Hannelore Hampl

Long-Term Results of Total Parathyroidectomy without Autotransplantation in Patients with and without Renal Failure

The optimal surgical procedure for severe renal secondary hyperparathyroidism (sHPT) is still a point of controversy. Total parathyroidectomy (PTX) without auto-transplantation was abandoned for fear of an adynamic bone condition; however, in the case of autotransplantation recurrent sHPT is frequent and promotes atherosclerosis. We studied 11 hemodialysis patients (age 59±12 years) on dialysis for 18 (12–30) years in whom total PTX was performed due to severe sHPT (group I; intact PTH: 1,240±230 pg/ml), and 5 patients (age 55±10 years) without renal insufficiency who inadvertently received total PTX during thyroid surgery (group II). After total PTX (group I, 26±18 [9–59] months; group II, 252±188 [22^480] months) both groups showed no measurable intact PTH levels. Calcium homeostasis was maintained by oral substitution with calcium (group I, calcium dialysate of 2.0 mmol/l), vitamin D and calcitriol (serum parameters in groups I and II: calcium 2.4 and 2.2 mmol/l; phosphate 1.8 and 1.1 mmol/l; 25(OH)-vitamin D3 21 and 34 ng/ml; 1,25(OH)2-vitamin D3 32 and 41 pg/ml, respectively). In group I, after total PTX there was a rapid and sustained improvement in bone pain with markedly enhanced physical activity and endurance. High turnover osteopathy markedly improved as indicated by declining levels of native osteocalcin (90±17 vs. 26±18 ng/ml), bone alkaline phosphatase (74±12 vs. 12±6 ng/ml), and carboxyterminal cross-linked telopeptide of type-I collagen (65±16 vs. 40±21 ng/ml) but increasing levels of carboxyterminal propeptide of type-I procollagen (120±36 vs. 148±41 ng/ml). Recalcification of bone was excellent as demonstrated by X-ray and confirmed by bone histology. Itching extravascular calcific deposits and calcifications of blood vessel and cardiac valves immediately stopped after total PTX. Moreover, 6 sHPT patients suffered from severe atherosclerotic lesions such as thoracic aortic aneurysm (n = 3) or abdominal aortic aneurysm (n = 3) which showed size progression before but not after total PTX when annually controlled by ultrasonography. In group II, even long after total PTX, there was no clinical, radiological, histological or biochemical evidence for low turnover osteopathy. In conclusion, our data indicate that substitution with vitamin D3 metabolites and calcium can prevent deleterious bone effects of hypoparathyroidism in hemodialysis patients and in patients with normal kidney function and may compensate for the missing PTH action. Over this, a better survival rate is expected as a consequence of the beneficial effect of total PTX on the progression of atherosclerotic lesions. We suggest reconsideration of total PTX without autotransplantation in dialysis patients with severe sHPT who are not eligible for renal transplantation.

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

Oxidative stress in renal anemia of hemodialysis patients is mitigated by epoetin treatment.

Background/Aims: Oxidative stress often occurs in chronic hemodialysis (HD) patients. The objective of our study was to investigate the interrelationship between oxidative stress and the degree of renal anemia. Methods: In 107 consecutive HD patients, serum concentrations of two major aldehydic lipid peroxidation (LPO) products, 4-hydroxynonenal (HNE) and malondialdehyde (MDA), and of protein carbonyls were analyzed as parameters of oxidative stress and related to the degree of renal anemia. Additionally, in 76 patients treated with epoetin long-term changes in the serum levels of aldehydic LPO products were observed. Results: In HD patients, serum levels of HNE, MDA, and protein carbonyls are increased in comparison to controls. The lower the hemoglobin, i.e. the stronger the degree of renal anemia, the higher the serum concentrations of HNE, MDA, and protein carbonyls. The HNE and MDA levels decreased during HD. Long-term studies on the correction of renal anemia by epoetin demonstrated a mitigation of oxidative stress during this therapy. During periods of 1 and 2 years, it was observed that the serum levels of HNE and MDA could be reduced. Conclusion: Chronic renal failure is connected with oxidative stress which correlates with the degree of renal anemia, and the serum levels of aldehydic LPO products could be reduced during correction of renal anemia by epoetin.

Serum Concentrations of F2-Isoprostanes and 4-Hydroxynonenal in Hemodialysis Patients in Relation to Inflammation and Renal Anemia.

