Karel M.L. Leunissen

Inflammation, overhydration and cardiac biomarkers in haemodialysis patients: a longitudinal study

BACKGROUND Inflammation, overhydration and elevated cardiac biomarkers are related to outcome in haemodialysis (HD) patients. Here, we explored the relationship between the body composition (BC), inflammation and cardiac biomarker concentrations in HD patients longitudinally. METHODS A total of 44 HD patients were followed for 6 months. BC was assessed by multifrequency bioimpedance (BIA). Serum concentrations of cardiac troponin T (cTnT), high-sensitive C-reactive protein (hsCRP), brain natriuretic peptide (BNP) and N-terminal proBNP (NT-proBNP) were assessed at 2 monthly intervals. The longitudinal data analysis was conducted with a marginal model. RESULTS During the follow-up, the parameters describing the BC were highly predictive of both BNP and NT-proBNP and independent of gender, time, hsCRP and cTnT concentrations. The intracellular water (ICW)/body weight (BW) ratio (reflecting malnutrition) exerted a negative effect, whereas the extracellular water (ECW)/BW ratio (reflecting overhydration) had a positive effect on BNP and NT-proBNP concentrations. HsCRP and cTnT concentrations were significantly associated with each other. Furthermore, NT-proBNP concentrations were predictive of cTnT and hsCRP concentrations. CONCLUSIONS In the present study, we find a significant relation between BIA-derived BC parameters and natriuretic peptide concentrations. This relationship was independent of the cardiac history of the patient and suggests that the natriuretic peptide levels are to some degree modifiable by changing a patients fluid distribution. Moreover, cTnT, BNP, NT-proBNP and hsCRP were significantly related, showing a complex relation between overhydration, malnutrition, inflammation and cardiac biomarkers in dialysis patients.

Acute Hemodynamic Response and Uremic Toxin Removal in Conventional and Extended Hemodialysis and Hemodiafiltration: A Randomized Crossover Study

BACKGROUND Intensive hemodialysis (HD) may have significant benefits. Recently, the role of extended hemodiafiltration (HDF) has gained interest. The aim of this study was to evaluate the acute effects of extended HD and HDF on hemodynamic response and solute removal. STUDY DESIGN Randomized crossover trial. SETTINGS & PARTICIPANTS Stable patients with end-stage renal disease undergoing conventional HD. INTERVENTION 13 patients randomly completed a single study of 4-hour HD (HD4), 4-hour HDF (HDF4), 8-hour HD (HD8), and 8-hour HDF (HDF8), with a 2-week interval between study sessions. Between study sessions, patients received routine conventional HD treatments. OUTCOMES Acute hemodynamic effects and uremic toxin clearance. MEASUREMENTS Blood pressure and heart rate, pulse wave analysis, cardiac output, and microvascular density by sublingual capillaroscopy, as well as relative blood volume and thermal variables, were measured. Clearance and removal of uremic toxins also were studied. RESULTS Long treatments showed more stability of peripheral systolic blood pressure (change during HD4, -21.7±15.6 mm Hg; during HDF4, -23.3±20.8 mm Hg; during HD8, -6.7±15.2 mm Hg [P=0.04 vs. HD4; P=0.08 vs. HDF4]; and during HDF8, -0.5±14.4 mm Hg [P=0.004 vs. HD4; P=0.008 vs. HDF4]). A similar observation was found for peripheral diastolic and central blood pressures. Cardiac output remained more stable in extended sessions (change during HD4, -1.4±1.5 L/min; during HDF4, -1.6±1.0 L/min; during HD8, -0.4±0.9 L/min [P=0.02 vs. HDF4]; and during HDF8, -0.5±0.8 L/min [P=0.06 vs. HD4; P=0.03 vs. HDF4), in line with the decreased relative blood volume slope in long dialysis. No differences in microvascular density were found. Energy transfer rates were comparable (HD4, 13.3±4.7 W; HDF4, 16.2±5.6 W; HD8, 14.2±6.0 W; and HDF8, 14.5±4.3 W). Small-molecule and phosphate removal were superior during long treatments. β2-Microglobulin and fibroblast growth factor 23 (FGF-23) reduction ratios were highest in HDF8. LIMITATIONS Small sample size, only acute effects were studied. CONCLUSIONS Treatment time, and not modality, was the determinant for the hemodynamic response. HDF significantly improved removal of middle molecules, with superior results in extended HDF.

