Sclerostin levels predict cardiovascular mortality in long-term hemodialysis patients: A prospective observational cohort study.

Sclerostin is a protein which is involved in bone metabolism and probably also in vessel wall function. This prospective observational cohort study evaluated the prognostic significance of sclerostin in hemodialysis (HD) patients. In total, 106 HD patients and 25 healthy controls participated in the study. HD patients were prospectively followed up for five years. Sclerostin was measured in serum using standard ELISA kits by Biomedica. Sclerostin concentrations in serum were higher in HD patients compared to the controls (89.2±40.3 pmol/l vs. 32.8±13.0 pmol/l, p<0.001). Sclerostin levels were significant for cardiovascular mortality but not for overall mortality and mortality due to infection. A higher cardiovascular risk was connected to sclerostin concentrations above the median (>84 pmol/l), HR (95 % CI): 2.577 (1.0002-10.207), p=0.04. When sclerostin was evaluated together with residual diuresis in Kaplan-Meier analysis the worst prognosis due to cardiovascular events was observed in the group with high sclerostin and zero residual diuresis compared to all other patients (p=0.007). In summary, serum sclerostin levels in HD patients were increased when compared to healthy subjects. High sclerostin levels were demonstrated as a risk factor for cardiovascular mortality. Further studies are required to clarify the pathophysiological mechanisms of sclerostin action in patients with renal failure before therapeutic measures can be established.

[Vitamin D metabolism and current options for therapeutic activation of vitamin D receptor in patients with chronic kidney disease or renal failure]. / Metabolizmus vitaminu D a soucasné moznosti terapeutické aktivace receptoru pro vitamin D pri chronickém onemocnení a selhání ledvin.

Chronic kidney disease (CKD), and chronic renal failure in particular, is associated with vitamin D deficiency and with a disorder of all metabolic processes that are associated with vitamin D. Calcidiol levels are often low. At present, efforts are made to test and to pharmacologically modulate its levels and thus to contribute to greater availability of the substrate for external calcitriol production. Calcitriol production is reduced in CKD patients not only as a consequence of diminishing functional renal parenchyma but also as a consequence of 1-α-hydroxylase inhibition by FGF-23 and other factors. On the other hand, although parathormone (PTH) increases renal production of calcitriol, it also causes secondary hyperparathyroidism. Synthetic calcitriol (or α-calcidiol) supresses PTH production and is used to treat secondary hyperparathyroidism. This approach is often associated with adverse increase in calcaemia and phosphataemia as the effect on parathyroid glands is associated with an effect on the gastrointestinal tract where calcium and phosphor absorption is increased by calcitriol. Synthetic analogues of vitamin D inhibit parathyroid gland but have significantly lower effect on gastrointestinal tract. Paricalcitol is a selective VDR (vitamin D receptor) activator, used for targeted suppression of parathyroid glands. Vitamin D deficiency in general population is associated, at least in epidemiological studies, with a range of medical complications and the same also applies to patients with renal disease. Although randomised studies are not available, clinical observational studies repeatedly showed treatment with VDR activators to be associated with better prognosis. As other fields of medicine, nephrology currently pays a great attention to vitamin D and vitamin D receptor activation.

Thyroid hormone abnormalities in hemodialyzed patients: low triiodothyronine as well as high reverse triiodothyronine are associated with increased mortality.

Numerous abnormalities of thyroid hormones in end-stage renal disease (ESRD) have been described. Our aim was to analyze the impact of these abnormalities on survival. In 167 hemodialyzed ESRD patients, TSH and thyroid hormone levels (T4, fT4, T3, fT3, rT3) were determined. The patients were then prospectively followed up for up to 5 years and the possible impact of any observed abnormalities on their mortality was studied. Only 16.8 % patients had all six tests within the reference range. The pattern of nonthyroidal illness syndrome was found in 56.3 %. Low T3 was particularly common (44.3 %), and clearly associated with increased 6- and 12-month mortality and decreased overall survival (log rank test, P=0.007). Independent of T3 levels (Spearman correlation, NS), increased rT3 was more frequently observed (9.9 %) than expected from the literature, and was also related to increased mortality and decreased survival (log rank test, P=0.021). Increased rT3 may be more common in ESRD patients than previously described, and together with decreased T3 it may serve as an indicator of poor prognosis in subsequent months.

[Bone disease in chronic renal failure and its modern therapy]. / Kostní choroba u chronického selhání ledvin a její moderní terapie.

