[Clinical significance of the determination of antibodies to thrombospondin type 1 containing domain 7A (THSD7A) in membranous nephropathy].

BACKGROUND: Membranous nephropathy (MN) is an immunocomplex glomerular disease, which is the most common cause of nephrotic syndrome in adults. Numerous studies have established that autoantibodies against the target podocyte autoantigens, including the thrombospondin type 1 domain containing 7A (THSD7A), play a leading role in the development of idiopathic MN. AIM: To evaluate the prevalence of anti-THSD7A autoantibodies (anti-THSD7A AB) in a group of Russian patients with MN. MATERIALS AND METHODS: Serum titers of anti-THSD7A AB were tested in 61 patients with biopsy-proven MN and 12 healthy controls. RESULTS: The prevalence of anti-THSD7A AB was not differing significantly in patients with MN and in the control group (110.9 [71.63; 210.62] and 159.25 [125.64; 231.97] pg/ml, respectively; p=0.111). When comparing subgroups of anti-PLA2R-negative patients and patients who did not receive immunosuppressive therapy with the control group, there were also no statistically significant differences in the Anti-THSD7A AB levels (p>0.05). In the MN group, 1 (1.6%) patient was anti-THSD7A-positive: a 60-year-old man with anti-PLA2R-negative MN and the presence of hormonally inactive adenomas of both adrenal glands and colon polyps (villous adenoma with focal moderate dysplasia, tubulo-villous and tubular adenoma with focal moderate severe dysplasia). CONCLUSION: THSD7-associated MN is a rare variant of MN and is usually detected in PLA2R-negative patients. Screening for malignancies in THSD7A-positive MN patients is proposed.

[Frailty and chronic kidney disease - the real problem of modern nephrology: A review].

The article deals with the syndrome of frailty or senile asthenia in patients with chronic kidney disease. The questions of prevalence, diagnosis, pathogenesis of this syndrome and its clinical consequences in chronic kidney disease are discussed.

[Lupus nephritis in the XXI century].

Lupus nephritis (LN) is the most common organ lesion in systemic lupus erythematosus (SLE), developing in 4050% of patients. Due to immunosuppressive therapy, the survival of patients with SLE has increased significantly over the past 50 years, and the proportion of severe kidney damage in the death structure has decreased. However, LN relapses and complications of immunosuppression, accelerated atherogenesis, concomitant diseases lead to the accumulation of organ damage and an increased risk of death. The article consideres the place of kidney damage in the SLE, the risk factors for LN development, the main renal histopathological changes, it identifies a number of issues that need to be addressed to optimize treatment and improve LN long-term outcomes, including, the revision of pathogenetic therapy regimens with restriction of glucocorticosteroids and prescribing drugs with steroid-sparing activity, the integration of new drugs for LN treatment, wider use of modern nephroprotection capabilities.

[Modern view on the complement system role in membranous nephropathy].

Membranous nephropathy (MN), an immune-mediated glomerular disease, is the most common cause of adult nephrotic syndrome. In MN, proteinuria is developed by podocyte damage due to the complement system activation in response to the subepithelial deposition of immune complexes containing various auto- and exogenous antigens. Membrane-attacking complex (MAC) is the terminal product of any complement pathways activation (classical, lectin or alternative) and plays the leading role in the complement-mediated podocytic damage. Thus far, the main pathway of complement activation leading to the formation of MAC in MN has not been established. The review highlights current evidence of various complement pathways activation in the development of MN, as well as recently established new molecular mechanisms of complement-mediated podocyte damage.

[The Rehberg-Tareev test in assessing the glomerular filtration rate].

The history of glomerular filtration rate assessment is presented, an important step of which was the glomerular filtration rate evaluation by the endogenous creatinine clearance (known as the RehbergTareev test). The article highlights the diagnostic value of the RehbergTareev test and its place among modern methods for assessing glomerular filtration rate.

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

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.

[Modern view on treatment of membranous nephropathy].