Undercarboxylated Matrix GLA Protein Levels Are Decreased in Dialysis Patients and Related to Parameters of Calcium-Phosphate Metabolism and Aortic Augmentation Index

Background: Vascular calcifications are related to cardiovascular mortality and morbidity in dialysis patients. Limited data exist on the role of calcification inhibitors, such as matrix-carboxyglutamic acid protein (MGP) in dialysis patients. Methods: In 120 dialysis patients and 41 age-matched healthy controls, circulating undercarboxylated (uc) MGP levels were measured with a novel ELISA-based competitive assay. The association between ucMGP levels and determinants of bone mineral metabolism, including the calcification inhibitor fetuin-A, was studied. Moreover, the relation between ucMGP levels and arterial stiffness was investigated. Results: The ucMGP level was significantly lower in dialysis patients compared to controls (173 ± 70 vs. 424 ± 126 nmol/l; p < 0.0001). After adjustment for age, sex and duration of dialysis an independent negative association between time-averaged phosphate levels [regression coefficient β with 95% confidence interval = –64 (–107 to –21)] and a positive association between serum ucMGP and fetuin-A [131 (55–208)] was observed. Duration of dialysis was inversely correlated with ucMGP (r = –0.24, p = 0.007). ucMGP levels were not related to high-sensitivity C-reactive protein or time-averaged calcium levels. After adjustment for age, sex, cardiovascular disease, diabetes, height and mean arterial pressure, ucMGP level was negatively associated with the aortic augmentation index [–0.036 (–0.061 to –0.010)] but not with pulse wave velocity or pulse pressure. Conclusion: Significantly lower serum ucMGP levels were observed in dialysis patients compared to healthy controls. ucMGP levels were inversely associated with phosphate and positively associated with serum fetuin-A levels. Furthermore, ucMGP levels were inversely associated with the aortic augmentation index. These data suggest that low ucMGP levels may be a marker of active calcification.

The functional, metabolic, and anabolic responses to exercise training in renal transplant and hemodialysis patients.

Background. Exercise intolerance is common in hemodialysis (HD) and renal transplant (RTx) patients and is related to muscle weakness. Its pathogenesis may vary between these groups leading to a different response to exercise. The aim of the study was to compare intrinsic muscular parameters between HD and RTx patients and controls, and to assess the response to exercise training on exercise capacity and muscular structure and function in these groups. Methods. Quadriceps function (isokinetic dynamometry), body composition (dual-energy x-ray absorptiometry), and vastus lateralis muscle biopsies were analyzed before and after a 12-week lasting training-program in 35 RTx patients, 16 HD patients, and 21 healthy controls. Results. At baseline, myosin heavy chain (MyHC) isoform composition and enzyme activities were not different between the groups. VO2peak and muscle strength improved significantly and comparably over the training-period in RTx, HD patients and controls (ptime<0.05). The proportion of MyHC type I isoforms decreased (ptime<0.001) and type IIa MyHC isoforms increased (ptime<0.05). The 3-hydroxyacyl-CoA-dehydrogenase activity increased (ptime=0.052). Intrinsic muscular changes were not significantly different between groups. In the HD group, changes in lean body mass were significantly related to changes in muscle insulin-like growth factor (IGF)-II and IGF binding protein-3. Conclusions. Abnormalities in metabolic enzyme activities or muscle fiber redistribution do not appear to be involved in muscle dysfunction in RTx and HD patients. Exercise training has comparable beneficial effects on functional and intrinsic muscular parameters in RTx patients, HD patients, and controls. In HD patients, the anabolic response to exercise training is related to changes in the muscle IGF system.

Effect of dialysate temperature on energy balance during hemodialysis: Quantification of extracorporeal energy transfer

