Fibroblast growth factor-23 (FGF-23) / soluble Klotho protein (sKlotho) / sclerostin glycoprotein ratio disturbance is a novel risk factor for cardiovascular complications in ESRD patients receiving treatment with regular hemodialysis or hemodiafiltration.

AIM: Aim of the study was to explore the role of the FGF-23/sKlotho/sclerostin ratio disturbance in the determining of cardiovascular risk in end stage renal disease (ESRD) patients, receiving treatment with regular hemodialysis (НD) or hemodiafiltration (НDF) online in Russia. MATERIALS AND METHODS: 42 patients with ESRD, at the age of 18-55 years, treated with HD or HDF on line for at least 6 months, were examined. 22 (52.3%) patients received traditional HD, the remaining 20 (47.7%) - HDF online. In all the patients, in addition to a general examination, the serum levels of FGF-23, sKlotho, sclerostine (by ELISA), their associations with cardiovascular risk factors (left ventricular hypertrophy (LVH), acute coronary syndrome (ACS), serum troponin I levels) with the numbers of techniques (ECG; Eho-CGF (with calculation of left ventricular myocardium mass index (LVMMI), as well as the relative thickness of the walls of the left ventricle (RWT); sphygmography (central (aortal) blood pressure (CBP), subendocardial blood flow (SBF) - by «Sphygmocor¼), and the effect of regular HD and HDF on serum levels of the studied markers, were assessed. RESULTS: An independent effect of FGF-23 on the risk of LVH, as well as on the increase of serum troponin I in the studied ESRD patients [ß=3.576 p<0.01, and ß=1.115, p<0.05, respectively] was found. Serum Klotho was the factor most associated with the CBP [ß=-0.023; p<0.001]. The increased serum sclerostin was correlated with a lower incidence of both reduced SBF [r=0.492; p<0.05], symptoms of coronary heart disease [r=-0.449; p<0.05] and rhythm disturbances [r=-0.446; p<0.05]. In addition, in HD patients higher FGF-23 and lower Klotho and sclerostine serum levels were associated with: inadequate dialysis syndrome (Kt/V <1.1; r=0.463; p<0.05), chronic inflammation (C-reactive protein >10 mg/L; r=0.612; p<0.01), and with a decrease in serum albumin level (<35 g/l; r=0.459; p<0.05). The FGF-23/sKlotho/sclerostin ratio disturbance was more pronounced in patients treated with traditional HD then HDF online. A direct correlation (r=0.445; p<0.05) was established between FGF-23 serum levels and serum phosphorus, which was more pronounced in HD patients (r=0.545; p<0.01). CONCLUSION: In HD and HDF ESRD patients, higher serum FGF-23 and lower sKlotho and sclerostin levels were associated with a chronic inflammation, malnutrition, secondary hyperparathyroidism, and may considered as predictors of cardiovascular complications such as LVH, ACS, rhythm disturbances, persisting of subincreased serum troponin I.

Quality of life of chronic kidney disease patients on renal replacement therapy.

The study demonstrated the results of the comparative analysis of various types of renal replacement therapy effects on the quality of life patients with terminal stage of chronic kidney disease on the basis of standardized questionnaires. It has been shown that the quality of life is significantly improved after a kidney transplantation. At the same time, it has also been found that the introduction of home dialysis, epoetins, active metabolites of vitamin D, calcimimetics in the clinic care expanded the opportunities for the labor rehabilitation of the dialysis patients and made their quality of life comparable with the same of the kidney transplant recipients.

HCV-associated mixed cryoglobulinemia and b-cell non-Hodgkin's lymphoma - pathogenetically related problems.

Hepatitis C virus (HCV) is a global population problem due to its high prevalence, usually late diagnosis, the difficulties of treatment. In the prognosis of patients with HCV not only hepatic, but increasingly frequent of extrahepatic HCV manifestations, such as mixed cryoglobulinemia (CG), are important. Mixed CG is currently considered as a B-cell benign lymphoproliferative disorders. The role of HCV virus in the pathogenesis of lymphoproliferative diseases is confirmed by a large number of epidemiological studies, as well as by the effectiveness of antiviral therapy in patients with non-Hodgkin's lymphoma (NHL). The purpose of the review was to provide an overview of recent literature data and the meta-analysis of epidemiological data explaining the role of HCV in the development of NHL. The review also discusses the treatment for HCV-associated NHL by antiviral therapy or other therapeutic options, such as chemotherapy.

