Effects of recombinant human erythropoietin on hematopoietic progenitors of chronic hemodialysis patients in vitro and in vivo

Erythroid progenitors were assayed in 20 chronic hemodialysis patients before and after administration of recombinant human erythropoietin (rhEpo) using a methylcellulose culture method. Hemoglobin concentrations, hematocrit values and the proportion of marrow erythroblasts increased significantly during rhEpo treatment. The numbers of erythroid progenitors (CFU-e and BFU-e) in the patients' marrow also increased following rhEpo administration. Our data suggest that rhEpo is an effective drug for treating anemia caused by chronic renal failure and the administration of rhEpo results in an increase in the numbers of erythroid progenitors.     

Polyamine concentrations in red cells and urine of patients with chronic renal failure

Spermidine and spermine concentrations were measured in 6 healthy subjects, 18 patients with chronic renal failure and 6 patients undergoing maintenance hemodialysis. In nondialyzed patients with advanced renal failure (serum creatinine levels greater than 6 mg %), red cell spermidine concentrations were significantly higher than in normal subjects (54.8±14.5 vs. 24.8±63 SD nmoles/ml packed cells). However red cell spermine concentrations were unchanged as compared to normal subjects (18.7±7.3 vs. 12.4±3.4 nmoles/ml packed cells). In patients with serum creatinine levels below 6 mg%, neither red cell spermidine or spermine concentrations were significantly different from normal subjects. There was a significant correlation between red cell spermidine values and both serum urea and serum creatinine levels, but no correlations were observed for red cell spermine. Red cell spermidine values were also significantly higher in patients undergoing maintenance hemodialysis than in normal subjects. In each patient, red cell spermidine concentrations were no different after a hemodialysis treatment than immediately prior to dialysis. In urine, excretion rates of polyamines as well as the precursor diamine, putrescine, were lower in patients with chronic renal failure than in normal subjects. Hence in renal failure, one factor contributing to the accumulation of spermidine in red cells would appear to be a decrease in the urinary excretion of polyamines.     

Studies of fibrinolytic activity of uremic and longterm hemodialytic patients with special reference to fibrinolytic inhibitor.

Fibrinolytic activities on cases with chronic renal failure, 13 cases at pre and post introduction of hemodialysis and 40 cases at pre and post hemodialysis of maintenance hemodialysis with 38 normal controls were investigated. The plasminogen activator of untreated chronic renal failure was lower than controls, yet increased with the introduction of hemodialysis. On the other hand the antiplasmin was lowered with the introduction. In cases with maintenance hemodialysis, the plasminogen activator was lower than controls, but was elevated with hemodialysis. The level of antiactivator was higher in uremia of either pre or post hemodialysis than controls. The levels of alpha 2-macroglobulin and alpha 1-antitrypsin were reduced at prehemodialysis state comparing to controls, and yet, increased with hemodialysis, respectively. The low molecular weight antiplasmin and antiactivator, molecular weight below 30,000 were separated with Sephadex G-50 gel filtration of plasma. The low molecular weight fibrinolysis inhibitors of plasma with untreated uremia were elevated comparing to controls, but decreased with the hemodialysis. The removable fibrinolytic inhibitors were indicated, however, the ratio of the low molecular weight fibrinolytic inhibitors to the total fibrinolytic inhibitors were little.     

Atrial natriuretic hormone secretion in patients with renal failure

To study the effects of volume overload and renal failure on plasma levels of immunoreactive atrial natriuretic hormone (IR-ANH), we measured levels of this hormone in normal subjects, in patients with advanced chronic renal failure (CRF) with and without clinically evident volume overload, and in patients with end-stage renal disease (ESRD) treated with chronic hemodialysis. The levels were 13 +/- 2 pmol/l in normal volunteers, 77 +/- 24 pmol/l in patients with CRF without volume overload, and 219 +/- 50 pmol/l in patients with CRF and clinically evident volume overload (analysis of variance, p less than 0.001, alpha = 0.05 compared to normals). In patients with ESRD, the levels of IR-ANH were 145 +/- 46 pmol/l before dialysis and decreased to 87 +/- 31 after dialysis (p less than 0.025). No correlation was found between the decrease in IR-ANH levels and the decrease in weight during dialysis. A significant positive correlation was found between the IR-ANH levels and blood urea nitrogen in patients with CRF (r = 0.658, p less than 0.01). Volume overload appears to be the most important stimulatory factor for ANH secretion in renal failure patients but other mechanisms, especially a decrease in metabolic clearance, may also contribute to elevated plasma levels. The increased secretion of ANH in patients with renal failure may be an important adaptive response to volume overload and hypertension.     