Renal bone disease is one of the most serious complications of chronic renal failure. Secondary hyperparathyreosis is decisive for its pathogenesis. Current prevention and treatment emphasises pathogenetic and clinical interrelationships between bone tissue involvement and cardiovascular complications (CKD-MBD, bone and venous involvement associated with chronic renal disease). The treatment should first correct hyperphosphatemia and, subsequently, hyperreactivity of parathyroid glands through vitamin D receptor (VDR) and calcium receptor (CaR) modulation. Three groups of drugs play a fundamental role here (GIT phosphate binders, calcimimetics and vitamin D receptor activators). Certain other therapeutic approaches are used in some specific situations such as, among others, refractory hyperparathyreosis or calciphylaxis.

[Clinical significance of vascular damage in patients with diabetes and renal impairment--a nephrologist's view]. / KIinický význam cévního postizení u diabetiku s onemocnením ledvin--pohled nefrologa.

Care for diabetic patients with renal impairment and vascular damage is a typical example of care requiring inter-professional approach. Vascular damage in patients with diabetes may lead to renal disease (ischemic nephropathy, high incidence but frequently unrecognised in diabetic patients). Renal ischemia resulting from hypoperfusion due to vascular changes contributes to progression of nephropathy and accelerates destruction of functional renal parenchyma. Vascular damage is the leading cause of morbidity and mortality in patients on dialysis. Amputations are reported in 6% of patients and increase the risk of death by at least 50%. All these issues highlight the need for comprehensive and early inter-professional care aimed at protecting the vascular system, i.e. recognition and, whenever possible, elimination of all factors contributing to vascular damage in diabetic patients.

Fibroblast growth factor 23 and matrix-metalloproteinases in patients with chronic kidney disease: are they associated with cardiovascular disease?

BACKGROUND: High cardiovascular risk in patients with chronic kidney disease (CKD) may be related to mineral disorder and microinflammation. Fibroblast growth factor 23 (FGF-23) is a phosphatonin and inhibitor of calcitriol synthesis, which is associated with poor prognosis in CKD patients starting dialysis. Matrix-metalloproteinases (MMP-2, MMP-9) contribute to myocardial remodeling and arterial calcification. FGF-23 and MMPs levels are altered in CKD, however, little is known about their association and relation to cardiovascular (CV) disease. METHODS: Standard laboratory parameters, plasma levels of MMP-2, MMP-9, FGF-23, PAPP-A and CV disease history were assessed in 80 patients with CKD 1-5 and 44 healthy control subjects. RESULTS: FGF-23 and MMP-2 (assessed by ELISA) were higher in CKD patients compared to controls. FGF-23 increased from CKD 3, whereas MMP-2 increased only in CKD 5. FGF-23 was positively associated with MMP-2, adjusted to age, eGFR, phosphatemia, calcitriol and parathormone. FGF-23 independently correlated with parathormone and inversely with calcitriol, whereas MMP-2 was related to phosphatemia. FGF-23 was higher in subjects with a history of CV disease compared to those free of such history (559.0 vs.184.0 RU/ml), adjusted to age and eGFR. CONCLUSION: Our data suggest a possible relationship between FGF-23, MMP-2 and CV disease in CKD. Potential causality of this association remains to be elucidated.

Influence of continuous ambulatory peritoneal dialysis on some plasma and erythrocyte vitamins--retrospective study.

This paper reports a retrospective study on the clinical and laboratory analysis of some serum and erythrocyte vitamins in our chronic renal failure patients who were treated with Continuous ambulatory peritoneal dialysis (CAPD). In the first patient and in the next 10 patients the CAPD treatment began (in years 1980-1984) at the Internal Department-Strahov of General Faculty Hospital in Prague and after 2 or 3 weeks they continued in CAPD programme at the Dialysis Centre of IVth Internal Clinic, Faculty Hospital in Kosice. In the third group of CAPD patients (among them 8 patients were treated in Prague and 5 patients in Kosice) all biochemical parameters including vitamins were determined at Nephrological laboratory of the IVth Internal Clinic in Kosice. Besides that the aim of this paper was to show the above standard relationship and a long-term cooperation between above mentioned departments, and to contribute to Czech and Slovak reciprocity and to the history of clinical nephrology. The paper was presented on the important occasion of the 30th anniversary of the first continuous ambulatory peritoneal dialysis, which was performed at Internal Department-Strahov, Prague in the year 1978.