Membranous nephropathy (MN) is the most common cause of nephrotic syndrome in adults. Since the moment of animal model creation and the recognition of podocytes damage as a key mechanism of MN development, the identification of antigens, first of all the phospholipase A2 receptor (PLA2R), and the development of methods of PLA2R autoantibodies detection and its monitoring opened a new era in the idiopathic MN (iMN) diagnosis, treatment and prognosis evaluation. MN continues to be actively studied in the new millennium, since a number of aspects of its pathogenesis still need to be clarified, and there is still no clear opinion on the iMN treatment optimal approach. Comprehensive clinical and serological assessment of patients with iMN can be the key to individual choice of treatment protocols. In patients with aPLA2R-positive iMN, the predictor of disease remission is the aPLA2R titer decrease or aPLA2R disappearance in the blood serum, and disease relapse is associated with the aPLA2R appearance ore increase of aPLA2R titer in the circulation. Studies which were conducted by today (GEMRITUX, MENTOR, STARMEN, NICE, etc.) confirmed the acceptable safety profile and effectiveness of iMN therapy by anti-CD20 monoclonal antibodies (rituximab): more than half of of iMN patients had remission of nephrotic syndrome or proteinuria decrease, remissions in anti-CD20 monoclonal antibodies treated patients were longer compared to traditional therapy. The obtained data allows us to consider rituximab and anti-CD20 antibody therapy of a new generation not only as an alternative to the more toxic treatment with cyclophosphane and calcineurin inhibitors, but as an independent promising direction of therapy for patients with IMN, which completely changes the paradigm of treatment of this glomerulopathy.

Risk factors for diastolic left ventricular myocardial dysfunction in patients with chronic kidney disease.

AIM: To examine the frequency and risk factors for the development of diastolic dysfunction (DD) of the left ventricle (LV) of the heart in patients with chronic kidney disease (CKD). MATERIALS AND METHODS: The study included 225 patients with stage I-CKD of non-diabetic etiology (median age 47.0 years, 50.2% of women). Depending on the degree of decrease in the glomerular filtration rate (GFR), all patients were divided into 3 groups. Group 1 (n=70) consisted of patients with GFR 89-45 ml / min / 1.73 m2, group 2 (n=120) - patients with GFR 44-15 ml / min / 1.73 m2, group 3 (n=35) - patients with GFR <15 mL / min / 1.73 m2. The control group includes persons without CKD. All patients underwent general clinical examination and transthoracic echocardiography; in 86 patients the level of cystatin C in the blood serum was determined. RESULTS: Hypertrophy of the left ventricle (LVH) of the heart was detected in 87 (38.7%) of 225 patients with CKD. Hypertrophic type (type I) of myocardial DD is diagnosed in 90 (41.4%) of 225 patients with CKD. The incidence of myocardial left ventricular dysfunction of the 1st type increased with a decrease in GFR, amounting to 30, 40 and 60% in groups 1, 2 and 3, respectively. The systolic function of the left ventricular myocardium was preserved. Patients with DD were older, they had a higher body mass index (BMI), a more pronounced decrease in GFR, a higher level of fibrinogen. They were more likely to have LVH. The level of cystatin C as the kidney function worsened, but when comparing the mean levels of cystatin C in patients with the presence / absence of DD in the groups isolated depending on the stage of CKD, no statistically significant differences were found. According to the multivariate analysis, the independent predictor of DD was the age (odds ratio 1.106, 95% confidence interval 1.051-1.157, p=0.00001). CONCLUSION: DD of the myocardium of the LV is detected on average in 40% of patients with CKD, the frequency of its development increases with the progression of renal dysfunction. The development of DD is influenced by traditional factors of cardiovascular risk (age, BMI), as well as the decline in GFR and closely related structural remodeling of LV myocardium.

Genetic determinants of the development and course of membranous nephropathy.

Membranous nephropathy (MN) is one of the most common causes of nephrotic syndrome in adults and is classified as either primary (idiopatic) or secondary MN according to underlying etiology (the later result from some known disease such as systemic autoimmune diseases, infections, malignancies, drugs, etc). In recent years, phospholipase A2 receptor 1 (PLA2R) and thrombospondin type-1 domain-containing 7A (THSD7A) were identified as two major podocytic antigens involved in the pathogenesis of idiopatic MN (IMN). And the discovery of circulating antibodies specific for these target antigens has transformed the diagnostic workup and significally improved management of IMN. However why do such antibodies develop is not conclusively established. The role of underlying genetic factors is discussed. The review presents the results of recent studies, that have shown significant associations of specific genetic factors (particularly human leucocyte antigen class II and PLA2R1 genes) with IMN.

