Volker Wizemann

The mortality risk of overhydration in haemodialysis patients

Background. While cardiovascular events remain the primary form of mortality in haemodialysis (HD) patients, few centres are aware of the impact of the hydration status (HS). The aim of this study was to investigate how the magnitude of the prevailing overhydration influences long-term survival. Methods. We measured the hydration status in 269 prevalent HD patients (28% diabetics, dialysis vintage = 41.2 ± 70 months) in three European centres with a body composition monitor (BCM) that enables quantitative assessment of hydration status and body composition. The survival of these patients was ascertained after a follow-up period of 3.5 years. The cut off threshold for the definition of hyperhydration was set to 15% relative to the extracellular water (ECW), which represents an excess of ECW of ∼2.5 l. Cox-proportional hazard models were used to compare survival according to the baseline hydration status for a set of demographic data, comorbid conditions and other predictors. Results. The median hydration state (HS) before the HD treatment (ΔHSpre) for all patients was 8.6 ± 8.9%. The unadjusted gross annual mortality of all patients was 8.5%. The hyperhydrated subgroup (n = 58) presented ΔHSpre = 19.9 ± 5.3% and a gross mortality of 14.7%. The Cox adjusted hazard ratios (HRs) revealed that age (HRage = 1.05, 1/year; P < 0.001), systolic blood pressure (BPsys) (HRBPsys = 0.986 1/mmHg; P = 0.014), diabetes (HRDia = 2.766; P < 0.001), peripheral vascular disease (PVD) (HRPVD = 1.68; P = 0.045) and relative hydration status (ΔHSpre) (HRΔHSpre = 2.102 P = 0.003) were the only significant predictors of mortality in our patient population. Conclusion. The results of our study indicate that the hydration state is an important and independent predictor of mortality in chronic HD patients secondary only to the presence of diabetes. We believe that it is essential to measure the hydration status objectively and quantitatively in order to obtain a more clearly defined assessment of the prognosis of haemodialysis patients.

Effect of Membrane Permeability on Survival of Hemodialysis Patients

The effect of high-flux hemodialysis membranes on patient survival has not been unequivocally determined. In this prospective, randomized clinical trial, we enrolled 738 incident hemodialysis patients, stratified them by serum albumin < or = 4 and >4 g/dl, and assigned them to either low-flux or high-flux membranes. We followed patients for 3 to 7.5 yr. Kaplan-Meier survival analysis showed no significant difference between high-flux and low-flux membranes, and a Cox proportional hazards model concurred. Patients with serum albumin < or = 4 g/dl had significantly higher survival rates in the high-flux group compared with the low-flux group (P = 0.032). In addition, a secondary analysis revealed that high-flux membranes may significantly improve survival of patients with diabetes. Among those with serum albumin < or = 4 g/dl, slightly different effects among patients with and without diabetes suggested a potential interaction between diabetes status and low serum albumin in the reduction of risk conferred by high-flux membranes. In summary, we did not detect a significant survival benefit with either high-flux or low-flux membranes in the population overall, but the use of high-flux membranes conferred a significant survival benefit among patients with serum albumin < or = 4 g/dl. The apparent survival benefit among patients who have diabetes and are treated with high-flux membranes requires confirmation given the post hoc nature of our analysis.

Towards improved cardiovascular management: the necessity of combining blood pressure and fluid overload

BACKGROUND Hypertension and fluid overload (FO) are well-recognized problems in the chronic kidney disease (CKD) population. While the prevalence of hypertension is well documented, little is known about the severity of FO in this population. METHODS A new bioimpedance spectroscopy device (BCM-Body Composition Monitor) was selected that allows quantitative determination of the deviation in hydration status from normal ranges (DeltaHS). Pre-dialysis systolic blood pressure (BPsys) and DeltaHS was analysed in 500 haemodialysis patients from eight dialysis centres. A graphical tool (HRP-hydration reference plot) was devised allowing DeltaHS to be combined with measurements of BPsys enabling comparison with a matched healthy population (n = 1244). RESULTS Nineteen percent of patients (n = 95) were found to have normal BPsys and DeltaHS in the normal range. Approximately one-third of patients (n = 133) exhibited reasonable control of BPsys and fluids (BPsys <150 mmHg and DeltaHS <2.5 L). In only 15% of patients (n = 74) was hypertension observed (BPsys >150 mmHg) with a concomitant DeltaHS >2.5 L (possible volume-dependent hypertension). In contrast, 13% of patients (n = 69) were hypertensive with DeltaHS <1.1 L (possible essential hypertension). In 10% of patients (n = 52), BPsys <140 mmHg was recorded despite DeltaHS exceeding 2.5 L. CONCLUSION Our study illustrated the wide variability in BPsys regardless of the degree of DeltaHS. The HRP provides an invaluable tool for classifying patients in terms of BPsys and DeltaHS and the proximity of these parameters to reference ranges. This represents an important step towards more objective choice of strategies for the optimal treatment of hypertension and FO. Further studies are required to assess the prognostic and therapeutic role of the HRP.

