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In many types of cardiovascular pathophysiology such as hypercholesterolemia and atherosclerosis, diabetes, cigarette smoking, or hypertension (with its sequelae stroke and heart failure) the expression of endothelial NO synthase (eNOS) is altered. Both up- and downregulation of eNOS have been observed, depending on the underlying disease. When eNOS is upregulated, the upregulation is often futile and goes along with a reduction in bioactive NO. This is due to an increased production of superoxide generated by NAD(P)H oxidase and by an uncoupled eNOS. A number of drugs with favorable effects on cardiovascular disease upregulate eNOS expression. The resulting increase in vascular NO production may contribute to their beneficial effects. These compounds include statins, angiotensin-converting enzyme inhibitors, AT1 receptor antagonists, calcium channel blockers, and some antioxidants. Other drugs such as glucocorticoids, whose administration is associated with cardiovascular side effects, downregulate eNOS expression. Stills others such as the immunosuppressants cyclosporine A and FK506/tacrolimus or erythropoietin have inconsistent effects on eNOS. Thus regulation of eNOS expression and activity contributes to the overall action of several classes of drugs, and the development of compounds that specifically upregulate this protective enzyme appears as a desirable target for drug development.
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PMID:Regulation of endothelial-type NO synthase expression in pathophysiology and in response to drugs. 1238 13

In this review the authors present data on biological and medical properties and high therapeutic efficacy of recently produced recombinant drugs of alfa and beta erythropoietin in the treatment of erythropoietin-deficient anaemia in patients with malignancies, diabetes mellitus, and nephropathies of other genesis. The article contains materials of international congresses held in 2001 addressing the above issues besides the newest publications.
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PMID:[Biological and therapeutic properties of erythropoietin]. 1266 61

Prevalence of cardiovascular disease is high in diabetic patients on renal replacement therapy (RRT); therefore we examined the role of diabetes mellitus on determining the degree of coronary artery stenosis. Twenty-five patients underwent coronary angiography, 12 were awaiting kidney transplantation and the examination was performed regardless of cardiac symptoms, 13 were affected by ischaemic heart disease (IHD). Diabetic and nondiabetic status together with the other risk factors for cardiovascular disease such as age, sex, length of time on RRT, smoking and elevated phosphorus levels history, clinical diagnosis of IHD, cerebrovascular and peripheral vascular disease, mean blood pressure, cholesterol, triglycerides, calcium, phosphate, albumin, haemoglobin, haematocrit and weekly dose of erythropoietin were derived from clinical records. All investigated parameters were matched in diabetic (group 1, n=10) and nondiabetic patients (group 2, n=15) and showed no differences. Clinical evidence of IHD was detected in 80% of patients in group 1 and 46% in group 2 and the percentage of patients on the renal transplant waiting list was not statistically different in the two groups (30 vs 60%). In 60% of patients in group 1 there were 3 or more stenotic lesions equal or greater than 75% of normal reference segment in the major coronary arteries, whilst in 53% in group 2 there were no haemodynamically significant narrowings. Narrowing percentage of the coronaries in group 1 and 2 were: right coronary artery 83 +/- 30 vs 32 +/- 41 (p<0.05), left anterior descending artery 80 +/- 25 vs 44 +/- 34 (p<0.05), left circumflex artery 46 +/- 37 vs 18 +/- 29 (p=0.05) respectively. Our study confirms that IHD is a clinical feature of uraemic diabetic patients and that diabetes is the main cardiovascular risk factor for determining the degree of coronary stenosis.
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PMID:Relationship between diabetes mellitus and degree of coronary artery disease in uraemic patients investigated with coronary angiography. 1270 84

In December of 1999 and 2000 we visited all hemodialysis centers of Lithuania and collected data about all hemodialysis patients, using special questionnaires. The aim of the study was to evaluate the relationship between lethality of hemodialysis patients, erythropoietin dosage for renal anemia treatment and hemodialysis quality. The patients with higher Kt/V, higher levels of iron and albumin, normal levels of phosphorus and parathyroid hormone (PTH) requested lower doses of erythropoietin (analysis of the patients who were on hemodialysis in 2000 more than 6 months). So, we can conclude that adequate hemodialysis procedure and good management of hemodialysis patient are leading to the decrease request of erythropoietin doses for anemia treatment. We compared two groups of patients in order to examine relationship between hemodialysis quality and lethality of hemodialysis patients. We selected incident patients registered in December of 1999 and we divided these patients in December of 2000 in two groups: a) 175 patients, who continued hemodialysis treatment and b) 41 patients, who died in 2000. The results revealed, that dead patients were elder, their duration of weekly hemodialysis was shorter, Hb concentration lower, they had worse nutritional status (blood albumin level was lower). Lethality was associated with underlying diseases such as diabetes, hypertensive nephropathy and renal amyloidosis.
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PMID:[Relationship between lethality of hemodialysis patients, erythropoietin dosage for renal anemia treatment and hemodialysis quality]. 1276 33

