RIs depend on patient age and pulse pressure. The RIs are associated with GFR and PU in the group of glomerular diseases and with kidney sizes and structure in that of interstitial diseases. The interlobar arterial RI is the most sensitive predictor for worsening renal function with a threshold of 0.65, which is comparable to the prognostic value of PU. CONCLUSION: The main renal and intrarenal vessel RIs may be considered as a predictor for worsening renal function.

[Impact of interleukin-10 and interleukin-28 gene polymorphisms on the development and course of lupus nephritis].

AIM: To assess the relationship of the carriage of IL-10-1080 G/A and IL-28 rs8099917 C/T polymorphisms to the course of lupus nephritis (LN). SUBJECTS AND METHODS: Ninety-nine patients with systemic lupus erythematosus (SLE), including 68 with LN, were examined. Gene polymorphisms were analyzed using standard molecular genetic techniques. The frequency of the clinical manifestations of LN was analyzed; renal survival (RS) was estimated by the Kaplan-Meier method. RESULTS: Ten-year RS rates were 80 and 86% of the patients with and without the mutant IL-10 allele, respectively (p = 0.78). The 10-year RS was lower (75%) in carriers of the mutant IL-28 rsl2979860 allele than in patients without this mutant allele (83%; p = 0.049) and in those of the mutant IL28 rs8099917 allele than in patients without the above mutant allele (67 and 88%, respectively; p = 0.047). LN patients, carriers of the mutant IL-10-1028 G/A allele, were observed to have higher-grade proteinuria in the presence of nephritic syndrome (mean 6.1 g/l) than those without the mutant allele of this gene (mean 2.9 g/l; p = 0.034). However, the mutant allele carriers responded to treatment better (p = 0.050). The mutant IL-10 and IL-28 alleles were unassociated with the development of rapidly progressive nephritis, the activity of a renal lupus process, and the rate of onset of SLE and LN. CONCLUSION: In the LN patients, the carriage of the mutant IL-10 allele A is associated with a better response to treatment and that of the mutant IL-28 allele is linked to the severe course of the disease.

[Endothelial dysfunction gene polymorphisms and the rate of liver fibrosis in chronic hepatitis C].

AIM: To assess the association of the CYBA, NOS3, and MTHFR gene polymorphisms and a rate of fibrosis progression in chronic hepatitis C (CHC). SUBJECTS AND METHODS: One hundred and nine CHC patients with the verified stage of liver fibrosis and cirrhosis at its onset were examined. The disease duration was determined in all the patients and additional risk factors of liver lesion were absent. A group of rapidly progressive fibrosis comprised 55 patients with a calculated fibrosis progression rate of 0.130 fibrosis units/year or higher and 54 patients with a progression rate of less than 0.130 fibrosis units/year were assigned to a slow fibrosis group. A compression group consisted of 299 healthy blood donors. The polymorphism of the genes under study was determined by polymerase chain reaction-restriction fragment length polymorphism analysis. RESULTS: The mutant TT genotype of the CYBA gene was significantly more common in the CHC patients with rapidly progressive fibrosis than in those with slowly progressive fibrosis (odds ratio for TT 9.09 at 95% confidence interval, 1.09 to 74.83; p = 0.0161). No significant differences were found in the distribution of the alleles and genotypes of the NOS3 and MTHFR genes between the groups of patients with slowly and rapidly progressive fibrosis. CONCLUSION: The findings make it possible to regard the TT genotype of the CYBA gene from the C242T locus as profibrogenic and as one of the markers of the poor course of CHC.

[Prognostic value of allelic variants affecting the hemostatic system in the development of antiphospholipid syndrome and kidney lesion in patients with systemic lupus erythematosus].