[Nutrition for the diabetic patient with kidney disease]. / Výziva diabetika s onemocnením ledvin.

Malnutrition is a major problem in chronically ill patients. The combination of diabetes and renal insufficiency increases the risk of malnutrition, also due to dietary interventions associated with the two diseases. Resulting malnutrition intensifies inflammatory activity and further compromises nutrition intake. This results in a vicious circle which significantly reduces the quality of life of the affected patients and increases their mortality. Proper nutritional care for such patients is an integral part of their treatment.

[Specific issues of dialysed diabetics in outpatient practice]. / Specifické problémy u dialyzovaných diabetiku v ambulantní praxi.

Approximately 40% of patients on dialysis have diabetes mellitus (DM). The basic characteristic of those patients are numerous associated organ complications, especially heart and artery diseases. These and other associated complications in dialysed diabetic patients have a modified pathogenetic and clinical picture and contribute to their poorer prognosis. Anaemia, immunodeficiency as well as malnutrition are manifested earlier and in a more significant manner. Dialysis therapy has the same rules for diabetic and non-diabetic patients. Tolerance to ultrafiltration is lower and haemodynamic instability is easier to provoke in diabetics than in non-diabetic patients. The use of a dialysis solution is beneficial from the point of view of glucose concentration balance. Insulin doses are lower as a result of extended insulin half-time. There is also a degree of insulin resistance, but it can be managed to a great extent by adequate dialysis. There are no fixed guidelines for insulin dosing; the doses roughly amount to half of the doses in patients with normal renal function. The assessment of diabetes compensation is based on glycated haemoglobin, and glycated albumin is also recommended in certain cases. Deciding on the therapy (oral antidiabetic drugs vs. insulin therapy or a combination of both) is based on diabetic care standards; cooperation between the diabetologist and the dialysis doctor is desirable. Customized, specifically designed and targeted intervention in diabetic patients may slow down the progression of diabetic vascular changes, improve diabetes compensation and the patients' quality of life.

Increase of nocturnal melatonin levels in hemodialyzed patients after parathyroidectomy: a pilot study.

In hemodialyzed patients hormonal disturbances are known to occur. However, melatonin levels have not been completely studied. The aim of the study was to find whether changes in calcaemia affect melatonin secretion. For this reason we followed the nocturnal serum concentrations of melatonin and parathyroid hormone (PTH) in 9 hemodialyzed patients (6 women and 3 men, aged 37-65 years) both before and 1-3 months after parathyroidectomy at 6 p.m., 9 p.m., 11 p.m., 2 a.m., 5 a.m. and 7 a.m. At 6 p.m. blood samples to evaluate the levels of calcium and phosphate were also collected. Parathyroidectomy resulted in an increase in nocturnal melatonin levels. As expected, the parathyroidectomy was followed by considerable PTH decrease. PTH showed no nocturnal variation before or after parathyroidectomy. Calcium levels significantly decreased after the operation while phosphate levels increased. In summary, in hemodialyzed patients with hyperparathyroidism, parathyroidectomy significantly increases the nocturnal secretion of melatonin. Relationships between the pineal gland and parathyroid glands have yet to be elucidated.

[The MIAC (malnutrition, inflammation, atherosclerosis, calcification) syndrome]. / Syndróm MIAC (malnutrition, inflammation, atherosclerosis, calcification).

The number of patients with chronic renal failure is on the rise; these patients have a 10 to 20 times higher risk of development and progression of cardiovascular diseases. Higher cardiovascular risk in such patients cannot be satisfactorily explained by traditional risk factors defined in the Framingham study. On the contrary, a concept of reverse epidemiology has been brought forward, designating a situation in which the incidence of obesity and hyperlipoproteinemia is associated with a higher survival rate of the patients concerned. Higher risk is today explained by the "MIAC (malnutrition, inflammation, atherosclerosis, calcification) syndrome", which is present in patients with chronic kidney disease. New evidence has been recently obtained of different circulating molecules associated with atherosclerosis, the plasmatic levels of which are decreased or increased in such patients and which are in a way linked with the MIAC syndrome and the progression of atherosclerosis. Clinical management of the syndrome could increase survival in the future, and reduce morbidity and the number of hospitalisations. Circulating molecules could serve as markers evidencing the presence of the syndrome and its severity, as well as the success of treatment.

