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.

[Effects of keto/amino acids and a low-protein diet on the nutritional status of patients with Stages 3B-4 chronic kidney disease]. / Vliianie keto/aminokislot i ogranicheniia belka na status pitaniia bol'nykh khronicheskoi bolezn'iu pochek IIIB-IV stadii.

AIM: To evaluate the efficacy of keto/amino acids in maintaining protein balance and preventing mineral metabolic disturbances and the development of uremic hyperparathyroidism in the long-term use of a low-protein diet (LPD) in patients with Stages 3B-4 chronic kidney disease (CKD). SUBJECTS AND METHODS: Ninety patients with CKD caused by chronic latent glomerulonephritis in 65 patients and chronic tubulointerstitial nephritis of various etiologies (gout, drug-induced, and infection) in 25 were examined. The investigators conducted clinical, laboratory, and instrumental examinations, including bioelectrical impedance analysis (body mass index (BMI), the percentages of lean and fat mass), echocardiography and radiography of the abdominal aorta in the lateral projection (the presence of cardiac valvular and aortic calcification), and pulse wave velocity measurements using a Sphygmocor apparatus (vessel stiffness estimation). The stages of CKD were defined according to the 2012 Kidney Disease: Improving Global Outcomes (KDIGO) criteria; glomerular filtration rate was calculated using the CKD EPI equation. According to the diet used, all the patients were divided into 3 groups: 1) 30 patients who took LPD (0.6 g of protein per kg of body weight/day) in combination with the keto/amino acid ketosteril (1 tablet per 5 kg of body weight/day; Diet One); 2) 30 patients who used LPD in combination with the other keto/amino acid ketoaminol at the same dose (Diet Two); 3) 30 patients had LPD without using the keto/amino acids (Diet Three) (a control group). RESULTS: During a follow-up, there were no signs of malnutrition in Groups 1 and 2 patients receiving LPD (0.6 g protein per kg/day) in combination with the keto/amino acids ketosteril and ketaminol, respectively. At the same time, 11 (36.6%) patients in Group 3 (a control group) who did not take the keto/amino acids showed a BMI decrease from 24 (23; 26) kg/m2 to 18.5 (17; 19.2) kg/m2 (p < 0.05), including that of lean body mass from 37.4 (36; 38.8) to 30 (29.1; 34.7)% in the men (p<0.05) and from 29.8 (26.8; 31) to 23.9 (22; 25.7)% in the women (p<0.01). In addition, at the end of the study, there were elevated serum phosphorus levels (p<0.05) and mainly higher parathyroid hormone concentrations in Group 3 patients who received LPD without using the amino/keto acids than in Groups 1 and 2. As compared to Group 3, Groups 1 and 2 displayed no differences in the quantity of cardiac and aortic calcification and in the augmentation index (arterial stiffness). The ketosteril and ketaminol groups versus the control group had also higher s-Klotho levels (p<0.01) that were inversely correlated with glomerular filtration rate (r =-0.467; p<0.01). CONCLUSION: The keto/amino acids ketosteril or ketoaminol are an important component of LPD, which prevents malnutrition and an additional source of calcium that inhibits hyperphosphatemia and slows the development of uremic hyperparathyroidism. Incorporation of keto/amino acids into LPD leads to a less pronounced reduction in s-Klotho protein in relation to the degree of renal failure than does LPD without keto/amino acids.

[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.

[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.

[Impact of anemia correction on the production of the circulating morphogenetic protein α-Klotho in patients with Stages 3B-4 chronic kidney disease: A new direction of cardionephroprotection].

AIM: To investigate the impact of anemia correction with erythropoiesis stimulants on the serum level of the circulating morphogenetic protein α-Klotho in patients with Stages 3B--4 chronic kidney disease (CKD). SUBJECTS AND METHODS: 64 patients aged 42±8 years with Stages 3B--4 nondiabetic CKD were examined and divided into 2 groups: 1) 32 patients with anemia (the target hemoglobin levels could be achieved and kept with erythropoietin and iron saccharate in 20 patients (Group A) and those could not be done in 12 patients (Group 1B). A control group (Group 2) consisted of 32 non-anemic patients matched for gender, age, and degree of a glomerular filtration rate (GFR) reduction. Along with iron exchange indicators, the time course of changes in serum Klotho levels were examined in all the 64 patients during screening and one year after the end of the study. For correction of anemia, 32 patients with this condition (Groups 1A and 1B) took short-acting epoetin (hypodermic recormon 2,000 IU thrice per week + iron (intravenous venofer 5 ml of 100 mg once per week)) under control of hemoglobin levels and serum transferrin iron and ferritin saturation. After achieving the target hemoglobin level of 110-120 g/l, for its keeping, all the patients received, instead of short-acting epoetin, long-acting hypodermic darbepoetin-α 1.5 µg once every 2 months and intravenous iron saccharate 100 mg once every 2 weeks. RESULTS: Among the 32 anemic patients in Group 1, 20 (63%) (Group 1 A) could achieve the target hemoglobin level (110--120 g/l) and maintain it within this range, by performing therapy with epoitin-ß + iron saccharate; anemia (the hemoglobin level of <110 g/l) persisted in 12 (37%) patients (Group 1B) despite the fact that epoetin and iron saccharate had been administered. Group 1A was noted to have an increase in α-Klotho concentrations by an average of 100±11.6-pg/ml as compared to Group 1B (by only 72±4.2 pg/ml). At the same time, the α-Klotho levels in the control group by the end of the follow-up decreased by an average of 210±12.9 pg/ml as compared to the prescreening value. There was a direct correlation between hemoglobin and serum ferritin concentrations and iron ferritin saturation percentage and α-Klotho levels. It was ascertained that the hemoglobin concentration of ≥110 g/l with a sensitivity of 89% and a specificity of 75% could predict higher serum α-Klotho levels in CKD. The same patients were found to have an inverse relationship between the serum level of α-Klotho and the risk of cardiovascular events. CONCLUSION: The serum level of the protein Klotho is not only a marker for the severity of CKD and its complications (anemia, left ventricular hypertrophy, and heart failure), but also a pathogenetic factor of CKD progression. Anemia correction with erythropoiesis stimulants has been shown to enhance the renal and extrarenal production of α-Klotho.

[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.