High-Target Hemodiafiltration Convective Dose Achieved in Most Patients in a 6-Month Intermediary Analysis of the CONVINCE Randomized Controlled Trial.

Introduction: High convection volumes in hemodiafiltration (HDF) result in improved survival; however, it remains unclear whether it is achievable in all patients. Methods: CONVINCE, a randomized controlled trial, randomized patients with end-stage kidney disease 1:1 to high-dose HDF versus high-flux hemodialysis (HD) continuation. We evaluated the proportion of patients achieving high-dose HDF target: convection volume per visit of ≥23 l (range ±1 l) at baseline, month 3, and month 6. We compared baseline characteristics in the following 2 ways: (i) patients on target for all 3 visits versus patients who missed target on ≥1 visits and (ii) patients on target for all 3 visits or missing it once versus patients who missed target on ≥2 visits. Results: A total of 653 patients were randomized to HDF. Their mean age was 62.2 (SD 13.5) years, 36% were female, 81% had fistula vascular access, and 33% had diabetes. Across the 3 visits, 75 patients (11%), 27 patients (4%), and 11 patients (2%) missed the convection volume target once, twice, and thrice, respectively. Apart from diabetes, there were no apparent differences in patient characteristics between patients who always achieved the high-dose target (83%) and those who missed the target either once or more (17%) or twice or more (6%). Conclusion: Achieving high-dose HDF is feasible for nearly all patients in CONVINCE and could be maintained during the 6-month follow-up period. Apart from diabetes, there were no other indications for confounding by indication on multivariable analyses that may explain the potential survival advantage for patients receiving high-dose HDF.

A theoretical investigation of the supersaturation of basic calcium phosphate in serum of dialysis patients.

Extraosseous calcification in hemodialysis (HD) patients consists mainly of biological apatite, idealized as hydroxyapatite. Other suggested calcium phosphates are octacalcium phosphate (OCP) and brushite, both known to be hydroxyapatite precursors. Whatever the mechanisms of mineral deposition are, these mechanisms are always required to produce a supersaturated state, and that state can be calculated from the solubility product (SP) of the relevant mineral. Supersaturation in relation to serum ionized calcium [Ca 2+] and total inorganic serum phosphate (Pi) under normal and hyperphosphatemic conditions has been calculated. While supersaturation with respect to hydroxyapatite and OCP always exists, and supersaturation with respect to Ca5 (PO4)3 (HCO3) . 4H2O is just above the limit, supersaturation with respect to brushite solely occurs under hy-perphosphatemic conditions. In order to avoid supersaturation with respect to brushite the maximum serum phosphate level al-lowed is 1.9 mmol/L (5.8 mg/dl) and the calcium-phosphate product (Ca x P) 4.5 (mmol/L)2 (56 (mg/dl))2 .

Evidence of calcium phosphate depositions in stenotic arteriovenous fistulas.

This study investigates vascular samples from patients with and without end-stage renal disease (ESRD) to determine the occurrence of calcium depositions. Findings in stenotic arteriovenous (AV)-fistula veins were compared with those of nonstenotic AV-fistula veins, non-AV-fistula veins, and atherosclerotic vessels. Calcium and phosphorus content was measured by means of scanning electron microscopy and its built-in method of energy-dispersive spectrometry (EDS) X-ray analysis. We found calcium and phosphorus in samples from AV fistulas with stenotic areas with a calcium/phosphorus molar ratio of 1. Based on EDS analysis and crystal shape comparison, we conclude that calcium phosphate precipitations in stenotic AV fistulas are brushites with the composition CaHPO(4)*2H(2)O. This specific calcium phosphate deposition was found solely in stenotic AV fistulas, not in nonstenotic AV-fistula veins or non-AV-fistula veins regardless of whether the patient had ESRD. Moreover, this calcium phosphate deposition was different from calcium compounds found in atherosclerotic samples. Whether the precipitation of brushite is primarily involved in the development of vascular-access stenosis or represents a secondary consequence cannot be determined from the present study.

Corticotropin-induced reduction of plasma lipoprotein(a) concentrations in healthy individuals and hemodialysis patients: relation to apolipoprotein(a) size polymorphism.