[Risk factors for anemia in the early stages of chronic kidney disease]. / Faktory riska razvitiia anemii na rannikh stadiiakh khronicheskoi bolezni pochek.

AIM: To identify the early markers of anemia in chronic kidney disease (CKD) in patients with chronic glomerulonephritis (CGN) and glomerulonephritis (GN) in systemic diseases. SUBJECTS AND METHODS: Seventy-nine patients with some male preponderance who were aged 21 to 65 years (45.3±11.1 years) and had CKD (CGN and GN) in systemic diseases (systemic lupus erythematosus and Wegener's granulomatosis) in the early stages (Stages I-II) of CKD were examined. GN was diagnosed by a lifetime renal biopsy. Systemic diseases were diagnosed according to the criteria for each nosological entity. The stages of CKD were defined according to the 2012 Kidney Disease: Improving Global Outcomes (KDIGO) criteria; the glomerular filtration rate (GFR) was calculated using the CKD EPI equation (2012). According to the presence or absence of anemia, all the patients included in the study were divided into 2 groups: 1) 43 (54.4%) anemic patients; 2) 36 (45.6%) non-anemic patients (a control group). In addition to general clinical examination adopted for a nephrology department, special studies, such as determination of the serum levels of hepcidin, interferon-γ (IFN-γ), soluble Klotho protein (s-Klotho), as well as iron, ferritin, and transferrin saturation (TSAT) ratio, were performed to solve the set tasks. RESULTS: Forty-three anemic patients who had a hemoglobin level of 110 (100; 119) g/l and 36 control patients who had the similar values were noted to have statistically significantly (p<0.001) higher levels of IFN-γ (11 (10; 14) and 0.2 (0.09; 0.6) ng/ml), hepcidin (26 (25; 27) and 5.1 (3.8; 5.9) ng/ml) and C-reactive protein (1.5 (1.1; 2.1) and 0.3 (0.2; 0.6) mg/dl), and lower levels of s-Klotho protein (12 (10; 18) pg/ml) and TSAT (18 (14; 19)%. Forty-three patients with anemia were also found to have a statistically significantly (p<0.01) lower GFR (65 (62; 87) and 80.5 (62; 90) ml/min) and higher systolic blood pressure (145 (125; 160) and 120 (115; 16) mm Hg) as compared with those in 36 control patients. At the same time, the compared groups displayed no statistically significant differences in serum ferritin levels (123 (110; 150) and 115 (100; 140) µg/l). Among 43 CKD patients with anemia, its detection rate in the presence of systemic diseases was 3.2 times higher than that in CGN patients (41.7 and 12.7%). ROC analysis revealed that in the CKD patients with CGN and GN, the serum hepcidin level ≥ 25 ng/ml, with the sensitivity and specificity being of 89.7% and 74%, respectively (p > 0.001), was associated with the development of anemia. Moreover, the hemoglobin level of<120 g/ l was found to have an independent impact on the risk of reducing serum s-Klotho production. CONCLUSION: In Stage I-II CKD patients with CGN and GN in the presence of systemic diseases, elevated serum hepcidin levels should be regarded as a predictor for anemia of chronic disease (ACD). Herewith, the decrease in hemoglobin levels <120 g/l is associated with the reduced production of the nephroprotective factor s-Klotho. The treatment of ACD for Stages I-II CKD should encompass intravenous administration of iron in order to increase its content and availability for erythropoiesis.

[EVALUATION OF CARDIOVASCULAR RISKS WITH THE USE OF MORPHOGENETIC KLOTHO PROTEIN IN PATIENTS WITH CHRONIC RENAL DISEASE].

The aim: of the study was to explore the Klotho protein significance in patients with different stages of chronic kidney disease (CKD) and to assess the influence of antihypertensive therapy on Klotho protein serum levels. Materials and methods: 130 patients with stage 5 CKD1 were included in the study. Serum PTH, calcium and phosphorus were measured. ELISA was used to determine serum soluble alpha Klotho. Blood pressure including brachial and central (aortic) pressure was measured in all patients together with pulse wave velocity (using a «Sfigmokor¼ device); in addition, echocardiography (EchoCG), and X-ray examination of the abdominal aorta by Kauppila method were performed. Results: The dynamic study of serum Klotho level showed that it changes with decreasing glomerular filtration rate faster than a rise in phosphate and PTH levels starting from stage 3A of CKD. The two later variables increased at stages 4-5.According to the ROC analysis, the values of serum Klotho below 387 pg /ml suggested enhanced risk of myocardial calcification with 80% sensitivity and 76% specificity. In addition, the highest Klotho serum levels were observed in patients whose target BP values were achieved with angiotensin receptor blockers (ARB) compared to those who used other drugs [р<0,01] or failed to reached target BP levels [p=0,008]. Conclusion: The study showed the possibility of practical use of Klotho protein as an early diagnostic marker of cardiovascular risk. Reduced serum Klotho was less pronounced in patients who used ARB for correction of high blood pressure. Normal Klotho protein levels in serum have been associated with a lower frequency of heart and vessels calcification in CKD patients.

