In vivo effects of recombinant human erythropoietin on bone marrow hematopoiesis in patients with chronic renal failure

Studies of hemopoietic progenitors and precursors in bone marrow before and after two months of recombinant human erythropoietin (rhEpo) therapy in 12 patients with uremic anemia are the subject of this investigation caried out in order to have a better insight into the effect of Epo in vivo. Eight patients were on hemodialysis and four others were predialysis patients with chronic renal failure. The starting dose of rhEpo was 30-50 U/kg bw and was increased by 50 percent every four weeks. The mean hemoglobin values rose from 6.08 +/- 1.03 to 9.8 +/- 1.98 g/dl at the time of study. The number of bone marrow derived erythroid colonies, both early (BFU-E) and late (CFU-E) were found to be higher than subnormal values, found before the therapy. The percentage of erythroid progenitors in cell cycle increased to higher than normal values for BFU-E and to normal values for CFU-E. At the same time granulocytic progenitors (CFU-GM) decreased to the range of normal values (67.3 per 10 superset5 cells). Slightly increased Epo levels (approx. 30mU/ml) during the replacement therapy were optimal for correction of anemia. The rhEpo therapy induced an increase of percentage of erythroblasts and the decrease of myeloid to erythroid ratio (M/E) in the bone marrow. Only in predialysis patients in whom the target hemoglobin values were achieved by rhEpo therapy at the time of the study the percentage of erythroblasts in the bone marrow increased to normal values. Increase of erythroblasts in bone marrow in patients under two months of substitutive therapy with rhEpo with the increase of both, early and late erythroid progenitors we have observed, is significant indicating the stimulative effect of rhEpo on all subsets of erythropoiesis leading to normalization of erythropoiesis at all levels. No stimulative effect of rhEpo replacement therapy on granulopoiesis was observed.     

Management guidelines for progressive chronic renal failure. New Zealand Nephrologists Consensus Group

Consensus guidelines are provided for the conservative management of adult patients with chronic and progressive renal failure, together with a brief review of the evidence relating to various treatable complications. Blood pressure control, diet, hyperlipidaemia, calcium and phosphate metabolism, anaemia and acidosis are considered.     

Treatment of anemia in patients with chronic renal insufficiency with recombinant human erythropoietin

The discovery of recombinant human erythropoietin has enabled treatment of anaemia in patients whose anaemia was primarily caused by the lack of erythropoietin. This agent was most widely used in the treatment of anaemia in chronic renal failure patients. Non-regulated hypertension is considered to be the only absolute contraindication for recombinant human erythropoietin application, but thrombocytosis, predisposition to thromboses of arterio-venous fistulae, and convulsions are regarded as relative contraindications. Recombinant human erythropoietin may be administered intravenously, but the subcutaneous route is considered more rational. The treatment is initiated by low doses with gradual dose increase, what enables gradual anaemia correction and prevents the appearance of adverse effects. Haemoglobin level of around 100 g/l is considered the target haemoglobin level. The majority of patients respond well to treatment by human recombinant erythropoietin and the absence of anaemia improvement may be the result of iron deficiency, occult haemorrhages, chronic infection, inadequate dialysis, secondary hyperparathyroidism, aluminium intoxication. Anaemia improvement during the treatment with recombinant erythropoietin leads to the improvement of function of most organs and the quality of life in general as well as avoidance of blood transfusions and their adverse effects. The most frequent adverse effect of recombinant erythropoietin is the development of iron deficiency or hypertension aggravation.     

Influence of long-term human recombinant erythropoietin treatment on secretion of pancreatic polypeptide and gastrin in hemodialysed patients with chronic renal failure