Lipoprotein(a) [Lp(a)], a strong independent cardiovascular risk factor, consists of the unique apolipoprotein(a) [apo(a)] covalently linked to a low-density lipoprotein particle. Apo(a) contains a widely differing number of the plasminogen-like kringle IV, a size polymorphism that is codominantly inherited. In addition to powerful genetic control, renal failure is known to influence the plasma Lp(a) concentration. There is still a lot to be learned about the mode and site of catabolism of Lp(a), and there is no readily applicable Lp(a)-lowering treatment available. Therefore, it was of interest to study further the Lp(a)-lowering effect of corticotropin (ACTH) that has been demonstrated in small studies. The main purpose of the present study was to investigate the influence of ACTH on different apo(a) isoforms. Short-term treatment with ACTH decreased the plasma Lp(a) concentration in all 26 study participants. The two study groups (12 healthy individuals and 14 hemodialysis patients) responded similarly, with a median decrease in plasma Lp(a) of 39% and 49%, respectively. In subjects with two clearly separable apo(a) bands, apo(a) phenotyping and densitometric scanning of the bands before and after treatment with ACTH revealed a change in the proportion of apo(a) isoforms, ie, a shift toward the isoform with lower molecular weight. This was observed in seven of nine investigated subjects (four of five healthy individuals and three of four hemodialysis patients).

Circulating neuropeptide Y in plasma from uremic patients consists of multiple peptide fragments.

Increased plasma levels of neuropeptide Y (NPY)-like immunoreactivity (p-NPY-LI) have been described in hemodialysis (HD) patients. In this investigation the effect of a standard HD on p-NPY-LI, analyzed by radioimmunoassay and reverse-phase high performance liquid chromatography (HPLC), was studied. During dialysis p-NPY-LI increased from 128 +/- 5 to 154 +/- 8 pmol/l (p < 0.01). The change in p-NPY-LI during the treatment correlated with the ultrafiltration volume (rs = +0.72, p < 0.05). The HPLC separation revealed a complex pattern of NPY-immunoreactive peptides. This was true of the plasma of the control subjects as well as of the uremic plasma. In the case of the controls and the HD patients prior to dialysis, the amount of NPY-LI was rather small. After the dialysis qualitative as well as quantitative changes of the chromatogram were found. Some of the peaks seemed to have a retention time similar to that of the known fragments of synthetic human NPY used as markers. In conclusion, an increase in p-NPY-LI occurred during the dialysis, probably due to fluid removal. The increased level of NPY-LI in uremic plasma represents a mixture of different NPY fragments.

Changes in plasma levels of vasoactive substances during routine acetate and bicarbonate hemodialysis.

Hemodynamic stability is better preserved during bicarbonate hemodialysis compared to acetate. We have studied the effects of bicarbonate (HDB) and acetate hemodialysis (HDA) on plasma levels of vasoactive substances. The treatments were performed for 270 min. A cuprophan plate dialyzer was used. The ultrafiltration volume and the ultrafiltration rate were identical in the individual patients during the two treatments. In the case of vasoconstrictors there was an increase in neuropeptide Y (NPY) (20%, p < 0.01) during HDB and arginine vasopressin (AVP) was unchanged. Unlike this was the response during HDA when there was no change in NPY and a decrease in AVP (38%, p < 0.01). An increase in noradrenaline (NA) (41%, p < 0.05) occurred during HDA different from what was the case during HDB. There was a gradual increase in renin (PRA) during both HDB (141%, p < 0.05) and HDA (148%, p < 0.01). With respect to vasodilators there were no differences between the two regimes regarding calcitonin gene-related peptide (CGRP) and motilin (MOT). The change in substance P (SP) during the treatments was also similar but somewhat more pronounced during HDB. Thus, an initial rise occurred (HDB, 81%, p < 0.01; HDA, 36%, p < 0.05) followed by a decrease (HDB, 26%, p < 0.05) or a tendency to decrease (HDA, 12%, p = 0.058) during the remaining part of the treatment. A rise in beta-endorphin (beta-END) occurred during HDB (10%, p < 0.05) but not during HDA. An increase in vasoactive intestinal peptide (VIP) occurred during HDB (27%, p < 0.05) different from the decrease during HDA (11%, p < 0.05).(ABSTRACT TRUNCATED AT 250 WORDS)

Plasma concentrations of vitamin C, vitamin E and/or malondialdehyde as markers of oxygen free radical production during hemodialysis.

