Towards personalized hydration assessment in patients, based on measurement of total body electrical resistance: Back to basics.

BACKGROUND & AIMS: Assessment of tissue hydration by conventional bioelectrical impedance analysis (BIA) has produced conflicting results because of flaws in the algorithms that are used to translate measurements of total body electrical resistance (TBER) into liters of body water. This type of error can be eliminated by a return to the TBER measurement itself, without attempting to convert Ohms into liters of body water. Aims of this study were to quantify tissue hydration based on TBER, to establish TBER normal values (TBERnorm), to improve the prediction of TBERnorm values in individual patients, and to evaluate this approach in patients on hemodialysis (HD). METHODS: TBERnorm values were obtained in 213 healthy controls and corrected for body height (H-TBERnorm). Inter-individual H-TBERnorm variability was reduced by correction for arm muscle cross-sectional area (AMA). Performance of this approach was evaluated in 94 patients on HD. RESULTS: H-TBERnorm was inversely related to AMA. Correction for AMA reduced the H-TBERnorm standard deviation by 31% in men and 23% in women. When applied to patients on HD, H-TBER changes within subjects were inversely related to ultrafiltration volumes, with a mean R2 of 0.95 ± 0.04 in men and 0.93 ± 0.07 in women. Clinically significant H-TBER increments occurred after volume reductions of 0.39 ± 0.25 L in men and 0.37 ± 0.18 L in women. CONCLUSIONS: TBER measurements, corrected for height and AMA, have the potential to become an objective and sensitive method to assess hydration in patients. Its clinical value remains to be shown in intervention studies.

Long-term blood pressure monitoring and echocardiographic findings in patients with end-stage renal disease: reverse epidemiology explained?

BACKGROUND: In patients with end-stage renal disease (ESRD) hypertension is common and often leads to left ventricular (LV) hypertrophy and diastolic dysfunction, but hypotension at the onset of dialysis is associated with increased mortality. We studied blood pressure data over longer periods of time in patients on haemodialysis and related them to echocardiographic outcome, in order to elucidate these contradictory findings. METHODS: In 50 haemodialysis patients mean arterial pressure (MAP) and pulse pressure (PP) were calculated in the first three months of haemodialysis, the complete period from the start of haemodialysis until echocardiography and the last three months of haemodialysis before echocardiography. Hypertension load, pulse pressure and interdialytic weight gain were quantified and related to echocardiography. RESULTS: LV mass index was associated with MAP in all three periods, and also with the hypertension load, PP and PP load. In patients with LV dilatation, MAP and PP averaged over the complete period of dialysis were 5 to 7 mmHg higher than in patients without LV dilatation. Blood pressure parameters were the same in patients with or without LV diastolic dysfunction or systolic dysfunction. Systolic dysfunction was more frequent in patients undergoing long-term haemodialysis treatment. Interdialytic weight gain was not associated with any of the echocardiographic variables. CONCLUSION: When long-term blood pressure values are considered, hypertension is associated with parameters of early cardiac damage such as increased LV mass index and not with parameters of advanced heart failure such as systolic dysfunction. This supports the hypothesis that the presence of advanced heart failure reciprocally influences blood pressure in a negative way, thereby explaining the 'reverse epidemiology' of blood pressure and mortality in ESRD.

[Nephrogenic fibrosing dermopathy]. / Nefrogene fibroserende dermopathie.

A 58-year-old man with renal insufficiency, who was being treated by haemodialysis, developed progressive skin lesions. He had thickening and hardening of the skin at the extremities and swelling of the toes and fingers with flexion contractures. His face was not affected. Laboratory evaluation was unremarkable and a skin biopsy [table: see text] showed an increase of collagen and mucin, without an inflammatory infiltrate. These clinical features resemble a recently reported new disorder: nephrogenic fibrosing dermopathy. This disorder manifests as scleromyxedema-like cutaneous skin lesions without associated paraproteinemia, occurring in the setting of renal disease. The histopathologic features of nephrogenic fibrosing dermopathy, i.e. thickened collagen and mucin deposition, are unique. The incidence, prevalence and cause of the disease are unknown and there is currently no effective treatment. The Centers for Disease Control and Prevention (CDC) in the USA are calling on physicians who have encountered patients suffering from this type of lesions to contact the CDC for an intended control study.

