Eberhard Riedel

Effects of optimized heart failure therapy and anemia correction with epoetin β on left ventricular mass in hemodialysis patients

Background: In chronic hemodialysis (HD) patients, the presence and degree of left ventricular hypertrophy (LVH) correlates with mortality. Previous studies have shown that interventions, such as anemia correction or treatment of hypertension and/or chronic heart failure (CHF), can result in moderate regression of LVH. The primary objective of our study was to investigate the effects of a multi-interventional treatment strategy on LVH in HD patients. Methods and Results: In a series of 202 consecutive HD patients, we combined optimized CHF therapy, including β-blockers (BB), ACE inhibitors and angiotensin receptor blockers (ARBs), to target doses with full anemia correction by epoetin β (hemoglobin (Hb) target males 14.5 g/dl, females 13.5 g/dl). Serial echocardiograms were recorded every 3–6 months. Mean follow-up was 3.4 ± 1.2 years. Mean Hb at baseline was 11.4 ± 1.4 vs. 14.6 ± 1.6 g/dl (p < 0.001) at study end. There was a significant reduction in left ventricular mass index (LVMI, 159 ± 65 vs. 132 ± 46 g/m2 (p < 0.001)), an improvement in left ventricular ejection fraction (LVEF, 60 ± 15 vs. 66 ± 12% (p < 0.01)) and in NYHA class (2.8 ± 0.76 vs. 1.96 ± 0.76 (p < 0.01)) from baseline to follow-up in the overall study population. In a subgroup of 70 patients, LVMI returned to normal (169 ± 33 vs. 114 ± 14 g/m2 (p < 0.001)) after 1.4 ± 1 years. Conclusions: Our study shows that optimized CHF therapy, in combination with anemia correction to normal Hb targets, results in a significant reduction of LVH, an increase in LVEF and an improvement in NYHA class. Moreover, in contrast to previous studies, our data also demonstrate that complete regression and prevention of LVH in HD patients is possible.

α-Ketoglutarate Application in Hemodialysis Patients Improves Amino Acid Metabolism

In hemodialysis patients, free amino acids and α-ketoacids in plasma were determined by fluorescence HPLC to assess the effect of α-ketoglutarate administration in combination with the phosphate binde

Cardiac Disease in the Dialysis Patient: Good, Better, Best Clinical Practice

Proven strategies to reduce cardiovascular events and cardiac mortality in hemodialysis patients are given on the basis of pathophysiology. This is an overview of our clinical know-how acquired during the last 30 years. We try to answer the following questions: (1) how to reduce cardiovascular events and cardiac mortality in hemodialysis patients; (2) how to achieve regression of left ventricular hypertrophy, the most important predictor of sudden cardiac death; (3) how to manage iron status during full correction of renal anemia to prevent iron deficiency-induced reactive thrombocytosis, which is recognized to cause fatal stroke and cardiovascular thrombosis; (4) how to maintain responsiveness to erythropoiesis-stimulating agents during correction of renal anemia, thereby avoiding unnecessarily high doses and so reaching ultimate cost-effectiveness. Conclusion: Normalization of renal anemia is not responsible for increased risk of cardiovascular events/cardiac mortality. The inability to adequately address iron status in hemoglobin normalization studies and the underprescription of effective cardiac/antihypertensive medication might explain the adverse outcome. Effective cardiac/antihypertensive medication, intensive iron therapy during normalization of hemoglobin, optimized correction of metabolic acidosis and supplementation of vitamins which are involved in the energy metabolism should be considered to significantly improve the outcome of hemodialysis patients.

Optimized heart failure therapy and complete anemia correction on left-ventricular hypertrophy in nondiabetic and diabetic patients undergoing hemodialysis.

Background: According to new guidelines, diabetes mellitus per se can be considered as stage I chronic heart failure (CHF). Available evidence suggests that patients suffering from both diabetes mellitus and renal insufficiency have disproportionately high rates of left-ventricular hypertrophy (LVH). Methods: Optimized heart failure therapy, including β-blockers, ACE-inhibitors and AT II-type-1-receptor-blockers, was prescribed in combination with complete anemia correction using epoetin beta (target hemoglobin: 13.5 g/dl for women; 14.5 g/dl for men) to 230 patients (55% male) with ambulatory hemodialysis, including 60 patients (52% male) with diabetes. Echocardiographic follow-up examinations were performed over a mean period of 4.4 ± 1.2 years. Results: Mean hemoglobin levels at the study end significantly increased to target levels in the entire study population and in patients with diabetes (both p < 0.001). Compared with baseline, significant improvements were seen in hemodialysis patients – both without and with diabetes – in left-ventricular mass index (–28.8 g/m2 [p < 0.001] and 29.0 g/m2 [p < 0.005], respectively), left-ventricular ejection fraction (+7.0% [p < 0.001] and +8.3% [p < 0.01], respectively) and in NYHA class (–0.84 [p < 0.01] and –1.12 [p < 0.01], respectively). Similar to the results in the overall population, a highly significant reduction in LVH (p < 0.005) and significant improvements in LVEF (p < 0.01) and NYHA class (p < 0.01) were seen in the high-risk subgroup of diabetic patients. Conclusions: Patients undergoing hemodialysis, with or without concomitant diabetes, benefit considerably from optimized, multifactorial heart failure therapy combined with complete anemia correction.

