[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.

[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.

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.

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.

[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.

[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.

[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.

[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.

Soluble leptin receptor levels in patients with chronic renal failure.

Soluble leptin receptor (SLR) is the extracellular part of the leptin receptor. This protein is released into circulation and constitutes the main circulating leptin-binding protein. The aim of our study was to measure SLR concentrations in patients with chronic renal failure (CRF) and healthy subjects and to explore the relationship of SLR to other hormones and cytokines. The patients with CRF had significantly higher serum leptin, TNF-alpha and insulin levels than healthy subjects (25.1+/-23.5 vs. 9.4+/-7.6 ng.ml(-1) (S.D.); 14.2+/-4.2 vs. 4.55+/-2.5 ng.ml(-1); 39.8+/-36.1 vs. 20.3+/-11.1 mU.l(-1)). Serum soluble leptin receptor levels did not differ between these groups (19.1+/-11.3 vs. 19.6+/-6.1 U.ml(-1)). An inverse relationship between serum SLR and leptin levels was found in both groups. In patients with CRF the inverse relationship between SLR and insulin, body fat content and total protein levels were also found, while in healthy subjects only inverse relationship of SLR with insulin and albumin concentrations were detected. We conclude that soluble leptin receptor levels in patients with chronic renal failure do not differ from those of healthy subjects despite higher serum leptin levels in CRF patients. The physiological consequences of this finding require further investigation.

Beta 2-microglobulin serum levels during dialysis: effect of cuprophan and serum osmolality changes.

New cuprophan dialysers were used in twenty, re-used dialysers in twelve dialyses and new dialysers in ten sequential ultrafiltrations. Serum beta 2-microglobulin (beta 2m) concentration was measured before and after all these procedures. Serum osmolality changes were compared with changes in serum beta 2m concentrations. These concentrations rose in dialyses with new and re-used dialysers, but remained unchanged during sequential ultrafiltration. beta 2m increased with serum hypo-osmolality, decreased with serum hyperosmolality and did not change during iso-osmolar dialysis. These results indicate that cuprophan membrane does not raise beta 2m concentration during dialysis. It is hypo-osmolality that is responsible for the increment of beta 2m in serum.

Comparison of different techniques of hemodialysis vascular access flow evaluation.

Measurement of vascular access flow (QVA) has been suggested as a method of choice for vascular access quality (VAQ) monitoring. Besides traditional duplex Doppler, a number of bedside methods based mostly on the Krivitski principle of QVA evaluation from recirculation at reversed needles (RX), have been developed. This work compares ultrasonic dilution (UD), taken as a reference, HD01, Transonic Systems; duplex Doppler (DD); thermodilution (TD), BTM, Fresenius; optodilutional RX measurement (ORX), Critline III, R-mode, HemaMetrics; direct optodilutional QVA evaluation from jumpwise changes in ultrafiltration rate at both normal and reversed needles connection (OABF), Critline III, ABF-mode; and direct transcutaneous optodilutional QVA evaluation (TQA), Critline III TQA. Firstly, reproducibility of each method was assessed by duplicate measurement at unchanged conditions. This was followed by paired measurement with each method performed at controlled change in relevant measurement condition (two different extracorporeal blood flows in UD and TD, changed sensor position in TQA). Finally paired measurements by each method and the reference method performed at identical conditions were evaluated to assess accuracy of each method. The simple Krivitski formula QVA=QB(1-RX)/RX was used wherever manual QVA calculation was needed. Very high reproducibility was seen in UD, both for measurement at the same extra corporeal blood flow (QB) (correlation coefficient of duplicate measurement r=0.9702, n=58) and for measurement at two different QB (r=0.9735, n=24), justifying its current status of a reference method in QVA evaluation. Slightly lower reproducibility of TD measurement at the same QB (r=0.9197, n=40) and at two different QB (r=0.8508, n=168) can be easily overcome by duplicate measurement with averaging. High correlation of TD vs. UD (r=0.9543, n=54) makes TD a viable clinical alternative in QVA evaluation. Consistently different QVA obtained at two different QB should prompt closer investigation of anatomical conditions of the access. Use of the simple Krivitski formula in TD (which measures total recirculation, i.e. sum of access recirculation and cardiopulmonary recirculation) brings about underestimation of QVA, which progressively increases from QVA of about 600 mL/min up. Good correlation, although with significant scatter (r=0.8691, n=27) was found between the DD- and UD-based QVA. By far the worst reproducibility at the same QB from among the investigated methods was found in ORX (0.6430, n 23). Also the correlation of ORX vs. UD was lower than in other methods (r=0.702, n=33) and general overestimation of QVA by about 25% was noted. Correlation of OABF vs. UD (r=0.6957, n=26) was slightly better than that of ORX and it gave less overestimated values. The TQA method showed very high reproducibility (r=0.9712, n=85), however only for unchanged sensor position. Correlation of QVA measured at two different sensor positions was much worse (r=0.7255, n=22). Correspondence of TQA vs. UD was satisfactory (r=0.8077, n=36). Skilled and experienced operators are a must with this method.