Ferric saccharate induces oxygen radical stress and endothelial dysfunction in vivo.

BACKGROUND: Intravenous iron supplementation is used widely in haemodialysis patients. However, nontransferrin-bound iron (NTBI), which increases after intravenous supplementation of ferric saccharate, has been suggested to act as a catalytic agent in oxygen radical formation in vitro and may thus contribute to endothelial impairment in vivo. MATERIALS AND METHODS: In 20 healthy volunteers the effect of 100 mg ferric saccharate infusion was investigated. Vascular ultrasound was used to assess endothelium-dependent vasodilatation at baseline, and 10 and 240 min after ferric saccharate infusion. Whole blood was collected to measure NTBI and in vivo radical formation was assessed by electron spin resonance. A time-control study was performed using saline infusion. RESULTS: Infusion of ferric saccharate induces a greater than fourfold increase in NTBI, as well as a transient, significant (P < 0.01) reduction of flow-mediated dilatation 10 min after infusion of ferric saccharate, when compared with saline. The generation of superoxide in whole blood increased significantly 10 and 240 min after infusion of ferric saccharate by, respectively, 70 and 53%. CONCLUSIONS: Iron infusion at a currently used therapeutic dose for intravenous iron supplementation leads to increased oxygen radical stress and acute endothelial dysfunction.

Nontransferrin-bound iron in the plasma of haemodialysis patients after intravenous iron saccharate infusion.

BACKGROUND: Many haemodialysis patients treated with recombinant human erythropoietin (r-HuEPO) receive intravenous iron supplementation on a regular basis. It has been shown previously that this may result in a transient "oversaturation" of transferrin. METHODS: Ten stable haemodialysis patients on r-HuEPO treatment received 100 mg iron saccharate in 60 min, and 1 week later 100 mg in 6 min. Conventional iron metabolism parameters and nontransferrin-bond iron, detected with HPLC after addition of nitrilotriacetate and pretreatment with cobalt, were measured. Also, iron was measured in dialysate. RESULTS: Serum iron increased from 9.6 +/- 6.2 to 213.7 +/- 49.4 micromol L(-1) (P < 0.001) when iron was given in 60 min, and from 11.1 +/- 4.7 to 219.3 +/- 43.7 micromol L(-1) (P < 0.001) when iron was given in 6 min. Transferrin saturation increased from 0.22 +/- 0.18 to 4.75 +/- 1.35 in protocol 1 and 0.26 +/- 0.16 to 4.91 +/- 1.38 in protocol 2. Nontransferrin-bound iron increased from 0.74 +/- 0.69 to 3.79 +/- 1.41 micromol L(-1) in protocol 1, and from 0.90 +/- 0.92 to 2.90 +/- 0.96 micromol L(-1) in protocol 2. No significant iron concentrations were found in dialysate before or during the iron saccharate infusion. CONCLUSION: Nontransferrin-bound iron exists in plasma of dialysis patients after infusion of iron saccharate. There was no difference when 100 mg iron was given in 60 min or in 6 min. Before iron infusion, appreciable concentrations of nontransferrin-bound iron could already be detected. The clinical significance is not clear, but the findings may be important since nontransferrin-bound iron can act as a catalytic agent in the formation of hydroxyl radicals, thus potentially inducing cell damage and atherosclerosis.

Clinical outcome of daily dialysis.