Importance of normohydration for the long-term survival of haemodialysis patients

BACKGROUND Fluid overload and hypertension are among the most important risk factors for haemodialysis (HD) patients. The aim of this study was to analyse the impact of fluid overload for the survival of HD patients by using a selected reference population from Tassin. METHODS A positively selected HD population (n = 50) from Tassin (Lyon-France) was used as a reference for fluid status and all-cause mortality. This population was compared to one dialysis centre from Giessen (Germany) which was separated into a non-hyperhydrated (n = 123) and a hyperhydrated (n = 35) patient group. The hydration status (ΔHS) of all patients was objectively measured with whole-body bioimpedance spectroscopy in 2003. All-cause mortality was analysed after a 6.5-year follow-up. RESULTS Most of the reference patients from Tassin were normohydrated (ΔHS = 0.25 ± 1.15 L) at the start of the HD session. The hydration status of the Tassin patients was not different to the non-hyperhydrated Giessen patients (ΔHS = 0.8 ± 1.1 L) but significantly lower than in the hyperhydrated Giessen group (ΔHS = 3.5 ± 1.2 L). Multivariate adjusted all-cause mortality was significantly increased in the hyperhydrated patient group (hazard ratio = 3.41)- no difference in mortality could be observed between the Tassin and the non-hyperhydrated group from Giessen-even considering the fact that Tassin patients presented a significantly lower blood pressure. CONCLUSIONS Fluid overload has a very high predictive value for all-cause mortality and seems to be one of the major killers in the HD population. Patients might strongly benefit from active management of fluid overload.

Analysis of left-ventricular changes associated with chronic hemodialysis: a noninvasive follow-up study

To assess the reasons for the frequent cardiovascular complications in patients with end-stage renal disease (ESRD), 61 out of 131 normotensive ESRD patients originally examined (mean ESRD duration: 71 +/- 41 months) were followed over 2.5 years by echo-, electro- and mechanocardiography. Clinical and biochemical parameters were comparable. The prevalence of pericardial effusion (3%), pericardial thickening (14%), aortic valve sclerosis (14%) and mitral valve anulus sclerosis (12%) was unchanged. The interventricular septum diameter (14.3 +/- 3.0 vs. 16.4 +/- 3.4 mm), index of left-ventricular (LV) wall asymmetry (1.25 +/- 0.30 vs. 1.52 +/- 0.36) and left atrial diameter (38.3 +/- 5.4 vs. 42.6 +/- 3 mm) increased (p less than 0.001). The LV end-systolic diameter decreased slightly (35.8 + 6.3 vs. 34.2 +/- 6.4 mm; p less than 0.05), with no significant changes for end-diastolic diameter (50.4 +/- 6.3 vs. 49.3 +/- 6.1 mm), muscle mass index (189 +/- 57 vs. 197 +/- 50 g/m2), stroke volume (86.1 +/- 26.2 vs. 85.7 +/- 26.7 7 ml/m2) and fractional shortening (29.1 +/- 7 vs. 30.8 +/- 8.6%). We conclude that the predominant finding in ESRD is an LV hypertrophy progressing towards an asymmetric septum hypertrophy, while the increase of the primarily enlarged left atrial diameter over 30 months reflects a further deterioration of the diastolic LV dysfunction.

Whole-Body Spectroscopy (BCM) in the Assessment of Normovolemia in Hemodialysis Patients

Whole-body impedance spectroscopy (BCM) has been validated by comparing isotope dilution methods for precisely measuring body volume compartments. Clinical assessment as well as comparison to other methods shows that BCM predicts a reliable individual dialysis target weight in kilograms, which corresponds to a physiological (normal) extracellular volume. BCM is helpful in the management of volume status and arterial hypertension in hemodialysis patients as well as in patients with chronic kidney disease. Quantified by BCM, overhydration is a powerful predictor of death in hemodialysis patients.

Dialysis-Induced Cardiac Arrhythmias: Fact or Fiction?