The study aimed to assess the influence of long-term rhu-EPO treatment on secretion of pancreatic polypeptide (PP) and gastrin. A total of 27 haemodialysed patients and nine healthy subjects were examined. Nine patients with uraemic anaemia were treated with rhu-EPO for 12 months (EPO group), while another nine patients did not receive rhu-EPO (non-EPO group), but were monitored biochemically and clinically as patients of the EPO group. The third group (HD) comparised nine haemodialysed patients with a haematocrit value > or = 30% without rhu-EPO therapy. In all subjects plasma levels of PP and gastrin were estimated before and after administration of a test meal. Patients of the EPO and non-EPO group were examined before and after 6 and 12 months of rhu-EPO therapy (EPO group) or clinical monitoring (non-EPO group) respectively, while only one test was performed in patients of the HD group and healthy subjects. Six months rhu-EPO therapy was followed by an decrease of basal plasma level of PP and increased response of gastrin to the test meal. After 12 months of rhu-EPO therapy basal plasma level of PP was still lower, the response of PP secretion to a test meal was higher, while that of gastrin secretion lower that the pretreatment ones. Our results suggest, that rhu-EPO treatment exerts effect on secretion of PP and gastrin. These alterations seem not to be related to improvement of the haematological status.     

Nutritional intervention and growth in children with chronic renal failure

During fifties there were at most few tens of persons in this country who believed in the future of computers and cybernetics. One group of such enthusiasts, headed by Antonín Svoboda, was working at a construction of the first Czech computer SAPO. The other group tried to analyse, anticipate, and prepare in advance various applications for the new systemic conceptions and for the information processing machines. Members of both groups met for discussions which opened prospects to the future and influenced many of other activities for a long time. At the early sixties, the Czechoslovak Cybernetic Society was established at the Czechoslovak Academy of Sciences and in 1962 the Main Problem Committee for the Medical Cybernetics was founded at the Department of Health. It coordinated majority of the research programmes in the medical cybernetics and informatics. In 1967-1969 the Committee prepared an extensive project of a medical information system (ZIS), but its accomplishment was finally blocked by the then authorities. However, interests for that topics kept growing and the new working places equipped with available computer technology were formed at the health and clinical centres. The first tentative lectures in medical cybernetics and biocybernetics at our faculty were introduced into the students curricula in the late sixties. Thematically, medical cybernetics subsequently differentiated into the medical informatics, simulations of biological and medical systems, and the biosignal analysis. The growing interest enabled to hold conferences since the middle of seventies, some of which were held periodically, sometimes with international participation. It is not possible in brevity to include the whole spectrum to those goal-directed activities nor to appraise adequately their future significance.     

Quantitative bone histology in children with chronic renal failure

Quantitative bone histology (on undecalcified sections following double tetracycline labeling), radiographs, and biochemistry were studied in 47 children, ages 1 to 17 years, with glomerular filtration rates (GFR) below 80 ml/min/1.73m2. The earliest histologic change was an increased osteoid surface accompanied by increased osteoblast and tetracycline surfaces. However, significant bone disease (increased osteoclastic surface, fibrosis, increased osteoid area, increased mineralization lag time, and reduced tetracycline uptake at osteoid surfaces) occurred only at GFR below 30 ml/min/1.73m2. Radiographs and alkaline phosphatase were normal in 25% of children with significant bone disease; parathyroid hormone was increased in 48% of children without bone disease. Thus, these noninvasive investigations were poor predictors of disease presence. GFR was the most sensitive indicator because bone disease occurred only at GFR below 30 ml/min/1.73m2 and was present in all children with GFR below 20 ml/min/1.73m2. It was concluded that bone histology is required for early detection of bone disease and is an essential tool in experimental studies of renal osteodystrophy. However, because the level of GFR will indicate the presence or absence of bone disease in most children, bone biopsy can be avoided generally in clinical practice.     

Use of recombinant human erythropoietin for management of anemia in dogs and cats with renal failure

Green fluorescent protein (GFP) from Aequorea victoria has rapidly become a standard reporter in many biological systems. However, the use of GFP in higher plants has been limited by aberrant splicing of the corresponding mRNA and by protein insolubility. It has been shown that GFP can be expressed in Arabidopsis thaliana after altering the codon usage in the region that is incorrectly spliced, but the fluorescence signal is weak, possibly due to aggregation of the encoded protein. Through site-directed mutagenesis, we have generated a more soluble version of the codon-modified GFP called soluble-modified GFP (smGFP). The excitation and emission spectra for this protein are nearly identical to wild-type GFP. When introduced into A. thaliana, greater fluorescence was observed compared to the codon-modified GFP, implying that smGFP is 'brighter' because more of it is present in a soluble and functional form. Using the smGFP template, two spectral variants were created, a soluble-modified red-shifted GFP (smRS-GFP) and a soluble-modified blue-fluorescent protein (smBFP). The increased fluorescence output of smGFP will further the use of this reporter in higher plants. In addition, the distinct spectral characters of smRS-GFP and smBFP should allow for dual monitoring of gene expression, protein localization, and detection of in vivo protein-protein interactions.     