An impaired vascular response is implicated in the pathogenesis of dialysis-induced hypotension, which is at least partly related to changes in extracorporeal blood temperature (Temp). However, little is known about changes in core Temp and differences in energy balance between standard and cool dialysis. In this study, core Temp and energy transfer between extracorporeal circuit and patient, as well as the blood pressure response, were assessed during dialysis with standard (37.5 degrees C) and cool (35.5 degrees C) Temp of the dialysate. Nine patients (4 men, 5 women; mean age, 69 +/-10 [SD] years) were studied during low- and standard-Temp dialysis, each serving as his or her own control. Bicarbonate dialysis and hemophane membranes were used. Energy transfer was assessed by continuous measurement of Temp in the arterial (Tart) and venous side (Tven) of the extracorporeal system according to the formula: c. rho.Qb*(Tven - Tart)*t, where c = specific thermal capacity (3.64 kJ/kg* degrees C), Qb = extracorporeal blood flow, rho = density of blood (1,052 kg/m3), and t = dialysis time (hours). Core Temp was also measured by Blood Temperature Monitoring (BTM; Fresenius, Bad Homburg, Germany). Core Temp increased during standard-Temp dialysis (36.7 degrees C +/- 0.3 degrees C to 37.2 degrees C +/- 0.2 degrees C; P < 0.05) despite a small negative energy balance (-85 +/- 43 kJ) from the patient to the extracorporeal circuit. During cool dialysis, energy loss was much more pronounced (-286 +/- 73 kJ; P < 0.05). However, mean core Temp remained stable (36.4 degrees C +/- 0.6 degrees C to 36.4 degrees C +/- 0.3 degrees C; P = not significant), and even increased in some patients with a low predialytic core Temp. Both during standard and cool dialysis, the increase in core Temp during dialysis was significantly related to predialytic core Temp (r = 0.88 and r = 0.77; P < 0.05). Systolic blood pressure (RR) decreased to a greater degree during standard-Temp dialysis compared with cool dialysis (43 +/- 21 v 22 +/- 26 mm Hg; P < 0.05), whereas diastolic RR tended to decrease more (15 +/- 10 v 0 +/- 19 mm Hg; P = 0.07). Core Temp increased in all patients during standard-Temp dialysis despite a small net energy transfer from the patient to the extracorporeal system. Concluding, Core Temp remained generally stable during cool dialysis despite significant energy loss from the patient to the extracorporeal circuit, and even increased in some patients with a low predialytic core Temp. The change in core Temp during standard and cool dialysis was significantly related to the predialytic blood Temp of the patient, both during cool- and standard-Temp dialysis. The results suggest that the hemodialysis procedure itself affects core Temp regulation, which may have important consequences for the vascular response during hypovolemia. The removal of heat by the extracorporeal circuit and/or the activation of autoregulatory mechanisms attempting to preserve core Temp might be responsible for the beneficial hemodynamic effects of cool dialysis.

Blood Pressure Control and Hemodynamic Changes in Patients on Long Time Dialysis Treatment

In dialysis patients blood pressure can be well controlled with long dialysis (3 times a week for 8 h) in contrast to a more common short dialysis regime (3 times a week for 4 h). We studied whether the good blood pressure control in patients on long dialysis as compared to patients on short dialysis was associated with a decrease in extracellular fluid volume. Two-day interdialytic ambulatory blood pressure monitoring was performed in 26 non-diabetic patients on long dialysis, in 22 patients on short dialysis, matched for the years they were on dialysis treatment, and during 24 h in 19 healthy volunteers. After full equilibration, 24 h after dialysis, echography of the inferior caval vein was performed to determine fluid state. Cardiac dimensions and stroke index were measured by echocardiography. A blood sample was drawn for the determination of electrolytes and vasoactive hormones. 73% of the patients on short dialysis were using antihypertensive medication in contrast to none of the patients on long dialysis. However, blood pressure was significantly lower in patients on long dialysis (115 ± 21/67 ± 11 mm Hg) when compared to patients on short dialysis (143 ± 26/81 ± 16 mm Hg). Indexed caval vein diameter, left ventricular diameter index, and atrial natriuretic peptide were not significantly different in patients on long dialysis compared to patients on short dialysis. Also the cardiac index was comparable in patients on long and short dialysis. However, the total peripheral resistance index was significantly lower in patients on long dialysis compared to the patients on short dialysis and normal controls. The left ventricular mass index was increased in both patients on long and short dialysis compared to controls. We conclude that patients on long dialysis have adequate blood pressure control that seems mainly to be caused by a low total peripheral resistance. These data also suggest that factors other than a lower fluid state contribute to the good blood pressure control in patients on long dialysis.

Effects of hypervolemia on interdialytic hemodynamics and blood pressure control in hemodialysis patients