[Difficulties in correcting hyperphosphatemia in patients with chronic renal failure. A place of noncalcium-containing phosphate-binding drugs].

The review considers the current views of the mechanisms of hyperphosphatemia in patients with chronic renal failure. It shows indications for the use of different classes of phosphate-binding drugs to correct hyperphosphatemia.

[The serum level of the morphogenetic protein fibroblast growth factor 23 (FGF-23) as a marker for the efficiency of hyperphosphatemia therapy with phosphate-binding agents in chronic kidney disease]. / Uroven' morfogeneticheskogo belka - faktora rosta fibroblastov 23-go tipa (FGF-23) v syvorotke krovi kak marker effektivnosti terapii giperfosfatemii svyazyvayushchimi fosfat preparatami pri khronicheskoi bolezni pochek.

AIM: To study whether the excessive production of serum fibroblast growth factor 23 (FGF-23) may be reduced with phosphate-binding agents to treat hyperphosphatemia in patients with Stage VD chronic kidney disease (CKD). MATERIALS AND METHODS: The investigation enrolled 25 patients with Stage VD CKD on regular hemodialysis (HD) (12 patients with chronic glomerulonephritis, 8 with tubulointerstitial nephritis, and 5 with hypertensive nephrosclerosis); among them there were 15 men and 10 women at the age of 21 to 65 years; their mean age at inclusion in the study was 43±4.5 years. The clinical, laboratory, and instrumental examination similar to that in patients with the early stages of CKD was done. Serum FGF-23 levels (Human FGF-23 ELISA kit using monoclonal antibodies to the full FGF-23 molecule) were investigated in all the 25 patients. A whole blood sample was taken 2 days after the last session of HD before initiation of its regular procedure. RESULTS: The elevated serum FGF-23 concentrations in the patients on regular HD correlated with their HD duration (r=0.508; p<0.001). Along with this, a strong direct correlation (r=0.522; p<0.001) was found between the concentration of FGF-23 in the serum and inorganic phosphorus; at the same time hyperphosphatemia was less significantly associated with higher serum intact parathyroid hormone (PTH) levels (r=0.398; p<0.05). Lower FGF-23 and PHT levels were noted in a group of patients who could achieve and maintain the target serum inorganic phosphorus level (0.9-1.45 mmol/l) compared to that of patients with uncorrected hyperphosphatemia (>1.45 mmol/l) (p<0.01). A decrease in FGF-23 and PHT levels was achieved chiefly in the patients who had used phosphate-binders that contained no calcium (sevelamer hydrochloride). CONCLUSION: Lower FGF-23 levels were observed in the patients with CHD on regular HD who can achieve and maintain the target serum inorganic phosphorus level when using phosphate-binders that do not contain calcium than in those with uncorrected hyperphosphatemia (p<0.01).

[Role of the morphogenetic proteins FGF-23 and Klotho and the glycoprotein sclerostin in the assessment of the risk of cardiovascular diseases and the prognosis of chronic kidney disease].