Background Patients with end-stage renal disease (ESRD) undergoing hemodialysis (HD) are apparently exposed to enhanced oxidative stress and to inflammation. It was the aim of this study to characterize the state of systemic oxidative stress of ESRD patients before and following HD using highly specific biomarkers, F2-isoprostanes and 4-hydroxynonenal (HNE). Furthermore the question should be answered, if there are associations between inflammation and systemic oxidative stress and/or between systemic oxidative stress and renal anemia, which is more or less typical for HD patients. Patients and methods Concentrations of F2-isoprostanes, HNE, C-reactive protein (CRP) as marker of inflammation, and hemoglobin were measured in serum samples of patients with ESRD before and after HD and of healthy control persons for comparison. Total (esterified plus free) F2-isoprostanes were quantified by highly sensitive gas chromatography/mass spectrometry technique, HNE by thin layer chromatography and HPLC/UV detection, CRP by immunoturbidimetry and hemoglobin by clinico-chemical routine assay. Results 1. HD patients showed significantly higher serum concentrations of F2-isoprostanes and HNE than healthy human control subjects. 2. Total (esterified plus free) F2-isoprostane levels before HD were not significantly different from those after HD, whereas HNE levels were significantly decreased in patients after HD. 3. F2-isoprostane concentrations in HD patients correlated with the levels of CRP, whereas HNE concentrations inversely correlated with the content of hemoglobin. Conclusion Both, F2-isoprostanes and HNE serum concentrations are useful oxidative stress parameters in ESRD patients undergoing HD. Whereas HNE strongly correlates with the severity of renal anemia, leading to left heart insufficiency, F2-isoprostanes (sum of free plus esterified) highly correlate with the degree of inflammation.

Oxysterols Are Increased in Plasma of End-Stage Renal Disease Patients

Background/Aims: Oxidative stress occurs in chronic renal failure patients undergoing hemodialysis (HD). The objective of our study was to measure oxidation products of cholesterols, so-called oxysterols, in the serum of HD patients in comparison to healthy control persons. Methods: In 42 HD patients, plasma oxysterols were measured before and after HD. The values were compared with those in 40 healthy controls. The following cholesterol derivatives were analyzed: dienes, 7β-OH, β-epoxy, α-epoxy, 20α-OH, α-triol, and 7-keto cholesterol. Results: In HD patients, serum levels of oxysterols are increased in comparison to controls. The highest values were measured for β-epoxy cholesterol and for 20α-OH cholesterol. During HD oxysterol concentrations increased, obviously by water removal and concentration of nondialyzable compounds. Conclusion: Due to oxidative stress which is known as a typical sign of chronic renal failure the plasma concentrations of oxysterols are also significantly increased in comparison to healthy controls. This underlines the data on accelerated lipid peroxidation in end-stage renal disease (ESRD) patients. Accumulated oxysterols which are accused of exerting atherosclerosis-stimulating effects, which can contribute to the increased cardiovascular risk of ESRD patients, could either induce atherosclerosis via signaling or chronic effects. Direct chemical reactions stimulating plaque formation can be excluded because of the low levels of oxysterols. The share of oxysterols within the total cholesterol ranges from 4 to 15‰.

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.

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)

Erythropoiesis and Erythrocyte Age Distribution in Hemodialysis Patients Undergoing Erythropoietin Therapy

Renal anemia is caused in part by a reduced life span of red blood cells (RBCs) and by reduced erythropoietin biosynthesis in the damaged kidney. The RBC age can be determined by density gradient centrifugation and estimation of cell-age-dependent enzyme activities, as aspartate aminotransferase. The RBC age distribution influences the median density (D50) of RBCs and the blood rheology in coherence with the hematocrit. In our study, the median density was determined by Percoll density gradient centrifugation in 18 healthy subjects (D50 = 1.0674 +/- 0.0016 g/ml) and in 14 hemodialysis patients (D50 = 1.0674 +/- 0.0016 g/ml in the course of recombinant human erythropoietin (rhEPO) therapy. During the first 4 weeks of therapy, a strong rejuvenation of RBCs was observed whereby the D50 reached a minimum after 2 weeks (D50 = 1.0655 +/- 0.0022 g/ml; p less than 0.05 vs. value before therapy) and a steady state after 4 weeks (D50 = 1.0658 +/- 0.0013 g/ml; p less than 0.1 vs. value before therapy). In 5 of the patients with elevated plasma parathyroid hormone (i-PTH) concentrations greater than 10 pmol/l, a significantly (p less than 0.05) reduced amount of younger RBCs (D50 = 1.0675 +/- 0.0016 g/ml) was observed in the first 2 weeks of rhEPO therapy as compared to patients with i-PTH less than 10 pmol/l (D50 = 1.0677 +/- 0.0019 g/ml). Thus, erythropoiesis in the early phase of rhEPO therapy is strongly influenced by elevated plasma i-PTH concentrations. Therefore, a gradual increase in rhEPO doses is preferable before therapy at elevated doses with an uncontrolled increase in RBC amount.

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.