[MicroRNAs in chronic glomerulonephritis: Promising biomarkers for diagnosis and prognosis estimation]. / MikroRNK pri khronicheskom glomerulonefrite: perspektivnye biomarkery dlia diagnostiki i otsenki prognoza.

The review presents the results of recent experimental and clinical studies of the expression pattern of a number of miRNAs, a recently described new class of noncoding RNAS that are able to regulate the posttranscriptional expression of genes and thus to modulate several physiological and pathological processes in different morphological types of chronic glomerulonephritis. It considers the possibilities of using miRNAs as new biomarkers to diagnose the disease, to predict its course and a response to therapy.

[Role of the mechanisms of replicative cellular senescence in structural and functional changes of the vascular wall in chronic kidney disease]. / Rol' mekhanizmov replikativnogo kletochnogo stareniia v strukturno-funktsional'nykh izmeneniiakh sosudistoi stenki pri khronicheskoi bolezni pochek.

This review considers the mechanisms and risk factors for the development of replicative cellular senescence of the vascular wall in patients with CKD and discusses therapeutic approaches to slowing the accelerated vascular aging.

[Clinical value of TNF, IL-6, and IL-10 gene polymorphic markers in chronic glomerulonephritis].

AIM: To study the association of the polymorphic markers (PMs) G(-238)A of the TNF gene, G(-174)C of the IL-6 gene, and G(-1082)A of the IL-10 gene with the clinical characteristics of chronic glomerulonephritis (CGN) and a response to immunosuppressive therapy (IST). SUBJECTS AND METHODS: Clinical syndromes at the time of diagnosis, the morphological types of nephritis, and a response to IST were analyzed in relation to the carriage of the examined PMs of the TNF, IL-6, and IL-10 genes in 102 patients with CGN. RESULTS: No association was found between the PM G(-238)A of the TNF gene and the clinical features of CGN. The carriers of the C allele of the PM G(-174) C of the IL-6 gene versus the homozygous individuals were observed to have more frequently kidney dysfunction at the time of diagnosis (р=0.014). Hypertension was more common in the carriers of the AA genotype of the PM G(-1082)A of the IL-10 gene (p=0.023); moreover, they tended to have a more frequent concurrence of nephrotic syndrome and hypertension (p=0.082). Analysis of the distribution of the morphological types of CGN disclosed that the proliferative variants were more common in the patients with the GG genotype (the TNF gene) as compared to the A allele carriers (p=0.067); and the nonproliferative forms were in the individuals homozygous for GG (the IL-6 gene) as compared to the C allele carriers (p=0.067). Examination of an IST response showed that a complete response at 12 months of treatment occurred more frequently in the carriers of the C allele of the IL-6 gene (p=0.045) and in those of the GG genotypes of the IL-10 gene (p=0.030). CONCLUSION: There was an association of the PMs G(-174)C of the IL-6 gene and G(-1082)A of the IL-10 gene with the clinical features of CGN and a response to IST.

[Association of gene TP53 polymorphic marker Pro72Arg with clinical characteristics of chronic glomerulonephritis].

AIM: To study association of gene TP53 polymorphic marker Pro72Arg coding synthesis of p53 protein with onset, course and progress of chronic glomerulonephritis (CGN). MATERIAL AND METHODS: We examined 126 patients (63 males and 63 females, mean age 38.8 +/- 13.2 years) with CGN duration 13.0 +/- 9.1 years. When analyzing genetic predisposition to CGN, we compared incidence rate of alleles/genotypes of polymorphic marker Pro72Arg of gene TP53 in CGN patients and 69 controls free of renal disease. CGN clinical features were assessed retrospectively including analysis of nephritis onset, clinical and morphological variants. The course of CGN was analysed by changes in severity of hypertension, persistence of proteinuria > 3 g/day during 6 months and longer, conduction of immunosuppressive therapy and response to it. In analysis of progression rate, doubling of blood creatinine was considered as an end point. We used polymerase chain reaction with analysis of restriction fragment length for identification of alleles of Pro 72Arg polymorphic marker of TP53 gene. RESULTS: Distribution of the genotypes of the above polymorphic marker in CGN patients and in controls did not significantly differ. Depending on Pro allele carriage, CGN patients were divided into two groups: Arg/Arg group (59 carriers of genotype Arg/Arg) and Pro group (63 patients with genotype Arg/Pro and 4 with genotype Pro/Pro). Carriage of Pro allele of gene TP53 was associated with high CGN activity at onset, presence of arteriolosclerosis and IgA deposits in kidney biopsy. Patients with genotype Arg/Arg more frequently developed nephritic syndrome without renal dysfunction syndrome. CONCLUSION: We have discovered association of gene TP53 polymorphic marker Pro72Arg with clinical manifestations of CGN. Carriers of Pro allele more often have signs of active glomerular inflammation and vascular impairment with renal dysfunction while carriers of Arg/Arg genotype more frequently demonstrate isolated nephritic syndrome.