Summer camp hemodialysis for children with chronic renal failure

A hemodialysis unit was established at a rural summer camp for children. Required medical treatment was planned so as to interfere as little as possible with normal camp programs. Campers who require dialysis were mixed fully into the population of normal campers. Twenty-two children participated during the first summer of operation. Our experience indicates that children on maintenance hemodialysis can be integrated with normal peers in a recreational program and can improve their self-image and self-confidence. The program also demonstrates that chronic pediatric hemodialysis can be safely performed in a rural satellite unit.     

Renal histopathology in fatal cases of diarrhoea-associated haemolytic uraemic syndrome. British Association for Paediatric Nephrology

We report on a 32-year-old atopic female office employee with a moderate tree pollinosis who also suffered from indoor-related perennial rhinoconjunctivitis. Once when she repotted her two ornamental nonflowering green plants of the genus Tradescantia (synonym; Albifloxia; family Commelinaceae), she immediately experienced itching of the face, throat, and conjunctiva; swelling of the lips; and dyspnea and wheezing. Skin prick tests with the leaves of Tradescantia (T. albifloxia and T. fluminensis) (Ta and Tf) were strongly positive as was the specific IgE to Ta leaves extract. On RAST inhibition studies, no cross-reactivity was found between Ta and Ficus benjamina (weeping fig), a nonflowering green plant, which produces, in its milky sap, an important respiratory allergen. Green plants should be considered potential indoor allergens and tested in plant-keepers referred for allergologic investigation.     

Lipoprotein (a) in children with chronic renal failure treated conservatively

The aim of this study was to evaluate serum lipid abnormalities, particularly lipoprotein (a), [Lp(a)] as an independent risk factor for cardiovascular disease in children with mild and moderate renal failure. Study were performed on 14 children of whom serum creatinine levels were above 265.3 mumol/l and 32 patients with serum creatinine levels below 265.3 mumol/l. Control group consisted of 27 healthy age-matched subjects. All children were tested for concentration of serum Lp(a), total cholesterol (TC), triglycerides (TG), low density lipoprotein cholesterol (C-LDL) and high density lipoprotein cholesterol (C-HDL). It was found a significantly increase in Lp(a), TC, C-LDL and significantly decrease in C-HDL in children with more advanced renal insufficiency compared to the control. In children with mild renal failure concentration of serum Lp(a) also increased but not significantly. Patients in this group had elevated serum TC and decreased C-HDL. These results suggest that even in the early stages of renal insufficiency in children abnormalities of lipoprotein are present. Such abnormalities, particularly Lp(a) might contribute to accelerated atherosclerosis in this patients.     

Providing the right stuff: feeding children with chronic renal failure

The progressive loss of renal function in children with chronic renal failure (CRF) has a negative influence on their nutritional status and statural growth. Supportive therapies with 1-25 dihydroxy-vitamin D3, recombinant erythropoietin and growth hormone have significantly improved the biochemical and clinical features but the success of these therapies is largely related to an appropriate diet, with adequate protein/caloric intakes. Children more than adults have minimal protein requirements to avoid malnutrition and growth impairment FAO/WHO and RDA recommendations save as guidelines for a correct diet in children with CRF. Following these allowances leads to a "normoproteic" diet, with a protein intake which is often half the unrestricted one in Western European countries, but which is still likely to be not enough to protect against renal deterioration. Indeed the European Study Group for Nutritional Treatment of CRF in children failed to show a significant effect of diet on the mean decline of glomerular filtration rate over two years.     