Continuous blood volume monitoring and "dry weight" assessment.

There are two distinct facets of adequate fluid balance control in haemodialysis patients--estimation of dry weight (DW) as the target and adequate ultrafiltration (UF) strategy, i.e. the way to reach the target in a possibly symptom-free way. The article reviews the continuous blood volume monitoring (CBVM) based procedures to deal with the former facet-DW determination. The existing approaches are divided in three groups--methods defining certain alert value of relative blood volume (RBV) reduction, methods working with RBV response to constant UF rate, and methods evaluating dynamics of RBV response to UF pulse or chain of UF pulses. While the first and the third approaches are relatively easy to automate, the second group of methods are suitable mainly for observational evaluations only. All the discussed methods, without exception, need large-scale verification, as they all were evaluated in the majority by their authors only and on small patient cohorts.

[Resting energy expenditure during hemodialysis]. / Klidový energetický výdei pri hemodialýze.

Very few studies have so far reported about resting energy expenditure (REE) in chronic renal failure and there is no information available on REE during hemodialysis (HD). Hypothetically, we can expect an increase in REE during HD procedure (due to the inflammatory response to extracorporeal blood circuit). However, such increase in REE could be modified by thermal balance of the procedure. In our study, REE was measured by indirect calorimetry (Deltatrac Datex) in a group of 13 HD patients (7 males and 6 females, mean age 59.8 +/- 13.5 years). In each patient, REE was assessed during two HD sessions: one isothermic and one thermoneutral. All other HD parameters were kept constant. The control group consisted of 14 healthy subjects (4 males and 10 females, mean age 41.3 +/- 20.5 years) with normal renal function. There was a significant difference in thermal balance between the two HD settings: -199 kJ/HD in isothermic and -4kJ/HD in thermoneutral HD sessions (p < 0.01). Measured REE values obtained in HD patients before HD session (7 316 +/- 919 kJ/day/1.73 m2) did not differ significantly from those of the healthy controls (7 264 +/- 1 016 kJ/day/1.73 m2). Similarly, there was no significant difference in calculated EE values (Harris-Benedict equation). In the 10th minute of the HD session, there was a slight, transitory decrease in REE (mean decrease by 3.2% during isothermic and by 2.8% during thermoneutral HD session, ns). In the 70th minute, REE returned to pre-dialysis values. After a light meal in the 110th minute REE increased by 8% during isothermic and by 6.3% during thermoneutral HD session. At the end of the HD session (i.e. in the 215th minute) REE again returned to pre-dialysis values. Intra-dialysis changes in REE were similar in both isothermic and thermoneutral HD sessions. The results of our study did not confirm the expected influence of HD procedure on REE in the two different thermal HD settings. We conclude that there is no significant difference between REE in HD patients and healthy controls and that REE values are not significantly influenced by hemodialysis procedure.

Plasma levels of active and total ghrelin in renal failure: a relationship with GH/IGF-I axis.

Ghrelin was originally isolated from the rat stomach and significant amounts were found also in the kidney. Present study was designed to examine changes in ghrelin levels in renal failure and their relationship to the GH/IGF-I axis. Fourty patients with mild-to-severe CRF (19 men, 21 women, aged 62.5 +/- 2.2 years, BMI 27.57 +/- 0.73 kg/m(2)) and 34 healthy control subjects (17 men, 17 women, aged 60 +/- 2.6 years, BMI 27.55 +/- 0.79 kg/m(2)) were included in the study. Total ghrelin levels were significantly increased in patients with chronic renal failure (CRF) (p < 0.0001). Total ghrelin in CRF correlated positively with active ghrelin (p < 0.001), GH (p < 0.05), IGF-I (p < 0.05), free IGF-I (p = 0.0001), IGFBP-3 (p < 0.01), IGFBP-2 and -6 (p < 0.05). Active ghrelin in CRF correlated positively with IGF-I (p < 0.001), free-IGF-I (p < 0.005), IGFBP-2 (p < 0.05) and IGFBP-3 (p < 0.05). However, most of the correlation were markedly reduced and the significance disappeared after adjustment for different creatinine levels. Hemodialysis in patients with end stage renal disease (ESRD) resulted in a significant reduction of plasma total and active ghrelin (p < 0.01 and p < 0.001 respectively). In conclusion we demonstrated elevated plasma levels of total ghrelin in CRF, and a reduction of total and active ghrelin after a single course of hemodialysis in ESRD. The elevation of ghrelin levels could be caused by impaired clearance and/or metabolism of ghrelin in the kidney. We did not prove clearly significant relationship between ghrelin serum levels and parameters of GH/IGF-I axis in study subjects.