Dialysis patients are prone to malnutrition, which may be counteracted by daily home hemodialysis (DHHD, 6 times a week) due to improved clinical outcome and quality of life. Eleven patients were treated with DHHD during 18 months, after a run-in period with three dialysis sessions a week. The total weekly dialysis dose was kept constant during the first 6 months of DHHD, whereupon it was allowed to increase. KT/V was 3.1 +/- 0.5 at baseline, 3.2 +/- 0.5 after 6 months and 4.0 +/- 0.8 at 18 months. Blood pressure decreased from 142 +/- 19/83 +/- 8 to 130 +/- 25/79 +/- 9 mmHg with a more than 50% reduction in antihypertensive medication. Potassium did not change, but potassium binding resins could be stopped almost completely. Bicarbonate increased from 20.6 +/- 3.3 to 23.1 +/- 2.6 mEq/L after 18 months. Patients with a protein intake of less than 1.0 g/kg/d showed a greater increase in body weight (62.3 +/- 6.0 to 65.5 +/- 3.7, P: < 0.05) and normalized protein catabolic rate (nPCR) (0.87 +/- 0.08 to 1.25 +/- 0.36, ns) than patients with acceptable protein intake (>/=1.0 g/kg/d). Phosphate decreased, though not significantly, especially in the latter group. Erythropoietin dose could be reduced from 6400 +/- 5400 U/L at baseline to 5100 +/- 4000 U/L at 18 months. Quality of life improved significantly, especially with to respect to physical condition and mental health. The DHHD markedly improves hemodynamic control and quality of life. Overall nutritional parameters did not change, except cholesterol. Patients with a low protein intake, however, showed a significant increase in body weight, and a greater rise in nPCR.

Daily home haemodialysis in The Netherlands: effects on metabolic control, haemodynamics, and quality of life.

BACKGROUND: More frequent dialysis has been claimed to improve clinical outcome and quality of life. METHODS: Clinical status was optimized in 13 haemodialysis patients during a run-in period of 2 months with three dialysis sessions a week. Thereafter, daily home haemodialysis (DHHD, 6 sessions per week) was initiated. The total weekly dialysis dose (Kt/V) was kept constant. RESULTS: Weekly Kt/V was 3.2+/-0.13 (M+/-SEM) before, and 3.2+/-0.15 after 6 months of DHHD (NS), time-averaged concentration of urea (TACu) was 21.2+/-1.6 mmol/l and 20.1+/-0.9 mmol/l (NS). Urea reduction was 0.56+/-0.05 before DHHD, and 0.41+/-0.06 during DHHD (P<0.0001). Serum K remained unchanged, but significantly less exchange resins were used (P<0.02). Also, the dose of phosphate-binding agents could be decreased. Values for Na, K, Cl, bicarbonate, Ca, PTH, albumin, and Hb remained unchanged. Iron deficiency developed in some patients. Twenty-four-hour blood pressure monitoring showed a decrease of systolic blood pressure (141.1+/-17.2 mmHg before, and 130.9+/-19.2 mmHg during DHHD, P<0.001). Diastolic blood pressure remained constant (82.8+/-7.2 and 76.9+/-10.1 mmHg, NS). Mean arterial pressure decreased from 102.2+/-9.5 to 94.9+/-1.4 mmHg (P<0.02). Blood pressure decreased mainly in previously hypertensive patients. Mean target weight increased 0.8 kg. The amount of antihypertensive drugs used decreased from 1.88+/-0.35 to 0.75+/-0.17 (P<0.005, n=7). Dialysis sessions were much more stable, also in patients with cardiac insufficiency. Quality of life questionnaires (Rand 36, Nottingham Health Profile, Uraemic Symptoms Profile) showed a significant improvement of physical condition and fewer uraemic symptoms. CONCLUSION: DHHD compared to conventional thrice-weekly haemodialysis with similar weekly Kt/V results in an improved haemodynamic control and quality of life, but has lesser impact on metabolic regulation.

The absorption of iron is disturbed in recombinant human erythropoietin-treated peritoneal dialysis patients.