AIM: To analyze the prognostic value of the polymorphisms of the thrombophilic genes: plasminogen activator inhibitor type 1 (PAI-1) (-675 4G/5G), factor XIII (FXIII) (G485T), fibrinogen (FBG) (G(-455)A), glycoprotein Ia (GPIa) (C807T), glycoprotein IIIa (GPIIIa) (T106C), and p22phox (C242T), as well as protein genes involved in the pathogenesis of endothelial dysfunction: subunits of p22phox NADH-oxidase (p22phox) (C242T), endothelial NO-synthase (eNOS) (G894T), and methylenetetrahydrofolate reductase (MTHFR) (C677T) for the development of antiphospholipid syndrome (APS) and a type of progressive lupous nephritis (LN) in patients with systemic lupus erythematosus (SLE). SUBJECTS AND METHODS: One hundred patients with SLE were examined and, according to the presence of clinical and laboratory signs of APS were divided into 2 groups: 1) 50 SLE patients with APS; 2) 50 SLE patients without APS who were matched for gender and age with Group 1 patients. The gene polymorphisms were analyzed using standard molecular genetic techniques. The frequency of clinical manifestations of APS and the type of progressive nephritis were analyzed in view of the genotypes of the patients. RESULTS: Comparison of SLE patients with and without SLE revealed no statistically significant differences in the rates of alleles and genotypes. The patients with arterial and/or venous thrombosis in the presence of APS more frequently displayed a minor allele (T) and genotype (TT) of the p22phox gene than those with APS without thrombosis: T, 64.5 and 34%, respectively (p = 0.033); TT, 36 and 7% (p = 0.021); odds ratio (OR), 2.1 at 95% confidence interval (CI), 1.5 to 22.7). In the APS patients with livedo reticularis, the minor allele (T) and genotype (TT) of the eNOS gene were more common than in those without livedo: T, 33 and 10%, respectively (p = 0.019); TT, 15 and 0% (p = 0.031); OR, 2.49 at 95% CI, 1.2 to 28.9). In the patients with AFS and rapidly progressive LN (RPLN), the minor allele (T) and genotype (TT) of the MTHFR gene were much more frequently encountered: T, 46 and 27%, respectively (p = 0.038); TT, 30 and 0% (p = 0.033); OR, 3.1 at 95% CI, 1.4 to 32.7). The group of patients without APS exhibited no relationship between the examined polymorphisms and kidney lesion. CONCLUSION: The mutant allele of the p22phox gene increases the risk of arterial and venous thrombosis; the polymorphism of the eNOS gene may be related to the higher incidence of impaired blood microcirculation in SLE concurrent with APS. The risk of RPLN in SLE patients with APS is probably associated with MTHFR gene mutation.

[Significance of allelic variants of interleukin-28B gene in chronic hepatitis C].

Chronic hepatitis C remains one of the most urgent problems of today's medicine. The review unravels the current view of the role of a single nucleotide polymorphism of the interleukin-28B (IL-28B) gene in different aspects of hepatitis C virus infection. Major attention is paid to the discussion of the value of the allelic variants of IL-28B during standard double and current triple antiviral therapy for chronic hepatitis C. Furthermore, the paper covers the biological role of interferon-lambda, a product of IL-28A, B, and IL-29 gene expression, other associations of the allelic variants of the IL-28B gene with different clinical signs, as well as the possibilities of practical use of this genetic marker in chronic hepatitis C today and futures prospects.

[Significance of the factors of hypoxia and endothelial dysfunction in kidney injury in the presence of obesity].