Selective endocytosis of fluorothymidine and azidothymidine coupled to LDL into HIV infected mononuclear cells

Drug targeting via lipoproteins may be of benefit for use of cytotoxic drugs like fluorothymidine (FLT) or azidothymidine (AZT). Both drugs are potent inhibitors of the human immunodeficiency virus (HIV) reverse transcriptase and are used in the therapy of HIV infection. With regard to this project, the selective endocytosis in HIV infected human macrophages was studied after covalent coupling of AZT and LDL to low density lipoproteins (LDL). Cultured human macrophages and the lymphocytic Molt 4/8 cell line were infected with HIV-1 in vitro and subsequently treated with FLT-LDL or AZT-LDL. Viral replication was followed by determination of cell-released capsid antigen p24. Internalisation into HIV-1 infected human macrophages by the scavenger receptor pathway leads to a dose dependent inhibition of HIV replication. Otherwise, in HIV infected, but scavenger receptor missing lymphocytes (Molt 4/8 cells), neither endocytosis nor inhibition of HIV replication results. Thus, covalent coupling of drugs to LDL leads to a macrophage specific transport. This strategy could possibly avoid toxic side effects in the therapeutic use of antiretroviral drugs and thus may open a way for an earlier chemotherapy in HIV infection.

Preparation of Nucleoside-LDL-Conjugates for the Study of Cell-Selective Internalization: Stability Characteristics and Receptor Affinity

Antiviral therapy of human immunodeficiency virus (HIV) infection is currently based on inhibition of reverse transcriptase by dideoxynucleosides, such as azidothymidine. Because of widespread toxicity it is reasonable to selectively target these drugs to infected cells. This may be accomplished utilizing drug-LDL conjugates, which are internalized via cell specific receptor pathways. With respect to HIV infection, scavenger receptors of the macrophage system seems to offer a hopeful perspective. This pathway requires chemical modification of surface polarity of the LDL. Cell experiments were conducted in HepG2 hepatocytes, which express apolipoprotein B receptors, and in P388 macrophages, which express scavenger receptors. LDL particles to be conjugated were isolated from blood donor plasma and from LDL-apheresis waste material. Non-covalent LDL conjugation with amphiphilic nucleoside derivatives produced only an unspecific nucleoside transfer to cell membranes, due to instability of the LDL conjugates. An experimental method (coincubation test) was developed to identify those conjugates that are stable in the presence of other lipophilic compartments. Covalent coupling of nucleosides to the apolipoprotein B moiety of LDL particles resulted in stable conjugates. As a consequence, the surface charge became negative, and the LDL displayed scavenger receptor affinity rather than apolipoprotein B receptor affinity. Selective targeting of nucleosides to macrophages can be accomplished by covalent coupling to LDL.

Red Blood Cell Density Distribution in Uremic Patients on Acetate and Bicarbonate Hemodialysis

Renal anemia is the result of reduced erythropoietin (EPO) biosynthesis in the diseased kidney and also in part the result of a reduced life span of red blood cells (RBCs). An increase in density and a decrease in enzyme equipment (aspartate aminotransferase; GOT) of RBCs reflect cell age. In the following study, the density distribution (median density D50; determined by Percoll density gradients) and GOT activities of RBCs were measured in patients on acetate (HDA; n = 15) and bicarbonate (HDB; n = 51) hemodialysis. Hemoglobin (Hb) concentrations were: in the HDB group, 9.1 +/- 3.4 g/dl; in the HDA group, 6.2 +/- 1.2 g/dl, and, in a control (C) group of healthy persons, 14.0 +/- 1.5 g/dl. 14 HDB patients with severe anemia received EPO therapy during 1 year. D50 were found as follows: group C, 1.0674 +/- 0.0016 g/ml; HDB, 1.0674 +/- 0.0015 g/ml, and HDA, 1.0660 +/- 0.0012 g/ml (HDA vs. group C: p less than 0.05; HDA vs. HDB: p less than 0.05. D50 were elevated in the subgroups of HDA and HDB patients with severe anemia (Hb less than 8 g/dl). During activated erythropoiesis by EPO therapy, D50 decreased from 1.06739 +/- 0.0015 to 1.0656 +/- 0.0014 g/ml. The GOT activities in RBCs demonstrated a rejuvenation of the RBC population in the HDB group (6.4 +/- 2.5 U/g Hb) and HDA group (5.9 +/- 3.1 U/g Hb) compared to group C (3.9 +/- 1.3 U/g Hb).(ABSTRACT TRUNCATED AT 250 WORDS)