BACKGROUND: Intravenous iron supplementation is often necessary in recombinant human erythropoietin (r-HuEPO)-treated haemodialysis (HD) patients, but rarely in r-HuEPO-treated peritoneal dialysis (PD) patients. This may be due to differences in iron absorption or blood loss. METHOD: Iron absorption (whole-body counting after ingestion of a radiolabelled iron test dose) and iron metabolism were compared in eight iron-replete rHuEPO-treated PD patients (serum ferritin 100-500 microg/l) and 68 healthy iron-replete controls (sufficient iron in bone marrow specimen). RESULTS: Mucosal uptake (13.4+/-9.8%), mucosal transfer (0.34+/-0.18) and iron retention (4.9+/-4.0) in PD patients was significantly lower than in controls (42.9+/-18.8%, P < 0.0001, 0.63+/-0.18, P < 0.0001, and 28.0+/-16.7%, P<0.0001). CONCLUSION: Iron absorption is impaired in PD patients, as we have shown previously for HD patients. One reason for higher iron needs in HD patients may be higher blood losses due to the dialysis procedure and blood sampling for laboratory tests.

Iron absorption in erythropoietin-treated haemodialysis patients: effects of iron availability, inflammation and aluminium.

BACKGROUND: The response to recombinant human erythropoietin (rHuEpo) is determined primarily by the availability of iron. In contrast to i.v., iron, oral iron supplementation is often insufficient for an optimal response. METHOD: We studied iron absorption and the effects of iron status, aluminium status and inflammation in 19 chronic haemodialysis patients on maintenance rHuEpo therapy. Iron mucosal uptake after 24 h, iron retention after 2 weeks and mucosal transfer of iron were determined with a whole-body counter using an oral dose 59Fe. Iron absorption was measured once without, and once after the ingestion of 2 g aluminium hydroxide. RESULTS: On the basis of transferrin saturation, two groups of dialysis patients were distinguished: a group with a functional iron deficiency (n = 9), and an iron-replete group (n = 10). In the iron-deficient dialysis patients group, mucosal uptake, mucosal transfer, and iron retention were 49.9% +/- 29.4, 0.73 +/- 0.29, and 41.6% +/- 32.2, being significantly lower than in a non-uraemic iron deficient population (P < 0.01, P < 0.05, P < 0.01 respectively). In the iron-replete dialysis patients group, mucosal uptake, mucosal transfer, and iron retention were 20.0 +/- 12.3, 0.59 +/- 0.18, and 11.1 +/- 6.7, mucosal uptake and iron retention being lower than in a normal iron-replete population (P < 0.0005 and P < 0.003 respectively). Dialysis patients with high C-reactive protein (CRP) values showed lower iron absorption. Iron absorption data correlated significantly with transferrin saturation and CRP in the iron-deficient group, and with serum ferritin in the iron-replete group. Iron absorption decreased after an aluminium hydroxide challenge in the iron-deficient patients to the lower levels of the iron-replete subjects. Body aluminium stores, estimated by the desferrioxamine test, did not correlate with parameters of iron absorption. CONCLUSION: The absorption of iron in dialysis patients is decreased in haemodialysis patients, which may, at least in part, be due to inflammation. Aluminium ingestion further reduces absorption in functional iron-deficient patients.

The management of iron metabolism in recombinant human erythropoietin treated dialysis patients by Dutch nephrologists.