[Polymorphic markers Val762Ala and Leu54Phe of the ADPRT1 gene associated with chronic glomerulonephritis in Russian patients from the city of Moscow].

A comparative analysis of allelic and genotype distribution of polymorphic markers Val762Ala and Leu54Phe of ADPRT1 gene encoding poly(ADP-ribose)polymerase I has been performed in chronic glomerulonephritis patients compared to normal controls. This has shown a significant difference in the ADPRTI gene polymorphic marker Val762Ala allelic and genotype frequency distribution between chronic glomerulonephritis patients and healthy controls (according to Fisher's exact test). At the same time the allelic and genotype frequency for a polymorphic marker Leu54Phe distribution did not show significant difference between these groups. Therefore, we have concluded that the ADPRTI gene polymorphic marker Val762Ala is associated with the development of chronic glomerulonephritis in Russian patients of the Moscow region.

[Association of polymorphic markers D6S2414 and D6S1271 located in the MHC locus (6p21.31) with chronic glomerulonephritis in the Russian population of Moscow].

The distributions of the alleles and genotypes of Polymorphic markers D6S2414 and D6S1271 located among class II MHC genes have been studied in patients with chronic glomerulonephritis (CGN) and healthy donors. Both markers have been found to be associated with the disease. Since these microsatellites are located in the chromosomal region occupied by class II MHC genes, their association with CGN indirectly indicates that class II MHC genes are involved in the development of this pathology.

[The role of polymorphic markers of vasoactive hormones genes in clinical characteristics of chronic glomerulonephritis].

AIM: To examine association of polymorphic markers of I/D gene of angiotensin-converting enzyme (ACE), C(-344)T gene of aldosterone synthetase (CYP11B2) and 4a/4b gene of endothelial synthetase of nitric oxide (NOS3) with clinical picture of chronic glomerulonephritis (CGN). MATERIAL AND METHODS: The trial covered 167 CGN patients. Clinical characteristics of CGN (nephritis, debute, its clinical and morphological variants, analysis of the clinical course as regards arterial hypertension severity, rate of persistence of proteinuria (PU) of the nephrotic level for 6 months and longer, frequency of AH combination with persistent PU was made retrospectively in the groups of patients by genotypes of the genes ACE, CYP11B2 and NOS3. RESULTS: In CGN patients, carriage of the combination of allele D of ACE gene, allele C of CYP11B2 gene, and allele 4a of NOS3 gene was associated with more frequently occurring nephrotic syndrome and AH in the disease onset. A CGN course in patients with genotype DD (ACE gene) often complicates with AH, in patients with genotype CC (gene CYP11B2) and in carriers of allele 4a (gene NOS3)--with severe AH. Carriers of allele D (gene ACE) HA often combines with persistent PU the nephrotic level. A morphological variant of CGN is not associated with carriage of genotypes of polymorphic markers of genes ACE, CYP11B2 and NOS3. CONCLUSION: There is association of polymorphic markers I/D of ACE gene, C(-344)T of gene CYP11B2 and 4a/4b of gene NOS3 with clinical features of CGN. Carriers of alleles associated with high activity of PAAC--allele D of gene ACE, allele C of gene CYP11B2 and allele 4a of gene NOS3--had more severe clinical picture at all stages of the disease.

[Use of angiotensin-converting enzyme inhibitors in chronic kidney insufficiency]. / Primenenie ingibitorov angiotenzinprevrashchaiushchego fermenta pri khronicheskoi pochechnoi nedostatochnosti.