To investigate the effects of neutrophil activation during hemodialysis (HD), blood markers of oxygen free radical (OFR) activity were studied. Two groups of HD patients on standard cuprophane treatment were investigated after an overnight fast. In the first group (mean age 68 +/- 8 years; n = 6) vitamin supplementation was withdrawn two weeks prior to the study, whereas the second group (mean age 73 +/- 3 years; n = 7) continued their normal vitamin intake. The two control groups, one consisting of age-matched subjects (mean age 72 +/- 2 years; n = 21), the other of younger subjects (mean age 36 +/- 7 years; n = 11), were asked to cease vitamin supplementation two weeks before the study and to fast overnight before blood sampling. Serial blood and dialysate samples were collected during HD in the vitamin-deprived patient group, and a single blood sample was collected in the other three groups. Plasma concentrations of vitamin C (total and reduced form), vitamin E (alpha-tocopherol) and malondialdehyde (MDA) were determined with newly adopted and validated HPLC methods. Basal plasma vitamin C concentrations were lower among vitamin-deprived HD patients than among age-matched controls or vitamin-supplemented HD patients (22 +/- 6 microM versus 39 +/- 19 microM and 34 +/- 10 microM, respectively). During a 3-hour HD session, the mean decrease in total vitamin C was 40%. Basal alpha-tocopherol concentrations did not differ significantly between vitamin-deprived HD patients and vitamin-supplemented HD patients or age-matched controls (39 +/- 5 microM versus 40 +/- 11 microM and 38 +/- 6 microM, respectively), but were lower in younger controls (33 +/- 4 microM). No alpha-tocopherol was detected in the dialysate, and its plasma concentration did not change significantly during a single HD session. Basal plasma MDA concentrations were higher in vitamin-supplemented HD patients than in vitamin-deprived HD patients or age-matched controls (1.5 +/- 0.2 microM versus 0.9 +/- 0.2 microM and 1.1 +/- 0.2 microM, respectively). No MDA was detected in the dialysate, and its plasma concentration did not change significantly during a single HD session. Our results indicate an increased need of vitamin C supplementation in HD patients. The concentration of oxidized vitamin C seems to peak early during HD and may be of value as a marker of OFR production. alpha-tocopherol concentrations do not change during HD and do not differ from those in control subjects. MDA may increase over a longer period of time on dialysis, but does not change during a single HD treatment.

Dose regimen adjustment for milrinone in congestive heart failure patients with moderate and severe renal failure.

This study was designed to test a proposed dose modification for intravenous milrinone in congestive heart failure patients (CHF, NYHA I-II) with either moderate or severe renal impairment. All the patients were administered an intravenous loading dose of drug at 50 micrograms kg-1 over 10 min. This was followed by an 18 h maintenance infusion of milrinone at 0.45 or 0.35 micrograms kg-1 min-1 for the moderate (chromium-EDTA clearance of 31-75 mL min-1, n = 10) and severe renally impaired subjects (chromium-EDTA of clearance 10-30 mL min-1, n = 11), respectively. Plasma and urine samples were collected for up to 34 h and analysed for parent drug by validated HPLC methods. The mean (+/- s.d.) steady-state plasma concentrations of milrinone were within the therapeutic range (100-300 ng mL-1) for both groups, with values of 239 +/- 71 ng mL-1 and 269 +/- 32 ng mL-1 for the moderate and severe patients, respectively. No statistical differences were observed between the steady-state values for the two groups. With the exception of two patients per group, individual steady-state levels were also within the therapeutic range. Those outside the nominal range showed steady-state levels, ranging between 308 and 353 ng mL-1, that were not associated with any serious adverse events.(ABSTRACT TRUNCATED AT 250 WORDS)

The effect of dialysis on radiocaesium in man.