Age-related extracellular to total body water volume ratio (Ecv/TBW)--can it be used for "dry weight" determination in dialysis patients? Application of multifrequency bioimpedance measurement.

The article suggests a novel method for quantitative determination of optimal dry weight in dialysis patient based on their extracellular volume (ECV) to total body water (TBW) ratio and its relation to age. Values of ECV and TBW are evaluated by means of whole body multifrequency bioimpedometry. In an effort to find a suitable marker of hydration status in an individual from bioimpedance data, significant correlation has been found between ECV/TBW ratio and age in health. Assuming that all excess fluid in dialysis patients is stored exclusively in ECV and that distribution of their TBW at the state of optimal dry weight corresponds to that of a healthy person of the same age, the pre-dialysis ECV/TBW could be used for quantitative determination of optimal dry weight and/or of the ultrafiltration to reach this weight. Practical bioimpedance measurement of ECV/TBW in a group of dialysis patients both pre- and post-dialysis confirmed both above assumptions, i.e. nearly exclusively extracellular origin of ultrafiltration as well as normalisation of the ECV/TBW ratio towards the end of dialysis. Supporting evidence of increasing ECV/TBW value with age was also found in literature. Although the suggested method needs detailed analysis of possible disturbing factors (ethnic "specificity" of the reference ECV/TBW vs. age characteristics in health, possible difference in "biological" and "physical" age of dialysis patient and others), the article is published at this early stage to enable wider testing of the proposed novel method by different investigators.

Erythropoietin, an update, and where to in the future?

Recombinant human erythropoietin has been produced by genetic technology since 1985 and since then many clinical trials have repeatedly demonstrated its success in the correction of anaemia associated with renal failure. This paper discusses basic principles for its administration, potential side effects and strategies for non response to erythropoietin (Epo) therapy.

Erythropoietin and its use in renal failure.

Causative treatment of anaemia associated with renal failure with human recombinant erythropoietin (rHuEPO) represents undoubtedly one of the most exciting benefits in the complex therapeutic care of patients on maintenance dialysis. Ten years have passed since the first clinical experience with rHuEPO. At present, the number of patients on rHuEPO therapy has increased to more than 300,000 worldwide. All of us being involved in renal and dialysis care should have knowledge on how to deal with this drug, what its benefits are as well as its potential untoward effects and limits.

Vascular access monitoring evaluated from automated recirculation measurement.

Vascular access quality monitoring by means of vascular access blood flow (QVA) evaluated from automated thermodilutional measurement of recirculation with reverse needle position is described. This method provides significant advantages over conventional methods based on simple monitoring of pressures in the extracorporeal circuit and/or measurement of recirculation with normal needle position. AQVA evaluation protocol was developed and introduced into the system of primary nursing. The QVA values were found independent of the extracorporeal blood flow used during the recirculation measurement. QVA values from below 200 ml/min to over 2 l/min were seen. In general, lower values were found in diabetics compared to non-diabetics and in females compared to males. While blood flow below 600 ml/min is considered risky for synthetic vascular grafts, native AV-fistulae seem to remain stable and patent at a flow of 400 ml/min or even below. The method is able to detect erroneous needle placement in looped grafts, stenosis between needles, and is also well suited for effective evaluation of success/failure of interventions on access.