Proven strategies to reduce cardiovascular mortality in hemodialysis patients.

Background: In hemodialysis patients, left ventricular hypertrophy (LVH) correlates with mortality. The reason for LVH in uremics is multifactorial. The primary objective of our study was to investigate the effects of a multi-interventional treatment strategy on LVH. Methods: In 230 ambulatory patients, including patients with coronary artery disease, diabetes, diastolic and systolic dysfunction, we continued optimized cardiac therapy (β-blockers, angiotensin-converting enzyme inhibitors and angiotensin receptor blockers) with full anemia correction by intravenous epoetin-β. The dose of epoetin-β for maintaining target hemoglobin (Hb) was 68 ± 23 IU/kg/week. Serial echocardiograms were recorded every 3–6 months. The mean observation period was 4.8 ± 1.2 years. Results: Mean Hb at baseline was 11.2 ± 2.0 versus 14.1 ± 1.4 g/dl (p < 0.001) at study end. There was a significant reduction in left ventricular mass index (LVMI: 159 ± 50.4 vs. 130.2 ± 42.7 g/m2; p < 0.001). In a subgroup of 2/3 of the patients, LVMI returned to normal (169 ± 33 vs. 114 ± 14 g/m2; p < 0.001). Conclusion: Baseline LVMI (p < 0.001), Hb increase (p < 0.03), and triple cardiac therapy (p < 0.03) were significant and independent prognostic factors for a reduction in LVMI. The annual cardiovascular mortality was 5%. Even anemia correction from 12 to 14 g/dl results in further (p < 0.001) regression of LVMI.

Changes in the Concentrations of Hydroxyproline, Glycine and Serine in the Plasma of Haemodialysis Patients Undergoing, Erythropoietin Therapy

The concentrations of proline, hydroxyproline, glycine and serine were determined in the plasma of 39 haemodialysis patients and 18 healthy subjects, using liquid chromatography with fluorescence detection. Plasma concentrations of the N-terminal immunoreactive parathyrin were also measured. In haemodialysis patients, the plasma concentrations of glycine (p less than 0.01), hydroxyproline (p less than 0.05) and proline (p less than 0.10) were significantly increased, whereas the serine concentrations (p less than 0.01) were decreased, compared with those of the healthy controls. Haemodialysis patients showed greatly elevated plasma N-terminal immunoreactive parathyrin values (greater than 30 pmol/l), which showed a significant correlation with the hydroxyproline values (r = 0.79). Fourteen haemodialysis patients received erythropoietin therapy. In these patients, changes in the concentrations of plasma amino acids were observed up to one year after the beginning of therapy. In the course of the erythropoietin therapy, the plasma concentrations of glycine (p less than 0.05) and hydroxyproline (p less than 0.10) of the haemodialysis patients decreased, whereas the concentration of serine increased (p less than 0.05) to approximately normal values. The results indicate that erythropoietin therapy leads to a normalization of amino acid metabolism.

Cellular kinetics of prednimustine versus chlorambucil plus prednisolone in vitro

SummaryIntracellular concentrations of prednimustine (PM), chlorambucil (CLB), phenylacetic acid mustard (PAAM) and prednisolone (P) were measured in different experimental tumor cell lines that had been incubated with either PM or CLB+P. For intracellular analytical determination, we modified a high-pressure liquid chromatographic method for the detection of these substances in plasma. Intact PM could be detected in the intracellular compartment of the incubated tumor cells. PM-incubated cells from PM-injected rats exhibited a higher intracellular concentration-time integral (PAAM) and longer concentration-time profiles for drugs with alkylating capacity than did cells exposed to the CLB+P mixture or to CLB. PAAM was not detectable after incubation of cells with PM, whereas in CLB-incubated cells the AUC of PAAM exceeded that of the parent drug CLB. Our in vitro results therefore favour the concept of a facilitated intracellular uptake and an increased antiproliferative effect for PM versus CLB and CLB+P.