Dialysis is used for cleaning the blood in patients with end-stage renal disease. The most common methods are hemodialysis (HD) and peritoneal dialysis (PD). Dialysis patients might constitute a critical group because of poor elimination of radioactive elements ingested. On the other hand dialysis may be a useful decontamination method for radioactivity. The effect of dialysis on the turnover of radiocaesium was studied in 10 HD patients and 4 PD patients. The dialysis fluid, which contains electrolytes and the metabolic waste products, was analyzed for radiocaesium. In this connection the patients were whole-body counted for radiocaesium and 40K. The results show that HD patients generally have a lower body burden of radiocaesium than normal subjects, while PD patients show normal levels. At steady state both dialysis methods eliminate slightly less radiocaesium than normal kidneys do, but in the case of HD during a much shorter time. The calculated effective half-life for radiocaesium was normal in the HD patients, and somewhat longer in the PD patients. Considering that HD is performed only for 12-15 h weekly, the elimination rate of radiocaesium by HD is much higher compared with that by normal kidneys. Thus, HD might constitute an important method for decontamination of radiocaesium after accidental internal contamination.

Dialysis fluid temperature and vasoactive substances during routine hemodialysis.

Blood pressure stability is better during cold hemodialysis (HD). This has mainly been attributed to a more pronounced sympathetic activation during cold than during warm HD. The authors studied the effect of dialysate temperature on vasoactive peptides, noradrenaline (NA), and renin (PRA). Ten hemodynamically stable patients were dialyzed for 240 min with each of two dialysate temperatures: 38.5 degrees C (warm HD = WHD) and 34.5 degrees C (cold HD = CHD). A decrease (P < 0.05) in blood pressure occurred during WHD; however, during CHD, blood pressure was stable. There were no differences in vasoconstrictors between the two regimens. There was a decrease in NA (P < 0.05), a tendency of PRA to increase (NS owing to a large statistical spread), while arginine vasopressin was unchanged. During CHD, there was a small increase in neuropeptide Y (NPY); however, during WHD, NPY only tended to increase. However, the relative NPY levels (percent of baseline levels) after WHD and CHD did not differ. The vasodilator response was similar during both treatments. Calcitonin gene related peptide was unaltered. Motilin tended to decrease initially, but then increased (P < 0.05) to baseline levels. An increase occurred in beta-endorphin (P < 0.05) and substance P(P < 0.01). There was an initial rise (P < 0.05) in vasoactive intestinal peptide (VIP), followed by a tendency to decrease during the remainder of treatment. The authors concluded that blood pressure stability was better during CHD. However, this was not reflected by differences in plasma levels of the vasoactive peptides, nor did they find any difference in the sympathetic drive between the two regimens.

First clinical experience with a new concentrate system for dialysis with dry sodium chloride.

Clinical investigation of a new concentrate system for preparing the acid concentrate in bicarbonate dialysis was performed to evaluate handling, safety aspects, and correct mixing of the final dialysis fluid. The system is characterized by an acid concentrate prepared from two components: a cartridge containing 1.1 kg dry sodium chloride and a concentrate bag with 500 ml of a highly concentrated solution of electrolytes (KCl, MgCl2, CaCl2) and acetic acid. The investigation comprised a total of 142 treatments. The concentrate system was well accepted by the clinical staff and considered safe and easy to handle. Marginal deviations in electrolyte concentration of the dialysis fluid relative to set values were observed, but were considered to lack biologic or clinical relevance. The new concentrate system will facilitate the handling of dialysis concentrates and provide a convenient means for individual tailoring of the dialysis fluid composition.

Effects of sham hemodialysis on plasma levels of vasoactive peptides in patients with uremia.