Erythropoietin: current status

Understanding the regulation of red blood cell production has been greatly enhanced by the cloning and expression of the gene for human erythropoietin (Epo) and its receptor. The availability of recombinant human erythropoietin (rhEpo) for administration to patients has ushered in a new era in molecular medicine. Intravenous or subcutaneous administration of rhEpo can reliably cure the anemia of chronic renal failure and may be effective in the treatment of anemias secondary to chronic inflammation, malignancy, and marrow suppression from chemotherapy. In addition, rhEpo therapy will probably play a prominent role in transfusion medicine, both in preparing patients for auto-transfusions as well as in minimizing red cell transfusion requirements in the post-operative period.     

Increased plasma ghrelin levels in chronic renal failure are not associated with hemodynamic parameters.

BACKGROUND/AIMS: Hardly anything is known about the effect of renal function on plasma ghrelin levels. Ghrelin is an orexigenic hormone with important hemodynamic effects. We examined differences in plasma ghrelin levels between chronic renal failure (CRF) patients and healthy subjects, and ghrelin's relationship with indices of left ventricular (LV) function. METHODS: Fasting total plasma ghrelin levels were measured in 122 CRF patients (57 on, 65 not on hemodialysis) and 57 control subjects. Indices of LV function were evaluated using echocardiography. RESULTS: Total plasma ghrelin levels were higher in patients with CRF compared to controls, but were not different between patients on and those not on hemodialysis. In a multivariate linear regression model, presence of kidney dysfunction explained 41 % of the variability of ghrelin values. The etiology of renal failure (diabetic nephropathy or not) had no influence on ghrelin levels in the renal patients. Ghrelin levels were not associated with indices of LV systolic function or blood pressure in these patients. CONCLUSION: Fasting plasma ghrelin concentrations are higher in CRF patients regardless of their need for hemodialysis compared to controls. The etiology of renal failure does not have any effect on plasma ghrelin levels. In addition, ghrelin levels are not associated with hemodynamic parameters in patients with CRF.     

Dopamine control of aldosterone secretion in end-stage renal failure

The role of the tonic inhibitory effect of dopamine on aldosterone secretion has been investigated in 10 patients with chronic renal failure (CRF) on hemodialysis, in 8 normotensive renal transplant recipients (Tx) with normal renal function and in 8 normotensive volunteers (NV). The following tests were performed: the response of plasma aldosterone (PA) to metoclopramide administration; the response of plasma prolactin (PRL) to TRH administration, and the changes induced by Lisuride (a dopaminergic agonist, on the values of PA and PRL). The basal values of PA and PRL were higher in CRF than in NV and Tx. The inverse was true for plasma renin activity (PRA) values. The response of PA and PRL to metoclopramide showed blunted increases in CRF when compared to NV, in the absence of changes of PRA, cortisol and potassium. After TRH administration, PRL increase in CRF was also inferior. Lisuride induced a decrease of both PA and PRL both in CRF and NV. In Tx, basal values of PA and PRL were similar to NV. Nevertheless, the response to metoclopramide and TRH were partially blunted when compared to that of NV. These results point to the existence of a deranged dopaminergic regulation of aldosterone secretion in end-stage renal failure patients. The alterations are partially corrected by a well-functioning kidney graft.     

Implications for the role of endogenous nitric oxide inhibitors in hemodialysis hypotension

Hypotensive episodes during hemodialysis in patients with end-stage renal disease in the absence of inadequate maintenance of the plasma volume, preexistence of cardiovascular disease, or autonomic nervous system dysfunction is accompanied by increase in the plasma concentrations of the end-products of nitric oxide metabolism, above the levels expected based on the reduction of urea. Factors that can influence the synthesis of nitric oxide or the regulation of the effects of this free radical in patients with chronic renal failure are reviewed. Convergence of these factors and their interactions during the hemodialysis procedure are discussed as the basis for the generation of excessive amounts of nitric oxide that serves as an important contributing factor in the development of symptomatic hypotension.     