Plasma ghrelin levels in patients with end-stage renal disease.

Ghrelin is an acylated peptide stimulating secretion of the growth hormone (GH). It was originally isolated from the rat stomach as an endogenous ligand for the growth hormone secretagogue receptor. Although being predominantly produced by endocrine cells of the gastric fundus, its secretion has been found in various tissues including the kidney. To study the influence of renal failure on plasma ghrelin levels we examined 16 patients with end-stage renal disease (ESRD) receiving hemodialysis (8 men and 8 women) and 19 controls (10 men and 9 women). Both groups were comparable in age and BMI. In all subjects we assessed plasma levels of ghrelin, leptin, soluble leptin receptor, insulin, IGF-I, IGFBP-1, IGFBP-3 and IGFBP-6. Ghrelin levels were significantly higher in the group of dialyzed patients (4.49+/-0.74 vs. 1.79+/-0.15 ng/ml; p<0.001). These patients had significantly higher levels of GH, IGFBP-1, IGFBP-6, leptin and percentage of body fat (p<0.05). In the group of patients with ESRD plasma ghrelin levels positively correlated with IGFBP-1 (p<0.01). In the control group, ghrelin positively correlated with GH concentrations (p<0.01) and negatively correlated with the levels of insulin and creatinine (p<0.05). In conclusion, patients with ESRD have higher ghrelin concentrations, which might be caused by a decreased excretion/metabolism of ghrelin in the kidney during renal failure.

[Junctions of hepatology and nephrology]. / Stycné body hepatologie a nefrologie.

The liver and the kidney jointly or in a complementary manner play an important role in maintaining homeostasis of the internal environment, mainly regarding detoxification, excretion and regulation. Hepatorenal syndrome can develop under pathological circumstances due to severe hepatic impairment, when the metabolism of both organs is affected by various xenobiotics, when they are damaged by genetic defects as in renal polycystosis, glycogenoses, alpha-1 antitrypsin deficiency or in hereditary amyloidosis. In primary hyperoxaluria or familiar thrombotic microangiopathy renal impairment develops due to the metabolic defect in the liver. Both organs may be impaired also in some hemolytic anemias, viral hepatitis, AIDS, leptospirosis, in circulatory failure, intoxications, and after the bone marrow or solid organ transplantation. In the dialysis units, prevention of viral hepatitis and HIV infection is of the basic importance; its principles are discussed in more detail.

[An importance of vitamin D metabolites assessment in patients with impaired renal function]. / Význam stanovení metabolitu vitaminu D u pacientu se snízenou funkcí ledvin.

The goal of this prospective multicentric study was to assess concentrations of vitamin D metabolites in patients with renal insufficiency and to monitor response of calcium phosphate metabolism parameters to a focused individualised therapy. The sample consisted of 184 patients, 66 of them were undergoing regular dialysis (Ccreat 0.11 +/- 0.05 ml/sec., age 57.6 +/- 16.6) and 118 patients were dispensed for renal insufficiency (Ccreat 0.42 +/- 0.23 ml/sec., age 60.8 +/- 11.0). After an assessment of basic parameters of bone metabolism (Ca, Pi, ALP) and parameters of acidobasic balance, calcidiol, calcitriol, and parathormon were assessed by radiation immunisation and than the used treatment was evaluated and adjusted according to results of the assessment. Two month later laboratory tests were done. Entry concentrations of calcidiol were in 73% of patients in reference area. However, according to clinical recommendations the bottom value of the reference area had to be reevaluated towards higher values. Such more strict criteria suited only 20% of patients. Calcitriol levels in reference area were found in 30% of patients, after treatment adjustment in 49% of patients. Treatment with vitamin D pharmaceuticals was often limited by hyperphosphataemia, low PTH or hypercalinemia. Input levels of calcitriol in nondialised patients significantly correlated with input calcidiol, 1alpha-hydroxylasis in kidneys could be stimulated in them via calcidiol administration. Attention deserve especially low calcidiol and calcitriol levels in patients with renal failure because timely, individualised and controllable supplementation of vitamin D metabolites in renal insufficiency serves as a prevention of later advanced forms of bone metabolism impairment in a period of dialysis treatment.