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J Hegbrant

Publications and source records attributed to J Hegbrant.

At least 19 recordsLinked to original sources

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.

Adult↗

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).

Adrenocorticotropic Hormone↗

Influence of haemodialysis on plasma total homocysteine concentration.

BACKGROUND: The high prevalence of hyperhomocysteinaemia in uraemic patients is of interest because of the cardiovascular risk associated with increased plasma total homocysteine (tHcy) concentration. Treatment with folic acid lowers tHcy in haemodialysis patients, however, in most patients not to normohomocysteinaemic levels. With possible tHcy-lowering modifications in mind, we studied the influence of standard haemodialysis on tHcy. METHODS: In 56 folate-loaded haemodialysis patients, tHcy and parameters of dialysis adequacy were measured. In six patients, interdialytic curves of tHcy and serum creatinine concentrations were obtained and in five patients, the amount of homocysteine (Hcy) in dialysate was determined. RESULTS: tHcy (21.8+/-14.4 micromol/l) correlated significantly with Kt/V (r=0.32, P<0.05), total Kt/V (r=0.29, P<0.05), nPCR (r=0.30, P<0.05) and serum concentrations of albumin (r=0.28, P<0.05) and cobalamines (r=-0.27, P<0.05). In a multiple linear regression analysis, only serum albumin concentrations significantly predicted tHcy (r=0.34, P < 0.05). During dialysis, tHcy decreased by 28% and remained constant for at least 8 h after treatment. The amount of Hcy recovered in dialysate was 63 micromol (12-158 micromol). There was no difference in tHcy between those who had residual renal function and those who had not. CONCLUSIONS: The direct relationship between tHcy and Kt/V seemed to be mediated by the serum albumin concentration. The shape of the interdialytic tHcy curve suggested facilitated Hcy removal for at least 8 h after dialysis possibly due to reduced levels of inhibitory activities against relevant enzyme(s). The dialysed amount of Hcy did not seem to contribute significantly to Hcy removal. Thus, modifications of standard dialytic regimens are not likely to be effective from a tHcy-lowering point of view whereas convective procedures such as haemofiltration or haemodiafiltration might be more effective.

Aged↗

Assessment of pH and oxygen status during hemodialysis using the arterial blood line in patients with an arteriovenous fistula.

BACKGROUND: In patients with arteriovenous fistulas, assessment of pH and oxygen status during hemodialysis (HD) using the extracorporeal dialysis arterial blood line is widely used both in daily routine and in most studies investigating hypoxia during HD. We designed this study to evaluate whether results of blood gas samples drawn from the extracorporeal arterial line were clinically acceptable in assessing oxygen status. METHODS: We compared samples drawn from the extracorporeal arterial line with conventionally arterial punctures during 18 routine HD sessions. The samples were drawn simultaneously and analyzed immediately for blood gases, pH and hemoximetry values. RESULTS: No significant difference was found between the values from the radial artery and the extracorporeal arterial blood line except for FMetHb. CONCLUSION: Thus, obtaining samples from the extracorporeal dialysis arterial blood line to evaluate the parameters of the oxygen status (pH, pO(2), pCO(2), ctHb, sO(2), FCOHb and ctO(2)) during routine HD is a clinically convenient and accurate sampling approach.

Arteriovenous Shunt, Surgical↗

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.

Aged↗

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.

Aged↗

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.

Aged↗

Beneficial effect of cold dialysate for the prevention of hemodialysis-induced hypoxia.

Hypoxia occurs frequently during routine hemodialysis (HD). In this study the effect of dialysate temperature on arterial blood gas parameters was investigated. Ten stable HD patients (2 smokers) were dialyzed for 240 min with each of three different dialysate temperatures: 36.5 degrees C (normal temperature HD; NHD), 38.5 degrees C (warm HD; WHD) and 34.5 degrees C (cold HD; CHD). A cuprophane plate dialyzer was used. The ultrafiltration volume was identical in each patient. Arterial blood gas samples were frequently (approximately 10 times/treatment) taken during the dialysis and immediately analyzed. The dialysate temperature significantly affected PaO2 (p < 0.001) but not PaCO2. We also compared the effect of NHD with that of WHD and CHD, respectively, as regards PaO2. NHD and WHD differed significantly p < 0.01), whereas NHD and CHD were not significantly different. However, the relative PaO2 value (% of the baseline value) at the end of CHD (105 +/- 5%) was significantly higher than after both NHD (96 +/- 4%, p < 0.01) and WHD (91 +/- 3%, p < 0.01). In the case of NHD and WHD the fraction of time during which the patients had a PaO2 value below 80 mm Hg was 62 and 64%, respectively. The corresponding figure for CHD was 44%. Arterial oxygen saturation (SaO2) increased during CHD from 95.2 +/- 0.6 to 96.7 +/- 0.6% (p < 0.05), while SaO2 was unchanged during NHD and WHD. The positive effect of CHD was evident in 7 patients. In 1 patient PaO2 was not affected by the dialysate temperature, while in the remaining 2 patients (smokers) a decrease in PaO2 was induced by WHD as well as CHD. A separate statistical analysis with the 2 smokers excluded was performed, which showed that the dialysate temperature significantly affected PaO2 (p < 0.001). A comparison between NHD and CHD showed a significant difference (p < 0.001), whereas NHD and WHD did not differ significantly. When the 2 smokers were excluded from the analysis the fraction of time with a PaO2 value below 80 mm Hg was 60% during NHD and 56% during WHD, but it was reduced to 31% during CHD. In conclusion, despite the existence of interindividual variations most patients seemed to benefit from cold dialysate for the prevention of dialysis-induced hypoxia.