In a patient with chronic renal failure due to diabetes mellitus pure red-cell aplasia developed during treatment with erythropoietin (epoetin alfa). The treatment with erythropoietin was stopped and immunosuppressive therapy resulted in normalisation of the bone marrow function and increase of the Hb level to normal values. Pure red cell aplasia which develops during treatment with erythropoietin has recently been reported in a few other patients with anaemia due to chronic renal failure. Hitherto our patient is the first case reported in Denmark.
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PMID:[Pure red cell aplasia developed during treatment with erythropoietin. Complete remission during immunosuppressive therapy]. 1279 77

Nephrological work in China started in early 60s, but it was not until the middle of the 1980s before it became an independent discipline and linked with the international nephrology community. Due to the huge population and enormous territory, nephrologists are facing a great mission and momentous challenges. Most nephrologists reside in the coastal region, which has a higher education background than most of the rest of the country. Among them, Beijing, Shanghai, Guanzhong and Nangjing are the major centers for training graduate students to conduct basic and clinical research. Renal biopsy is widely performed in China. IgA nephropathy is the leading cause among the primary causes of glomerulonephritis that are diagnosed by renal biopsy, while lupus nephritis is the most prominent among the causes of second glomerulopathy. Though diabetic nephropathy now constitutes only about 10% of the cause of secondary glomerulopathy, the rapid rise of diabetes mellitus predicts a future prominent role of this disease in managing progressive renal failure in China. Both hemodialysis and peritoneal dialysis are widely used in China, with approximately a 40 to 50% survival rate in three years. About two thirds of the end-stage renal disease (ESRD) patients received erythropoietin; however, the hematocrit levels of most cases are less ideal. A variety of sources, mainly from the government, in several big cities provide financial support for ESRD dialysis, which has already become a heavy burden to public health. About 5000 patients receive renal transplantation every year in which the organs are mainly from brain dead cadavers. Renal disease registration has been established since 1999. Controlling the high incidence of diabetes and early treatment, studying the genetic and environmental mechanisms possibly related to the high incidence of IgA nephropathy in rural areas, and establishing a nationwide network to apply guidelines for dialysis and transplantation in a fashion relevant to real situations in China are major challenges to the Chinese nephrologists.
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PMID:Nephrology in China: a great mission and momentous challenge. 1286 86

Glucagonoma of the pancreas is a rare tumor with distinct clinical manifestations, such as necrolytic migratory erythema,weight loss, anemia, diabetes mellitus, and hypoamino-acidemia. We report the case of a 68-year-old Japanese man who underwent curative resection for malignant glucagonoma of the pancreas diagnosed through anemia and diabetes mellitus. The patient had had diabetes mellitus for 20 years. Anemia was diagnosed in 1998. On admission, the hemoglobin level was 8.3g/dl, but the levels of serum iron, vitamin B12, and erythropoietin and, the number of reticulocytes were within normal limits. The levels of carcinoembryonic antigen (CEA), carbohydrate antigen (CA)19-9, and DUPAN-2 were also within normal limits, and exocrine function of the pancreas (PFD, 75%) was normal. Ultrasonography (US) revealed a hypoechoic tumor in the distal pancreas. Computed tomography (CT) demonstrated a high-density area 4 cm in diameter with calcification. The serum glucagon level was very high (2360 pg/ml), but the levels of other hormones such as somatostatin or gastrin were within normal limits, while insulin was low. Glucagonoma of the pancreas was diagnosed, and distal pancreatectomy with splenectomy was performed. Histological examination revealed a malignant endocrine tumor,which was immunohistochemically positive for chromogranin A and glucagon. Two months after the operation, the serum glucagon level had decreased to within normal limits and the hemoglobin level had increased to 10.4 g/dl. The case of glucagonoma reported here was found through diagnostic examinations of anemia and treated by surgical resection, by which the patient's anemia was largely alleviated. Therefore, we recommend checking patients who have diabetes mellitus and anemia in order to diagnose and treat glucagonoma in its early stage.
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PMID:Malignant glucagonoma of the pancreas diagnoses through anemia and diabetes mellitus. 1291 65

Cardiovascular disease is a leading cause of death among kidney transplant recipients. Anemia, a risk factor for cardiovascular complications among patients with chronic kidney disease, has not been well characterized in kidney transplant recipients. We performed a retrospective cohort study of the prevalence of and factors associated with anemia among 240 patients who underwent kidney transplantation at our institution. The mean hematocrit (Hct) rose from 33% at 1 month after transplantation to 40% at 12 months after transplantation. The proportion of patients with Hct < 36% was 76% at transplantation and 21% and 36%, 1 year and 4 years after transplantation, respectively. Six months after transplantation, women had higher likelihood (OR = 3.61) of Hct < 36%, while higher Hct at 3 months (OR = 0.67 for 1% higher Hct) and diabetes (OR = 0.14) were associated with a lower likelihood of Hct < 36%. Similar associations were seen 12 months after transplantation. Even among patients with Hct < 30%, only 36% had iron studies, 46% received iron supplementation and 40% received recombinant human erythropoietin. Awareness of factors associated with a lower Hct may prompt better anemia screening and management, potentially improving cardiovascular outcomes among kidney transplant recipients.
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PMID:Anemia: a continuing problem following kidney transplantation. 1452 5