Frequency and grade of premature ventricular depolarizations were assessed in 10 patients on maintenance renal replacement therapy. All medication was withdrawn prior to the study. Each patient was treated sequentially by 8 different methods [acetate and bicarbonate hemodialysis (HD), hemofiltration, hemodiafiltration, ultrafiltration, use of 5 different membranes]. Despite marked changes in serum electrolyte concentrations there was no difference in frequency or grade of premature ventricular beats between the periods before, during, and after renal replacement therapy. Comparison of the 8 methods tested revealed no superiority of 1 method during the observation period of 192 h for each patient. In a second group of 8 patients with confirmed coronary artery disease, acetate HD had no effect on grade and frequency of ventricular arrhythmias, although arrhythmias occurred more often (p less than 0.05) and were more dangerous. We therefore conclude that the incidence of ventricular arrhythmias is primarily dependant on the presence of preexisting coronary artery disease and that HD or related methods do not increase the risk of ventricular ectopies in patients without digitalis medication.

Therapeutic equivalence of epoetin zeta and alfa, administered subcutaneously, for maintenance treatment of renal anemia

IntroductionThe primary objective of the trial was to prove the therapeutic equivalence of epoetin zeta to epoetin alfa when administered subcutaneously for maintaining target hemoglobin (Hb) in patients with renal anemia on chronic hemodialysis. Additional information was provided on the safety and tolerability of epoetin zeta with particular focus on the formation of anti-erythropoietin antibodies.MethodsA total of 462 patients were randomized to either epoetin zeta or alfa for 28 weeks after an open period of dose adjustment of 12–16 weeks with only epoetin zeta. The aim of treatment was to maintain Hb between 10.0–12.0 g/dL with constant epoetin dosage. Primary endpoints were the mean Hb level and the mean weekly epoetin dosage during the last 4 weeks of treatment. Safety endpoints were the occurrence of anti-erythropoietin antibodies, incidence of Hb levels above 13 g/dL, ratings of tolerability, and adverse events (AEs).ResultsThe mean Hb level (±SD) during the last 4 weeks of treatment was 10.94±0.84 g/dL (epoetin zeta) and 11.02±0.94 g/dL (epoetin alfa). The 95% confidence interval (CI) (″C0.28 g/dL to 0.12 g/dL) was entirely within the predefined equivalence range (±0.5 g/dL). The mean weekly epoetin dosage per body weight over the last 4 weeks of treatment was 97.0±94.3 IU/kg/week (epoetin zeta) and 86.0±78.0 IU/kg/week (epoetin alfa). The 95% CI (″C8.06 IU/kg/week to 29.96 IU/kg/week) was also within the predefined equivalence range of ±45 IU/kg/week. The most common AEs were infections and infestations (15.1% of patients on epoetin zeta and 14.8% of patients on epoetin alfa). None of the patients developed antierythropoietin antibodies.ConclusionsEpoetin zeta, administered subcutaneously, is equivalent to epoetin alfa in respect of its clinical efficacy. The safety profile of both products is similar: no unexpected AEs were observed, no patients developed anti-erythropoietin antibodies, and both epoetin preparations were well tolerated.

Organic Nitrate Therapy in Glaucoma

We determined the effect of organic nitrates on normal volunteers and patients with open-angle and narrow-angle glaucoma. Nitroglycerin lowered intraocular pressure in all patients when administered by the perfusion technique. Isosorbide dinitrate given orally (2 x 40 mg per day) has a potent decreasing effect on intraocular pressure, which cannot be explained by the influence on arterial blood pressure.

The MPO study: Just a European HEMO study or something very different?

Although results from observational and epidemiological studies suggested a survival benefit associated with high-flux hemodialysis, conclusive evidence from prospective randomized clinical trials has been lacking. Both the HEMO Study in the USA and the Membrane Permeability Outcome Study (MPO Study) in Europe are randomized studies investigating the effect of high- and low-flux hemodialysis on patient outcomes, even though there were some significant differences in the design of the two studies. An earlier randomized clinical trial could not show differences on patient survival between patient groups being treated with membranes of different material and permeability, but this trial was not designed specifically to examine this particular endpoint. Based on these previous experiences, the MPO Study addressed a hemodialysis patient population which was considered to be more susceptible to the intervention with high-flux dialysis. To identify these patients with an elevated risk, low serum albumin levels were chosen as an indicator; low serum albumin is associated with malnutrition, inflammation, atherosclerosis, and with increased risk of morbidity and mortality. Together with low serum albumin, patients had to be new to dialysis to be selected for the MPO Study. These particular considerations on patient selection, together with additional methodological refinements in the study design allow the conclusion that the MPO Study is valid on its own rather than being a European version of the HEMO Study.