Changes in HDL-cholesterol, subfractions HDL2 and HDL3 and apo-A, apo-A1 and apo-B lipoproteins in patients with chronic renal failure subjected to maintenance hemodialysis

Hyperlipoproteinemia was found in 200 patients affected by chronic renal failure on maintenance hemodialysis, due to increase in Total Cholesterol, VLDL-TG, LDL, TG, LDL and VLDL. In 30 of these patients, the analysis was extended to the dosing of decreased Total Serum HDL-Cholesterol, HDL2, HDL3, Apoprotein A and Apoprotein A1 values, and of increased Apoprotein B values. These findings further contribute to proving accelerated atherogenesis in the patients examined.     

Vasopressor challenges during chronic MAOI or TCA treatment in anesthetized dogs

Ten male mongrel dogs were treated in Phase I with tranylcypromine, 6 mg/kg IM b.i.d., for 21 days. Dogs were anesthetized at weekly intervals before, during, and up to four weeks after drug treatment with a combination of amylbarbital, 25 mg/kg, 1% enflurane in 70:30 N₂0:0₂) and fentanyl, 500 mcg. Bolus IV injections of norepinephrine, 0.1–0.6 mcg/kg, and ephedrine, 0.03–0.12 mg/kg were given while continuously recording arterial blood pressure, lead II of the ECG, heart rate, and rectal temperature. Awakening times were noted. In Phase II, the dogs were given imipramine, 25 mg/kg IM b.i.d., for 21 days. During Phase III, 14 days of tranylcypromine, 7 days of tranylcypromine plus imipramine, and 7 days of imipramine were administered. Anesthetic techniques were repeated in phases II and III. The fourth phase consisted of tranylcypromine injections, 6 mg IM b.i.d., and anesthesia with amylbarbital 25 mg/kg, 2.5% enflurane in 70:30 N₂0:0₂. Vasopressor challenges were repeated during each phase of the study. Following induction of anesthesia and prior to fentanyl challenge, baseline blood pressures and heart rates did not differ from control in Phase I, II, and III of this study. Responses to norepinephrine during all of the tranylcypromine phases were not significantly different from control but ephedrine responses were prolonged, peaking by the second week of treatment. During Phase II, dysrhythmias occurred following norepinephrine and ephedrine with one lethality following norepinephrine, 0.2 mcg/kg. Responses to norepinephrine and awakening times were significantly greater during Phase II compared to Phase I. In Phase III, during the first week of combined therapy the responses to norepinephrine were significantly greater than any other week of this phase. During Phase IV, resting blood pressure and the ephedrine responses were significantly increased during tranylcypromine when the anesthesia regimen did not include fentanyl. These results suggest that during initial treatment with tranylcypromine or imipramine, cardiovascular responses to vasopressor challenges were predicted by the pharmacology of the antidepressant. During tranylcypromine phases, we did not observe exaggerated cardiovascular effects during anesthesia and vasopressor challenges as had been previously reported.

The use of monoamine oxidase inhibitors (MAOIs), alone or in combination with tricyclic antidepressants (TCAs), has been increasing over the last few years because they appear to be more effective than TCAs alone in treating resistant affective disorders. (1,2) However, reluctance to use MAOIs has persisted because of reports of interactions with various foods and drugs. (3–6) In recent years, cell membrane receptor studies have shown that chronic treatment (greater than 14 to 21 days) with either MAOIs of TCAs results in physiological adaptations that partially reduce the interactions between drugs and their receptors. (7,8) Attenuation of arrhythmogenicity has been described in dogs after six weeks of TCA treatment. (9) Clinically, patients on chronic MAOI therapy have undergone elective surgery, including open-heart surgery, without adverse responses. (10,11) The cardiovascular response to analgesics, anesthetics, and vasopressors during the initial phase (less than 14 to 21 days) of treatment with MAOIs compared to TCAs has yet to be addressed. Therefore, the purpose of this study was to examine the cardiovascular responses of analgesic, anesthetic, and vasopressor agents before, during, and after the first three weeks of MAOI and TCA administration in dogs.     