Changes in plasma levels of vasoactive peptides during hemodialysis have mainly been attributed to changes in plasma volume and osmolality. This study investigated the effect of the extracorporeal circulation on plasma levels of vasoactive peptides, noradrenaline, and renin. Eleven stable hemodialysis patients were studied during sham dialysis for 60 min using a Cuprophan dialyzer (Alwall GFE11, Gambro AB, Lund, Sweden). With regard to vasoconstrictors, there was an increase in noradrenaline (NA) (13%, p < 0.05) and renin (PRA) (32%, p < 0.05), while arginine vasopressin and neuropeptide Y remained unaltered. Concerning vasodilators, an increase in substance P (SP) (23%, p < 0.05) and vasoactive intestinal peptide (VIP) (15%, p < 0.01) was observed, while a decrease in atrial natriuretic peptide (ANP) (17%, p < 0.05) and motilin (MOT) (24%, p < 0.01) occurred. Calcitonin gene related peptide and beta endorphin were unaltered. A decrease in blood pressure was observed, while heart rate remained unchanged. The authors conclude that the extracorporeal circulation, per se, affects plasma levels of vasoactive substances and influences vascular stability. The decrease in ANP and MOT might be due to adsorption to the dialysis membrane. The increase in some vasoconstrictors (NA, PRA) and vasodilators (SP, VIP) might be induced by the blood-artificial surface contact, or by other factors, e.g., heparin or cooling of the blood during the procedure.

Effects of recombinant human erythropoietin on the plasma levels of vasoactive regulatory peptides in patients on maintenance hemodialysis.

The plasma levels of nine vasoactive regulatory peptides were measured by radioimmunoassay in six stable patients with chronic renal failure on regular hemodialysis, before and during treatment with recombinant human erythropoietin (r-huEPO). All patients responded with significant increases in hemoglobin concentrations and hematocrit. Mean arterial blood pressure was not significantly changed nor were there any changes of body weight or interdialytic body weight gain. The mean plasma levels of atrial natriuretic peptide and motilin decreased significantly, by 38 and 16 percent respectively, during r-huEPO treatment. There were no changes in mean plasma levels of arginine vasopressin, calcitonin gene-related peptide, beta-lipotropin, gamma 2-melanocyte-stimulating hormone, neuropeptide Y, substance P or vasoactive intestinal peptide. No significant correlations were observed between changes of plasma peptide levels and changes of mean arterial blood pressure.

Development of a urea concentration gradient between muscle interstitium and plasma during hemodialysis.

In this pilot study, muscle interstitial urea concentrations during hemodialysis (HD) were determined with a microdialysis technique and the results were compared with plasma water urea concentrations. Three patients were investigated during a total of five treatments. Under predialysis steady-state conditions, no difference was observed. During treatment, the muscle interstitial urea concentration was on average 19% higher (range 13-28%, n=4) than the plasma urea concentration after 17+/-3 min, 29% higher (25-31%, n=3) after 53+/-10 min, 40% higher (26-50%, n=3) after 117+/-6 min, 31% higher (26-34%, n= 3) after 179+/-5 min, and 31% higher (27-36%, n=4) after 231+/-5 min. The gradient declined after the conclusion of HD, muscle interstitial concentrations being on average 16% (9-26%, n=4) higher than plasma urea concentrations 9+/-2 min after treatment, and 8% (6-10%, n=3) 25+/-3 min after treatment. Thus, a urea concentration gradient with a higher concentration in muscle interstitium than in plasma, developed during HD, and dissipated gradually after treatment. This is consistent with blood flow-dependent urea sequestration in muscle tissue, causing intercompartment disequilibrium of urea during HD, and its consequent redistribution after treatment contributing to postdialysis urea rebound.

Comparison of slow-release piretanide and bendroflumethiazide in the treatment of mild to moderate hypertension.