Insulin-like growth factor-binding protein-6 levels are elevated in serum of children with chronic renal failure: a report of the Southwest Pediatric Nephrology Study Group

Previous studies suggest that growth retardation in children with chronic renal failure (CRF) results in part from inhibition of insulin-like growth factor (IGF) action by excess serum IGF-binding proteins (IGFBPs). Excess IGFBPs in CRF serum include IGFBP-1, -2, and -3 and a diffuse approximately 24- to 28-kDa IGFBP band identified by [125I]IGF ligand blot. The present studies characterized this diffuse approximately 24- to 28-kDa band. Initial studies identified this band as IGFBP-6, because it was immunoprecipitated by antiserum raised against a synthetic peptide of human IGFBP-6 (hIGFBP-6). Additional [125I]IGF ligand blots found that the immunoprecipitated band was 1) recognized by [125I]IGF-II but not [125I]IGF-1, 2) more abundant in CRF than in normal serum, and 3) more abundant in serum from dialyzed than nondialyzed prepubertal CRF children. Using the hIGFBP-6 antiserum in a specific and sensitive RIA, we found that serum IGFBP-6 levels were 4.7 +/- 1.7 nmol/L in 10 normal prepubertal children, 21.4 +/- 6.1 nmol/L in 44 nondialyzed prepubertal CRF children, 73.5 +/- 14.4 nmol/L in 7 dialyzed prepubertal CRF children, and 94.6 +/- 26.2 nmol/L in 14 dialyzed pubertal CRF children. IGFBP-6 levels were also elevated in 71 nondialyzed European children with CRF. In nondialyzed CRF children, serum IGFBP-6 levels 1) correlated inversely with the glomerular filtration rate, 2) did not correlate with height SD score, and 3) were not altered by 12 months of daily recombinant hGH treatment. In summary, a specific antiserum and RIA were used to demonstrate elevated levels of intact IGF-II-binding IGFBP-6 in serum of CRF children. We postulate that the excess IGFBP-6 may modulate the action of IGF-II on target tissues.     

Effect of enteral feeding on lipid subfractions in children with chronic renal failure

Both the US FDA and EU guidelines recommend fundamental procedures for bioavailability and bioequivalence studies. The use of unacceptable procedures in conducting these studies can in fact complicate drug development at NDA or ANDA levels. The most common unacceptable procedures are as follows: the use of compartmental analysis in calculating Cmax, tmax and AUC, which must be evaluated with the non-compartmental approach in pivotal studies; the need to use only homogeneous concentrations in pharmacokinetic analysis, and to avoid using the sum of various individual concentrations, e.g. parent drug plus metabolite(s); the need to consider plasma clearance in evaluating absolute bioavailability with dose-dependent kinetics; the need to use the simultaneous fitting procedure when drugs and metabolite(s) are considered; the unacceptable procedure of either disregarding some experimental data or adding simulated data in pharmacokinetic and statistical analysis; and the use of the additive model rather than the multiplicative procedure in assessing bioequivalence with Cmax and AUC. This paper describes in detail acceptable and unacceptable procedures in bioavailability and bioequivalence studies, covering operating guidelines and principles of pharmacokinetics. (c) 1998 The Italian Pharmacological Society.     

Effect of chronic renal failure on the expression of erythropoietin message in a murine model

The anemia of chronic renal failure (CRF) is largely due to decreased production of erythropoietin (EPO) by the kidney. A small amount of EPO also originates from extra-renal sources, and this would be expected to assume a more important role in maintaining erythropoiesis when renal production is impaired. In this study, we examined the production of EPO mRNA by RT-PCR in kidney, liver, and bone marrow tissues isolated from normal mice, mice rendered acutely anemic by phlebotomy, and from mice with surgically induced CRF. The induction of acute anemia results in an expected increase in the expression of EPO mRNA in renal and hepatic tissue. In contrast, while the expression of EPO mRNA was expectedly reduced in the kidney from CRF mice, it was completely absent in the liver of these same animals. EPO mRNA expression was also absent in the bone marrow in both states of acute anemia and CRF. These results show that CRF can directly or indirectly can suppress the extrarenal production of EPO by the liver and that this effect may further aggravate the anemia of CRF.