Clinical estimation of 1-alpha-hydroxycholecalciferol in treatment of patients with chronic renal failure]

31 adult patients (15 male and 16 female) with chronic renal failure were treated for 6 months with 1-alfa-hydroxycholecalciferol on a dose 0.25-2.0 micrograms/24 h. 15 patients with not very advanced renal failure (serum creatinine level 176.8-442 mumol/l) received conservative therapy (group I), 16 patients with serum creatinine value 884-1326 mumol/l were treated by intermittent hemodialysis (group II). The statistically significant decrease of serum alkaline phosphatase activity in group I and II (p < 0.01), the rise of serum calcium level in group I (p < 0.005) were determined. Half of the patients from both the groups stated the relief or disappearance of bone and joint pains and muscle weakness. Besides in group I significant decrease of creatinine clearance (p < 0.001) and increase of serum urea and creatinine value (p < 0.01) were noticed. On the basis of these results we can conclude that the treatment with 1-alfa-hydroxycholecalciferol, produced by "Polfa", ought to be introduced gradually with increasing doses and frequent monitoring of calcium-phosphate metabolism and renal function parameters.     

Sibutramine plus meal replacement therapy for body weight loss and maintenance in obese patients

Objective: Our objective was to assess the efficacy and safety of sibutramine with a low‐calorie diet (LCD) and commercial meal‐replacement product in achieving weight loss and weight‐loss maintenance in obese patients. Research Methods and Procedures: Eight U.S. centers recruited 148 obese patients for a 3‐month comprehensive weight‐loss therapy (Phase I) comprising daily sibutramine 10 mg + LCD (two Slim‐Fast meal‐replacement shakes, one low‐calorie meal; total kcal/d = 1200–1500). Patients (N = 113) who lost ≥5% of initial body weight during Phase I were randomized for a 9‐month period (Phase II) to daily sibutramine 15 mg + LCD (one meal‐replacement shake; two low‐calorie meals: total kcal/d ～1200–1500) or daily placebo + three low‐calorie meals (total kcal/d ～1200–1500). Both phases included behavior modification. Efficacy was assessed by body weight change during each phase and by the number of patients at endpoint maintaining ≥80% of the weight they had lost by the end of Phase I. Other outcomes included changes in cardiovascular and metabolic risk factors, adverse events, and vital signs. Results: Mean body weight change during Phase I was ?8.3 kg (p < 0.001). Patients randomized to sibutramine in Phase II had an additional ?2.5 kg mean weight loss vs. a 2.8‐kg increase in the placebo group (p < 0.001). More sibutramine patients maintained ≥80% of their Phase I weight loss at the end of Phase II (85.5% vs. placebo 36.7%, p < 0.001). Most adverse events were mild or moderate in severity, and all serious adverse events were unrelated to sibutramine. Discussion: Sibutramine plus LCD with meal replacements and behavior modification is a safe and effective strategy for achieving and sustaining weight loss in obese patients.     

The anemia of chronic renal failure: in vitro response of bone marrow to erythropoietin.

Bone marrow cells of patients with chronic renal failure were studied in short-term in vitro cultures to determine erythropietin responsiveness. Seven normals and fourtheen patients on hemodialysis were studied. Bone marrow cells of normal subjects and of patients with chronic renal failure responded similarly to erythropoietin. Total heme synthesis was significantly lower in cultures prepared with uremic serum than normal serum. We conclude that there is a substance in the serum of uremic patients which suppresses general heme synthesis and that this "uremic toxin" may be responsible, in part, for the clinically severe anemia seen in these patients.     

Serum zinc concentrations in the maintenance hemodialysis patients

Zinc is necessary for growth and cells' division. Its deficiency may seriously affect antioxidant defense system and is usually related to renal failure, gastrointestinal diseases and alcoholism. It is very important to know zinc status in dialyzed patients and to prevent hypo- or hyperzincemia. Serum samples from 89 patients with chronic terminal renal failure on regular hemodialysis were withdrawn for the estimation of zinc concentrations immediately before and after dialysis. Serum zinc concentrations showed to be highly dependent on hemodialysis. In 57 (64%) patients, serum zinc concentrations decreased, sometimes from very high to normal values. In remaining 32 (36%) patients serum zinc concentrations tended to increase, but remained within normal range. Zinc supplementation may be recommended only in the patients with proven zinc deficiency, but for all chronic renal failure patients it is questionable.     