Adult↗

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.

Adult↗

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.

Body Burden↗

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.

Aged↗

Oxygen status during haemodialysis. The Cord-Group.

Hypoxia during haemodialysis, mainly acetate, has been reported several times. In our study we have monitored oxygen status during 258 bicarbonate haemodialyses. A significant drop below 80 mmHg in mean oxygen tension occurred. Mean oxygen saturation reflected this drop but did not reach levels below 90%. The mean oxygen concentration was on the whole critical low, though slightly increasing during each haemodialysis session due to ultrafiltration. It is concluded that both hypoxia and hypoxaemia do occur during bicarbonate haemodialysis. To a group of patients generally having limited cardiac reserves, a poor oxygen status is a potentially serious complication to haemodialysis. Monitoring oxygen status is thus advisable.

Acetates↗

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)

Adult↗

Delayed decrease in plasma levels of atrial natriuretic peptide during cold hemodialysis.

The high plasma levels of the vasodilating hormone atrial natriuretic peptide (alpha-ANP), observed in patients with chronic renal failure, decrease substantially during hemodialysis (HD), probably owing to volume reduction. Cardiovascular stability is better maintained by the use of cold dialysate although underlying mechanisms are unknown. In order to investigate the effects of different dialysate temperatures on hemodynamic stability and plasma levels of immunoreactive ANP (p-irANP), 10 stable HD patients were dialyzed with bicarbonate dialysis fluid for 240 min with each of 3 different dialysate temperatures: 36.5 degrees C (normal HD; NHD), 38.5 degrees C (warm HD; WHD) and 34.5 degrees C (cold HD; CHD). A Cuprophan plate dialyzer was used. The ultrafiltration volume and ultrafiltration rate were identical in each patient during the treatments. p-irANP was determined by radioimmunoassay, using 2 antisera which different cross-reactivity to ANP-related peptides. During NHD a nonsignificant decrease in mean arterial blood pressure from 111 +/- 5 to 103 +/- 8 mm Hg was observed. A significant (p < 0.05) decrease in mean arterial blood pressure from 109 +/- 4 to 96 +/- 6 mm Hg occurred during WHD, while during CHD it remained stable (111 +/- 4 before, 112 +/- 5 mm Hg after). Irrespective of the dialysate temperature or the antiserum used, p-irANP decreased significantly (p < 0.05) during the treatment. The reduction in p-irANP was delayed during CHD, the decrease being significantly (p < 0.05) less pronounced after 120 min. At the end of the treatment no significant difference was observed between the regimes.(ABSTRACT TRUNCATED AT 250 WORDS)

Adult↗

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)

Acetates↗

Changes in plasma levels of vasoactive peptides during standard bicarbonate hemodialysis.

During bicarbonate hemodialysis, there is an increase in peripheral vascular resistance of nonadrenergic origin, counteracting the hypotensive effect of fluid removal during the course of the dialysis. In this study, the plasma levels of vasoactive regulatory peptides, noradrenaline and renin, were investigated in 11 patients with chronic renal failure during standard bicarbonate hemodialysis (STHD) for 270 min. As regards vasoconstrictors, an increase in gamma 2-melanocyte-stimulating hormone (gamma 2-MSH), neuropeptide Y (NPY) and plasma renin activity (PRA) occurred. However, arginine vasopressin and noradrenaline were unchanged. With respect to vasodilators, calcitonin gene-related peptide was not changed. An initial increase in beta-endorphin (beta-END) occurred, followed by a decrease during the remaining part of the treatment. Motilin decreased during the first part of the treatment but increased to the baseline level during the latter part. An increase in substance P was observed while vasoactive intestinal peptide decreased. We conclude that an increase in vasoconstricting substances (gamma 2-MSH, NPY, PRA) occurs during STHD, probably owing to the decrease in plasma volume. With the exception of beta-END, the changes in vasodilators were fairly small. The data suggest that vasoactive substances might participate in the hemodynamic response to hemodialysis.

Adult↗

Changes in plasma levels of vasoactive peptides during sequential bicarbonate hemodialysis.

The hemodynamic response to isolated ultrafiltration (IUF) is characterized by a vasoconstriction, while there is no significant change in peripheral vascular resistance during isovolemic bicarbonate hemodialysis (IVHD). The present investigation was designed to study the plasma levels of vasoactive regulatory peptides together with noradrenaline (NA) and plasma renin activity (PRA) in 11 patients during sequential hemodialysis (SQHD) - IUF for 60 min, followed by IVHD for 210 min. During IUF, the vasoconstrictors arginine vasopressin (AVP), gamma 2-melanocyte-stimulating hormone (gamma 2-MSH), neuropeptide Y (NPY), NA and PRA increased. During IVHD, NPY and PRA remained unchanged on a higher level. A decrease in AVP below the baseline and in gamma 2-MSH and NA to the baseline levels occurred during IVHD. In the case of vasodilators, there were no changes in calcitonin gene-related peptide or motilin during SQHD. An increase in beta-endorphin (beta-END) occurred during IUF, followed by a decrease during IVHD. Substance P and vasoactive intestinal peptide were unchanged during IUF but decreased during IVHD. We conclude that SQHD is characterized by an increase in all the measured vasoconstrictors during IUF in response to loss of fluid, and by a decrease in some vasoconstrictors (AVP, gamma 2-MSH, NA) during IVHD. With the exception of beta-END, there were no changes or only minor ones in vasodilators during SQHD. There are changes in plasma levels of vasoactive substances during SQHD but the importance of these changes for the hemodynamic adaptation to ultrafiltration and dialysis needs to be studied further.

Adult↗