BACKGROUND: The regulation of iron metabolism is an important aspect of r-HuEPO treatment. METHOD: All Dutch nephrologists involved in dialysis were asked to complete a questionnaire about iron metabolism management in dialysis patients. RESULTS: The response rate was 68%, covering 83% of all Dutch dialysis units. Iron status is assessed before starting r-HuEPO by 96% of the respondents, but only 58% waits for the results. Serum ferritin is determined by 98%, MCV by 77%, transferrin saturation by 44%, the percentage hypochromic red blood cells by 6%, bone marrow iron staining by 4%, and serum transferrin receptors by 0%. Serum ferritin is considered to be the most important parameter by 48%, transferrin saturation by 37%, percentage hypochromic red blood cells and serum transferrin receptors by 0%. Of the respondents, 17% determines iron status twice a year, 13% three times, 54% four times, 4% six times, 4% eight times, and 8% twelve times. Iron is given to all patients by 40% of the nephrologists, 60% prescribes iron on indication. Oral substitution is preferred by 90%, but 27% incidentally prescribes intravenous iron without testing the effects of oral iron. Of all haemodialysis patients on r-HuEPO, 16% (SD 18, median 10) receives no iron substitution, 65% (+/- 28, 73) oral iron and 19% (+/- 28, 6) intravenous iron. Of all CAPD patients, 22% (+/- 24, 16) receives no iron substitution, 77% (+/- 24, 81) oral iron, and 1% (+/- 2, 0) intravenous iron. CONCLUSION: There is no communis opinio among Dutch nephrologists on the frequency of iron status assessment, the choice of parameters, the indications for iron substitution, or the decision between oral or intravenous substitution.

Low-dose aspirin does not prevent thrombovascular accidents in low-risk haemodialysis patients during treatment with recombinant human erythropoietin.

Treatment of the anaemia of renal disease with recombinant human erythropoietin results in an improvement of haemostasis and an increased risk of thrombovascular accidents. In this prospective, placebo-controlled, double-blind, and cross-over study, the effects of low-dose acetylsalicylic acid (30 mg daily) on thrombotic and bleeding events during the initial period of treatment with erythropoietin in anaemic haemodialysis patients without previous thrombovascular accidents or known increased risk for thrombosis were investigated. During correction of the haematocrit and the first 3 months thereafter, group A (n = 68) received placebo and group B (n = 69) 30 mg acetylsalicylic acid daily. Cross-over took place after the 3rd month of a stable haematocrit. The study ended 3 months later. Target haematocrit (30-35%) was reached in 12.4 +/- 8 weeks (M +/- SD). In group A the bleeding time was 382 +/- 285 s, decreasing to 282 +/- 208 before cross-over (P < 0.01), and increasing to 395 +/- 271 (P < 0.05) thereafter. In group B the bleeding time was 390 +/- 381 s, 406 +/- 267 (NS), and 285 +/- 238 (P < 0.05) respectively. Twenty-two thrombovascular accidents were seen (16%, 13 during acetylsalicylic acid and 9 during placebo, NS), including 17 fistula thromboses. The incidence of bleeding events was not significantly different between regimens. In conclusion, erythropoietin treatment resulted in a reduction of the bleeding time. When 30 mg acetylsalicylic acid was taken during the treatment, the bleeding time did not decrease.(ABSTRACT TRUNCATED AT 250 WORDS)

Iron metabolism in patients with the anaemia of end-stage renal disease during treatment with recombinant human erythropoietin.

Iron metabolism was studied in 21 patients with the anaemia of end-stage renal disease during 40 weeks of treatment with recombinant human erythropoietin (rhEPO). Oral iron was prescribed to all patients. Initial serum iron concentrations and transferrin saturation levels were subnormal, decreased during the correction period of treatment, and increased thereafter. In 81% of patients in whom pretreatment transferrin saturation was below 0.25, transferrin saturation decreased below 0.16, despite sufficiently high serum ferritin levels. Serum ferritin concentrations decreased significantly. There was no correlation between serum ferritin levels and serum iron or transferrin saturation. Ferrokinetic studies, performed before and during treatment, showed an increase in plasma iron turnover, in erythron transferrin uptake, and in the flux of iron binding sites through the plasma. The rhEPO dose needed to keep the haematocrit at the target level during the maintenance period of treatment was significantly correlated with transferrin saturation, and iron binding capacity, but not with serum ferritin concentrations. This suggests that the functional availability of iron in plasma, rather than the size of body iron stores, is a major factor in the determination of the response to rhEPO treatment in end-stage renal disease.