Utility of tumor marker CA 72.4 in patients with chronic renal failure.

The tumor marker CA 72.4 is composed of two monoclonal antibodies, B 72.3 and cc49, which detect the glycoprotein TAG 72 present in tumor cells. The levels of CA 72.4 may be modified depending on the route of excretion of the antigen TAG 72. The objective of this study was to evaluate the behavior of CA 72.4 in healthy subjects and to assess the influence of chronic renal failure (CRF) on the levels of this tumor marker. Random serum samples were collected in 181 individuals (148 healthy volunteers and 33 patients with CRF) and 214 determinations of CA 72.4 were performed. We also performed 66 determinations of plasma creatinine. In healthy subjects the cutoff value of CA 72.4 was established at 3 U/mL, with a sensitivity of 53% and a specificity of 85.8%. In the CRF patients we found no statistically significant differences when we compared the values of CA 72.4 predialysis and postdialysis (p = 0.197). However, a statistically significant difference was found in the plasma creatinine levels (p < 0.001). Chronic renal failure does not affect the result of CA 72.4 determinations; this tumor marker may therefore be useful in the monitoring of patients with cancer, independent of their renal function.     

Effects of atrial natriuretic peptide infusion and its metabolism in patients with chronic renal failure.

Synthetic alpha-human atrial natriuretic peptide (hANP) was infused continuously at a rate of 80 ng/kg/min for 20 min into normal volunteers and patients with chronic renal failure (CRF) receiving hemodialysis. Blood pressure (BP) decreased significantly both in normals and in patients with CRF. The magnitude and the duration of the decrease, however, were greater in patients with CRF. The plasma aldosterone concentration (PAC) decreased significantly in normals and only minimally in patients with CRF. The half time (T1/2) of plasma hANP in patients with CRF (M +/- SE: 4.5 +/- 0.5 min) was longer than that in normals (1.8 +/- 0.2 min). Moreover, the metabolic clearance rate in patients with CRF (64 +/- 7 ml/kg/min) was less than in normals (150 +/- 20 ml/kg/min). Thus, the T1/2 in plasma of hANP in patients with CRF was noticeably longer than in a normal control group. These findings suggest that hANP suppresses PAC regardless of electrocyte imbalances and/or volume change induced by kidney dysfunction and that the kidney may be important in degrading hANP.     

Bone marrow blood formation and iron stores in patients with chronic renal failure on maintenance hemodialysis

Iron stores, ferrokinetics and total bone marrow cellularity were determined in 35 hemodialysis patients. Some of the patients received hemotransfusions (group I), the others (group II) androgens and iron supplements. In group I the blood losses amounted to 23.9 +/- 2.4 ml/d, in group II to 7.7 +/- 0.5 ml/d. Serum iron and ferritin levels exceeded the normal values. Iron stores were 0.31 +/- 0.07 mg/100 mg (group I) and 0.25 +/- 0.05 mg/100 mg /100 mg (group II), whereas the normal values are 0.18 +/- 0.02 mg/100 mg desferrioxamine. Total bone marrow cellularity in patients of group I amounted to 8.3 +/- 2.3 . 10(9) cells/kg, and in group II to 27.4 +/- 3.2 . 10(9) cells/kg, while the normal values are 14.1 +/- 1.4 . 10(9) cells/kg. Hemotransfusions suppress considerably ferrokinetic indexes in dialysis patients. In massive blood losses hemotransfusions are the therapy of choice for the anemia, but they suppress blood formation. to correct iatrogenic blood losses, iron and androgens may be administered thus stimulating blood formation.     