AIM: To define the clinical significance of asymmetric dimethylarginine (ADMA) and that of methylenetetrahydrofolate reductase (MTHFR) gene polymorphism as factors of endothelial dysfunction (ED) in the development of early kidney injury in obese patients. SUBJECTS AND METHODS: The investigation included 86 patients (64 men and 22 women aged 44 +/- 11 years) with abdominal obesity. Along with physical examination, the authors determined albuminuria, calculated glomerular filtration rate (GFR) using the Modification of Diet in Renal Disease (MDRD) formula, estimated insulin resistance markers (fasting plasma insulin and C-peptide concentrations and homeostatic model assessment (HOMA) index), as well as serum ADMA levels by enzyme immunoassay in all the patients. C677T polymorphism in the MTHFR gene was studied by allele-specific polymerase chain reaction and restriction fragment length polymorphism analysis. Kidney injury (chronic kidney disease (CKD)) was diagnosed using the Kidney Disease Outcomes Quality Initiative (KDOQI) criteria. Early vascular remodeling was determined from the increased intima-media thickness (IMT) of the common carotid artery (CCA). RESULTS: CKD was diagnosed in 27(31%) patients. The latter, unlike the patients with CKD, were observed to have more pronounced obesity (body mass index (BMI) 36.8 +/- 8.0 and 32.0 +/- 4.7 kg/m2, respectively (p < 0.001)), waist circumference (119 +/- 18 and 109 +/- 11 cm (p = 0.002)), higher levels of C-peptide (1348 +/- 363 and 1028 +/- 363 pmol/I; p < 0.001), insulin (16.9 +/- 7.3 and 11.7 +/- 5.5 microU/ ml; p < 0.001), and HOMA index (4.3 +/- 1.7 and 2.9 +/- 1.5; p < 0.001). In the patients with Stage IIIa CKD, ADMA concentrations (0.77 +/- 0.19 micromol/l) was higher than in those with Stages I (0.58 +/- 0.11 micromol/l; p = 0.048) and II (0.61 +/- 0.13 micromol/l; p = 0.071). An association between ADMA concentrations, CCA IMT, and estimated GFR was revealed in the patients with CKD. The predictors of an estimated GFR reduction in obesity were elevated serum concentrations of ADMA, uric acid, insulin, and HOMA index. The combination of obstructive sleep apnea syndrome and metabolic syndrome increased the risk of CKD by 2.1-fold (95% confidence interval, 1.06-3.14). Evaluation of the impact of MTHFR gene polymorphism on kidney injury in obesity disclosed that the patients with homozygous carriage of the abnormal T allele of the MTHFR gene had a higher risk for Stages I-IIIa CKD (2.60 with 95% confidence interval, 1.32-3.88), more marked obesity and hyperinsulinemia, and increased serum ADMA concentrations. CONCLUSION: Insulin resistance and ED hold a central position in the pathogenesis of CKD in obese patients. The mechanisms of the atherosclerotic vascular remodeling associated with elevated serum ADMA concentrations are of paramount importance in the progression of early-stage CKD. The homozygous carriage of the abnormal T allele of the MTHFR gene increases the risk of Stages I-IIIa by more than twice.

[Changes in rheological blood properties in patients with lupus nephritis and IgA-nephropathy].

AIM: To compare changes of hemorheological parameters in patients with lupus nephritis (LN) and IgA-nephropathy (IgA-N). MATERIAL AND METHODS: Kinetics of spontaneous aggregation, disaggregation of red cells in shearing flow, red cell deformability were studied in 73 patients with LN including 6 patients with active LN with nephrotic syndrome, 38 patients with active LN with urinary syndrome, 29 with inactive LN; in 24 patients with a hematuric form of IgA-nephritis (IgA-N); in 24 healthy volunteers (controls). RESULTS: Patients with LN and a hematuric form of IgA-H were found to have disorders of microrheological blood characteristics (accelerated formation of erythrocytic aggregates -EA of high density) depending on the form and activity of the disease. All LN and IgA-N patients exhibited increased time of "coin columbs" formation and accelerated aggregation. The largest EA were detected in IgA-H patients. Flow deformation ability of the red cells was poor in all the examinees. LN patients showed a positive correlation between maximal EA size and hematuria severity even in cases of trace proteinuria. A correlation was demonstrated in IgA-N patients between IgA level and EA density, between inhibition of GFR and erythrocytic deformability index. CONCLUSION: The above findings show deteriorated process of aggregation-disaggregation resultant from deterioration of red cell physical properties. Severity of hemorheological disorders depends on LN activity. Hematuria associated with increased size of EA is an important marker of the disease activity Hemorheological disorders in patients with active LN and IgA-N are an additional pathogenetic component of hematuria.

[Remodeling of the cardiovascular system and development of chronic kidney disease in patients with metabolic syndrome and obesity: role of eNOS, subunit p22-phox of NADPH-oxidase and MTHFR genes].

AIM: To examine contribution of polymorphisms of genes of endothelial NO-synthase (eNOS), NADPH-oxidase and methylenetetrahydrofolate reductase (mTHFR) to development of remodeling of cardiovascular system and chronic disease of the kidneys (CDK) in patients with metabolic syndrome (mS) and obesity. MATERIAL AND METHODS. Standard clinical and device examinations were made and polymorphisms C242T of gene of subunit p22-phox of NADPH-oxidase, G894T of gene of eNOS and C677T of gene of MTHFR were studied in 66 MS patients (49 males and 17 females, age 19-62 years. RESULTS: The presence of even one prognostically poor allele variants of the genes studied was registered in 83 examinees. The genotype 242TTp22-phox of NADPH-oxidase subunit was associated with the highest insulin resistance, allele 894T of gene eNOS- with reduced glomerular filtration rate and progression of left ventricular hypertrophy. CONCLUSION: Polymorphism of the genes the products of which modulate endothelial function can be considered as potential predictors of severity of MS target organs impairment.