UNLABELLED: AIM. To analyze changes in the serum concentrations of the morphogenetic proteins fibroblast growth factor 23 (FGF-23) and Klotho, as well as sclerostin, an osteocyte-secreted glycoprotein, in relation to the degree of hypertension, left ventricular (LV) hypertrophy, and arterial stiffness in patients with chronic kidney disease (CKD) at its different stages. SUBJECTS AND METHODS: Sixty-five patients (33 men and 32 women) aged 20-65 years, including 25 with chronic glomerulonephritis, 15 with tubulointerstitial nephritis, and 25 with hypertensive nephrosclerosis, were examined. A control group consisted of 15 healthy volunteers matched to the study group patients for age and gender. Serum FGF-23 concentrations and blood pressure (BP) were measured in the all subjects. Patients with BPs > 140/80 mm Hg underwent echocardiography, followed by determination of LV mass (LVM) and calculation of LVM index. Vascular circulation, pulse wave velocity, cardiac and vascular calcifications, and vascular functional properties were estimated. RESULTS: There was a strong direct Correlation between the serum concentration of FGF-23 and the stage of CKD and an inverse correlation between the levels of Klotho and sclerostin and the stage of CKD. As the glomerular filtration rate became lower, the concentration of FGF-23 increased and that of Klotho and sclerostin decreased just in Stage III CKD while hyperphosphatemia and elevated parathyroid hormone levels were noted in Stages IV-V CKD. As CKD progressed, the serum concentrations of Klotho and sclerostin were inversely correlated with the levels of phosphorus and parathyroid hormone. The degree of blood pressure elevation correlated positively with serum FGF-23 concentrations and inversely with Klotho levels. There was no significant correlation of the level of sclerostin with the degree of BP increase. The direct correlation between higher FGF-23 level and higher VLM is most pronounced in hypertensive patients. There was a strong direct relationship between FGF-23 and Klotho levels and a strong inverse relationship between sclerostin levels and pulse wave velocity. Lower Klotho concentrations were associated with the detection rate of calcifications in the heart valves and large arteries (the abdominal aorta). The reduced serum levels of Klotho and sclerostin were also correlated with concentric LV remodeling. CONCLUSION: It was demonstrated that there was a clear link between increased serum FGF-23 and decreased Klotho concentration as CKD progressed, and that between arterial stiffness and calcification and myocardial remodelling regardless of traditional risk factors. More experimental and clinical studies are required to clarify the role of sclerostin in CKD.

[MORPHOGENETIC PROTEINS--FIBROBLAST GROWTH FACTOR AND KLOTHO, IN THE SERA OF PATIENTS WITH CHRONIC RENAL DISEASE].

The aim of the study was to evaluate the role of morphogenetic proteins--fibroblast growth factor-23 (FGF-23) and extracellular form (alpha) of Klotho protein, present in the sera of patients with chronic renal disease (CRD) as markers of cardiovascular risk. The study included 130 patients (64 men and 66 women) with stage I-VD CRD. The patients'age was 20-65 (mean 41 ± 6.7) years. 30 of them had chronic glomerulonephritis, 23 chronic tubulointerstitial nephritis, 28 hypertensive nephrosclerosis, 22 polycystic kidneys, 27 type 2 diabetes mellitus. Inclusion and exclusion criteria were standardfor clinical studies of CRD patients. Control group contained 30 healthy volunteers matched for age and sex. The patients were uniformly distributed by stages of CRD in terms of age and sex (18-20 per group). All of them were followed up during 1 year Standard clinical and laboratory examination was supplemented by the measurement of the parathyroid hormone (PTH), Ca and P levels. Serum FGF-23 and Klotho levels were determined by ELISA before and 1 year after onset of the study. Blood pressure including brachial (peripheral) and aortic (central) one as swell as the pulse wave velocity was measured by a Sphygocorr apparatus (Australia). Other studies included ECG, EchoCG, and X-ray of abdominal aorta in the lateral projection using the Kaupilla method. Comparison of FGF-23 and Klotho levels in patients at different stages of CRD revealed their decrease with decreasing glomerular filtration rate that started before (at IIIA stage) a rise in the serum P and PTG levels (IV-V stage). Negative relationship was documented between the Klotho level and the degree of cardiac calcinosis estimated from a semi-quantitative scale (r = 0.64; p < 0.01). Serum FGF-23 significantly correlated wiht myocardial remodeling (r = 0.612; p < 0.01). Multiple regression analysis showed that patients with elevated FGF-23 and P levels, high central systolic pressure and pulse wave velocity had greater left ventricular myocardium mass. ROC-analysis demonstrated that FGF-23 level over 412 pg/ml is indicative of left ventricular hypertrophy with sensitivity 80% and specificity 76%. Patients undergoing hemodialysis who died within 1 year after the onset of the treatment had a higher FGF-23 level than survivals on hemodialysis. The risk of death during the first year on hemodialysis correlated with the FGF-23 level (r = 0.564, p < 0.01). ROC-analysis showed that Klotho levels below 387 pg/ml suggested an increased risk of myocardiym calcification with sensitivity 80% and specificity 75%. It is concluded that morphogenetic proteins, fibroblast growth factor and Klotho, not only play an important role in mineral metabolism in patients with CRD but also produce pleiotropic effects on the development of cardiovascular complications (via involvement in cardiac and vascular calcification and remodeling). It provides a basis for the use of these proteins as early markers of cardiovascular risk in CRD patients.