The effects of peritoneal dialysis and hemodialysis on serum tumor necrosis factor-alpha, interleukin-6, interleukin-10 and C-reactive-protein levels

BACKGROUND: Markers of an acute phase reaction, such as C-reactive protein (CRP) or tumor necrosis factor-alpha (TNF-alpha) and interleukin (IL)-6, are predictive for cardiovascular morbidity and mortality in normal subjects and in chronic renal failure patients. In this study, we aimed to investigate serum TNF-alpha, IL-6, IL-10 and CRP levels in continuous ambulatory peritoneal dialysis (CAPD) and hemodialysis (HD) patients. MATERIALS AND METHODS: Serum levels of TNF-alpha, IL-6, IL-10 and CRP levels were measured in 30 patients who were just diagnosed with end-stage renal failure and treated, with 16 CAPD (nine female, seven male) and 14 HD (eight female, six male) patients, before CAPD or HD treatment and after 3 months from the beginning of CAPD or HD in patients with no clinical signs of infection. The control groups were 20 healthy persons of similar age and sex. Serum levels of TNF-alpha, IL-6, IL-10 and CRP were measured by enzyme-linked immunosorbent assay in stable CAPD and HD patients and in healthy persons. RESULTS: The mean serum levels of TNF-alpha, IL-6, IL-10 and CRP showed no significant differences between the CAPD and HD patients for the beginning values and the third month of treatment. However, serum TNF-alpha, IL-6, IL-10 and CRP levels were higher than the control group in the CAPD and HD patients regarding the beginning values and the third month of treatment (p < 0.001). CONCLUSIONS: CAPD and HD of the renal replacement therapy have no effects on serum CRP and cytokines.     

甲状旁腺激素水平对慢性肾衰竭患者维持性血液透析期间机体营养的影响

目的:探讨慢性肾衰竭(CRF)维持性血液透析患者血清甲状旁腺激素(PTH)水平与机体营养状况的关系。方法:选择2013年8月-2015年10月我院收治的慢性肾衰竭行维持性血液透析治疗的患者98例作为研究组,另选择同期接受健康体检的志愿者69例作为对照组。采用放射免疫法检测两组患者血清甲状旁腺激素(PTH)及血清学指标。采用微型营养评定法(MNA)评价两组患者营养状况;利用Spearman相关分析方法评价血清PTH与相关血清生化指标的相关性。结果:研究组营养不良发生率(31.63%)明显高于对照组(13.04%),差异具有统计学意义(P0.05)。研究组营养不良患者血清PTH,HDL-C,LDL-C,CRP,BUN及SCr水平均高于潜在营养不良和营养正常者,而血清TP,ALB,TC,TG及Hb均低于潜在营养不良和营养正常者(P0.05)。潜在营养不良患者血清PTH,HDL-C,LDL-C,CRP,BUN及SCr水平均高于营养正常者,而血清TP,ALB,TC,TG及Hb均低于营养正常者(P0.05)。慢性肾衰竭患者血清PTH与MNA,TP,TC,TG,CRP以及Hb呈负相关关系(P0.05);与BUN,SCr呈正相关关系(P0.05);与ALB,HDL-C,LDL-C无明显相关性(P0.05)。结论:CRF患者并发营养不良的发生率较高,血清PTH水平与机体营养状况存在一定相关性,临床应予以重视。     

The effect of recombinant human erythropoietin on serum selenium levels in hemodialysis patients

Successful results in the treatment of anemia, one of the main complications of chronic renal failure, can be achieved by the use of recombinant human erythropoietin (RhEPO), which is available almost fifteen years in clinics. On the other hand, as both chronic renal failure and maintenance hemodialysis reduce the levels of trace elements, this study was designed to evaluate the interaction potential of RhEPO with serum concentrations of selenium (Se) during four months. Thirty one adult hemodialysis outpatients participated in the study. Ten of them, not on any drug therapy to interact with RhEPO, recruited as “Control Group”, and the remainder, on RhEPO therapy, as “RhEPO Group”. Blood was drawn from the Control Group at the beginning of the study, and from the RhEPO Group at every month for four months. Serum erythropoietin levels were measured by a radioimmunoassay method and Se status by a spectrofluorometric method. It was found that Se levels were not affected by RhEPO treatment during 3 months of therapy, while an increase was seen on the fourth month. The observation indicates that the increase in serum Se levels would be significant in longer than three-month RhEPO treatment.