After 4 weeks of placebo treatment, 76 hypertensive patients were randomly allocated to 6 or 12 mg/day piretanide, or 2.5 mg/day bendroflumethiazide for 12 weeks in a double-blind study. Piretanide was given in a slow-release formulation and bendroflumethiazide as a tablet. All three treatments produced a significant reduction in supine and erect systolic and diastolic blood pressures after 2 weeks, and this effect was maintained throughout the study. Normotension (i.e. supine diastolic pressure less than or equal to 95 mmHg) was achieved in 73% of the patients receiving 12 mg/day piretanide and in 57% receiving 6 mg/day piretanide compared with 72% receiving bendroflumethiazide (not significant). Overall, five patients were withdrawn due to increased diuresis: two patients on each dosage of piretanide and one receiving bendroflumethiazide. Three patients receiving 6 mg/day piretanide were withdrawn due to diastolic blood pressure rising above 120 mmHg. Other side-effects reported were mild and transient. There were no significant changes in serum creatinine, glucose or high-density lipoprotein cholesterol. A small, but non-significant rise in uric acid level was seen in all three groups. Clinically relevant hypokalaemia requiring potassium supplementation occurred in three patients receiving bendroflumethiazide.

Generation of nitrate during dialysis as a measure of nitric oxide synthesis.

Nitric oxide (NO) is a recently identified messenger, which influences the local regulation of blood flow and platelets as well as neuronal and inflammatory pathways. Disturbed NO information might be involved in the uremic syndrome and might also cause hypotension during dialysis. To clarify these issues, we analyzed plasma and dialysis fluid concentrations of nitrate, the stable NO metabolite, in 9 patients during hemodialysis. Plasma nitrate was raised at the onset of dialysis as compared with healthy subjects (83 +/- 9 versus 26 +/- 2 mumol/L). The plasma concentration decreased to 20 +/- 2 mumol/L (p < 0.01) during the dialysis. The relative decrease was more pronounced than the relative reduction in creatinine, phosphate, and urea concentrations. A parallel decrease in nitrate was seen in effluent dialysis fluid (32 +/- 4 to 14 +/- 1 mumol/L; p < 0.01). Calculations of the amount of nitrate coming to and from the dialyzer were performed in 7 of the 9 patients, and in 5 of the 7 patients, generation of nitrate within the dialyzer could be postulated. This might explain the paradoxical venodilation noted during hemodialysis.

Heparin and vasoactive peptides in hemodialysis patients.

Plasma concentrations of vasoactive peptides have been reported to be influenced by various procedural features of hemodialysis (HD), such as ultrafiltration and isovolemic diffusion, dialysate buffer and dialysate temperature, but also by sham HD thus reflecting an effect of the extracorporeal circulation per se. In the present study the effect of heparin administration was investigated in 9 stable HD patients, and compared with that of saline. Blood samples were taken from the arteriovenous fistula before and 45 min after the administration of heparin or saline. After an interval of 2 weeks, the procedure was repeated with the exception that the patients who received heparin on the first occasion were given saline and vice versa. Plasma concentrations of the vasoactive peptides were measured by radioimmunoassay. Regardless of whether heparin was given or not, the plasma concentrations of the vasodilators atrial natriuretic peptide, beta-endorphin and vasoactive intestinal peptide did not change, nor did the concentration of the vasoconstrictor neuropeptide Y. The plasma motilin concentration decreased significantly when heparin was given, and that of substance P increased, both these peptides being vasodilators. Mean arterial blood pressure decreased regardless of whether heparin was given or not, and no difference between the two regimens was noted. Heart rate was unchanged with both regimens. To sum up, administration of heparin but not of saline affected the plasma concentrations of motilin and substance P. However, the decrease in blood pressure during the procedure seemed not to be related to the changes in these peptides, as it also occurred in the absence of heparin.

Elevated plasma levels of opioid peptides and delta sleep-inducing peptide but not of corticotropin-releasing hormone in patients receiving chronic hemodialysis.

The fasting plasma levels of corticotropin-releasing hormone (CRH), delta sleep-inducing peptide (DSIP), beta-endorphin (beta-END), methionine-enkephalin (m-ENK), beta-lipotropin (beta-LPH), and alpha-melanocyte-stimulating hormone (alpha-MSH) were measured by radioimmunoassay in 22 stable patients with chronic renal failure on regular hemodialysis treatment and compared with those of 10 healthy controls. The plasma concentrations of DSIP, beta-END, m-ENK, beta-LPH, and alpha-MSH were increased. The plasma level of CRH was not different from that of the controls. The elevated plasma levels of endogenous opioid peptides and DSIP may contribute to the uremic syndrome, although this must be further elucidated.