AIM: To study effects of ACE inhibitors in patients with diffuse renal diseases at the stage of chronic renal failure (CRF). MATERIAL AND METHODS: Acute changes in renal filtration and in renal hemodynamics in response to 100-200 mg captopril were studied in 7 patients with CRF and 6 patients with intact renal function. Effects of long-term ACE inhibitors were retrospectively studied in 50 patients with CRF (27 men, 23 women, mean age 46.0 +/- 1.9 years, 7 patients were over 60 years old). Sixteen patients were selected from this group who were followed up for a long time. They were examined for CRF progression rate when given conventional antihypertensive treatment and after treatment with ACE inhibitors. RESULTS: Acute response to ACE inhibitors was the following: SCF fell by 18.4% on the average by the end on therapy week 1; by the end of week 3 renal hemodynamics showed stability, SCF returned to normal, effective renal plasm flow rose by 16.9%, serum potassium rose significantly after 7 days of treatment but did not reach 6 mmol/l. Effects of long-term ACE inhibitor in CRF: the treatment was discontinued after 30-60 days in 12 of 50 patients because of high creatinine (> 20%); in 38 patients ACE inhibitor had a pronounced antihypertensive and antiproteinuric action for 2-3 years, creatinine growth inhibited. Progression of CRF became slow. CONCLUSION: ACE-inhibitors in CRF had a nephroprotective effect but blood creatinine levels should be controlled especially within the first 1-2 months of treatment.

[Kidney damage in primary antiphospholipid syndrome]. / Porazhenie pochek pri pervichnom antifosfolipidnom sindrome.

AIM: To characterize clinical manifestations, course and laboratory signs of nephropathy in primary antiphospholipid syndrome (PAS). MATERIAL AND METHODS: 6 patients with PAS and renal affection were observed for 10 years since 1991. They were examined for anticardiolipin antibodies and/or lupus anticoagulant. Renal tissue was studied morphologically in one patient. RESULTS: In all the patients renal damage manifested with arterial hypertension associated with isolated proteinuria. The majority of the patients had renal dysfunction. All of them had elevated level of antibodies to cardiolipin primarily in combination with lupus anticoagulant. Histological changes of renal tissue presented with thrombotic microangiopathy of glomerular and extraglomerular vessels, intimal proliferation and vascular wall thickening with occlusion of their lumen which combined with morphological indicators of focal segmental glomerulosclerosis. CONCLUSION: The thrombotic process in the intrarenal vessels in PAS dictates the necessity to develop novel approaches to treatment of such patients. In addition to immunodepressants the treatment should include indirect anticoagulants and antiaggregants.

[Polymorphism studies of angiotensin converting enzyme gene in chronic glomerulonephritis]. / Izuchenie polimorfizma gena angiotenzinprevrashchaiushchego fermenta pri khronicheskom glomerulonefrite.

AIM: To investigate the relationship between polymorphism of angiotensin-converting enzyme (ACE) gene and predisposition to chronic glomerulonephritis (CGN) as well as antihypertensive and anti proteinuric response to ACE inhibitors (ACEI) treatment, therapy with angiotensin II receptor antagonists. MATERIALS AND METHODS: Genotype was determined in 57 CGN patients and 113 subjects free of chronic diseases. Effects of ACE gene polymorphism on antihypertensive and antiproteinuric efficiency of ACEI and cozaar were studied in 35 CGN patients on monotherapy. 24-h proteinuria, levels of creatinine, potassium in the serum, arterial pressure, glomerular filtration rate were measured in all the patients. RESULTS: No significant differences were found between incidence of ACE gene genotypes and alleles in patients with CGN and controls. Maximal antihypertensive response to therapy was observed after a month treatment in patients with genotypes II and ID. Lowering of arterial pressure in patients with genotype DD was observed on month 6-12 of continuous therapy. Proteinuria diminished on the treatment month 1-3 in patients with genotypes II and ID, in genotype DD proteinuria rose for the same period of time. Proteinuria dropped similarly in all the groups by month 6-12. CONCLUSION: Relations between ACE gene polymorphism and genetic predisposition to CGN were not found. Patients with genotype II were most sensitive to IACE and cosaar treatment. Lack of an early anti proteinuric response in homozygotes DD does not determine effectiveness of long-term IACE treatment and should not be a reason for the above drug discontinuation.