Evaluation of anemia: Before beginning epoetin treatment, it is essential to evaluate the level of anemia (Hb < 11-12g/dL) by the following measurements: -Hb concentration -Red blood cell indices (MCV, MCH, MCHC) -Reticulocyte count -Iron stores and availability -C-reactive protein (CRP) Target for anemia treatment: The minimum target Hb concentration to be attained is 11 g/dL. The upper limit is established individually on a clinical basis. Pending further data, it is advisable to maintain and not exceed 12 g/dL for patients with cardiovascular disease, diabetes, and graft access. Use of iron: At the start of epoetin treatment, 150 mg of iron are needed for every expected increase of 1 g/dL of Hb. It is important to achieve and maintain levels of TSAT > 20%, serum ferritin 100 mcg/L and hypochromic red cells > 6% both before initiating epoetin treatment and during its administration. TSAT levels should not persistently exceed > 50% and serum ferritin > 500 mcg/L. When administering oral iron the dose should be at least 200 mg/die elemental iron; on the other hand, when the intravenous route is used, the dose should be 30-60 mg/IV dose in the form of low molecular weight salts (iron sodium gluconate) while the higher doses should be reserved for patients with transferring levels > 170 mg/dL. Administration of epoetin: The dosage of epoetin is individual with more than tenfold variability among individuals and all aiming at the same target Hb concentration. There are no clinical parameters entirely capable of predicting the necessary dosage. Therapeutic range is very wide, without any toxic effects for clinical use up to 100.000 IU/week. The target Hb concentration is reached in most patients with mild anaemia after 2 months' treatment with 4.000-10.000 epoetin (20-50 mcg darbepoetin alpha) per week. The HB concentration, along with the reticulocyte count, must be checked weekly following initiation and monthly during maintenance. Patients with a stable dose-response during conservative therapy may require less frequent monitoring (every 2-3 months). Inadequate response to epoetin treatment If any resistance is encountered, after excluding all the acute and chronic conditions of inadequate response, the reticulocyte count (severe reduction in the presence of anti erythropoietin antibodies) and the erythropoietin dosage should be measured. The target Hb concentration 11-12 g/dL is maintained in 90-95% of the patients by administering 1.000-30.000 IU of epoetin (5-150 mcg darbepoetin alpha) per week in the presence of adequate reserves of iron. Higher dosages define a state of resistance. Diagnosis of pure red cell (PRCA) from anti-erythropoietin antibodies is confirmed by bone marrow examination (almost total loss of erythroblasts). If antierythropoietin antibodies are present or there is a well founded suspicion of PRCA, the administration of epoetin and other similar treatment should be avoided. Side effects of epoetin treatment: The treatment of anaemia with epoetin does not hasten the progression of CRF. Blood pressure is to be checked regularly during initiation of epoetin and the treatment should be discontinued in cases of refractory hypertension or hypertensive encephalopathy. There should be increased surveillance of graft access, especially in those patients who risk vascular depletion. In general, heparin requirements do not increase but it may be advisable to evaluate a dose increase. PRCA from anti-erythropoietin antibodies has been detected with an incidence ranging from 0.12 to 1.1 cases/every 10 thousand patients treated.
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PMID:[Guidelines for the treatment of anemia in chronic renal failure]. 1466 4

This paper presents the role of erythropoietin application in diabetic patients with accompanying renal failure. The main cause of anemia in diabetics are: nephropathy, structural lesions of erythrocyte membrane and blood loss connected with diagnostic and therapeutic actions. There are publications which demonstrate that in patients with diabetes type 1 or 2 with accompanying nephropathy, anemia appears more frequently than in the group of patients with chronic renal failure caused by other factors. It is supposed, that the impaired erythropoietin synthesis in diabetics can be caused by autonomic neuropathy. Erythropoietin administration in case of diabetic nephropathy has a beneficial influence on fat metabolism, immune response and reduction of insuline resistance. Erythropoietin because of reduction of vascular endothelial growth factor synthesis blocks the development of diabetic retinopathy and macroangiopathy. Erythropoietin reduces the risk of the left-ventricular hypertrophy caused by anemia. Very important is that the erythropoietin resistance is lower in diabetics. Scientists who are adverse to erythropoietin administration in patients with diabetic nephropathy maintain, that it can lead to vascular complications and the deterioration of glycemia control.
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PMID:[Erythropoietin administration in diabetic patients]. 1497 47


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