The influence of hypervolemia on hemodynamics and interdialytic blood pressure, as well as in relation to vascular compliance, was investigated in 10 hemodialysis patients who were not receiving vasoactive medication. All subjects were studied during a relative normovolemic interdialytic period (from 1 kg below dry weight postdialytic until dry weight predialytic) and a hypervolemic interdialytic period (from 1 kg above dry weight postdialytic until 3 kg above dry weight predialytic). Interdialytic blood pressure was measured with an ambulatory blood pressure monitor. Cardiac output was echographically measured and total peripheral resistance calculated postdialytic, mid-interdialytic, and predialytic. At the same time, a blood sample was drawn for analyzing vasoactive hormones, sodium, and hematocrit. In all patients, ideal dry weight was estimated by echography of the caval vein. Arterial and venous compliance were measured with an ultrasound vessel wall movement detector system and a strain-gauge plethysmograph. After fluid load, an increase in intravascular volume, an increase in caval vein diameter and cardiac output, and a decrease in peripheral resistance was observed. No significant influence of a 3-L fluid load was found on interdialytic blood pressure course (153+/-24 mm Hg/90+/-19 mm Hg in the hypervolemic period and 146+/-27 mm Hg/89+/-22 mm Hg in the normovolemic period). Sodium and osmolality were similar in the hypervolemic and normovolemic interdialytic periods. After fluid load, a decrease in arginine vasopressin and angiotensin II was observed, which probably contributed to the decreased systemic vascular resistance. Catecholamines were not influenced by fluid load, but increased during the interdialytic period, suggesting accumulation after dialysis. Three of the 10 patients had higher systolic but not diastolic blood pressures after fluid load (159+/-13 mm Hg/81+/-22 mm Hg in the hypervolemic period and 135+/-16 mm Hg/81+/-22 mm Hg in the normovolemic period). No correlation could be found between arterial or venous compliance and blood pressure changes. We concluded that a 3-L interdialytic fluid load does not result in higher blood pressure in most hemodialysis patients.

Cardiovascular aspects in renal disease.

The majority of hemodialysis patients die from cardiovascular disease. However, the contribution of myocardial infarction to mortality is relatively minor, despite the fact that coronary artery disease is common in uremic patients. Hypertension seems to be the major risk factor for the development of atherosclerosis in hemodialysis patients, although abnormalities of the lipid spectrum, characterized by an increase in triglycerides and very low density lipoprotein levels and a decrease in high-density lipoprotein levels, are frequent in hemodialysis patients. The existence of left ventricular (LV) hypertrophy is a serious risk factor for morbidity and mortality in hemodialysis patients. LV hypertrophy can present as a dilated cardiomyopathy or as concentric or asymmetric septal hypertrophy. Loss of myocardial contractility by coronary artery disease or carnitine deficiency can lead to systolic LV dysfunction with a compensatory dilated cardiomyopathy. Furthermore, the presence of a hypercirculation in uremic patients, resulting from anemia, the arteriovenous fistula, or fluid overload, can also lead to a dilated cardiomyopathy. Systolic LV dysfunction occurs when the increase in LV wall thickness is inadequate for the increase in LV radius, which might be caused by increased levels of parathyroid hormone. LV diastolic dysfunction, resulting from an increase in LV mass due to the effects of hypertension or to uremic interstitial fibrosis, can both lead to pulmonary edema and hypotensive periods during hemodialysis and is a severe risk factor for mortality in hemodialysis patients. Therefore, in uremic patients, anemia should be corrected and hypertension adequately treated early in the development of renal failure. Chronic fluid overload should be prevented by adequate estimation of optimal dry weight.(ABSTRACT TRUNCATED AT 250 WORDS)

Continuous Renal Replacement Therapy for Critically Ill Patients: An Update

van Bommel EFH, Leunissen KML, Weimar W. Continuous renal replacement therapy for critically ill patients: an update. J Intensive Care Med 1994; 9: 265–280. Despite continuous progress in intensive care during the last decades, the outcome of critically ill patients in whom acute renal failure (ARF) develops is still poor. This outcome may be explained partially by the frequent occurrence of ARF as part of multiple organ systems failure (MOSF). In this complex and unstable patient population, the provision of adequate renal support with either intermittent hemodialysis or peritoneal dialysis may pose major problems. Continuous renal replacement therapy (CRRT) is now increasingly accepted as the preferred treatment modality in the management of ARF in these patients. The technique offers adequate control of biochemistry and fluid balance in hemodynamically unstable patients, thereby enabling aggressive nutritional and inotropic support without the risk of exacerbating azotemia or fluid overload. In addition, experimental and clinical data suggest that CRRT may have a beneficial influence on hemodynamics and gas exchange in patients with septic shock and (nonrenal) MOSF, independent of an impact on fluid balance. We review both technical and clinical aspects of various continuous therapies, including their impact on serum drug levels and nutrient balance. In addition, an attempt is made to clarify the possible beneficial role of CRRT in reducing patient morbidity and mortality in the ICU.

Influence of Interdialytic Weight Gain on Blood Pressure in Hemodialysis Patients

The role of fluid overload in the pathogenesis of hypertension in hemodialysis patients is not clear. One problem is the lack of techniques to determine the fluid state. Recent new noninvasive techniques have become available which make it possible to accurately determine the dry weight in these patients. Therefore, we studied the influence of interdialytic weight gain on interdialytic blood pressure in 10 normotensive and 10 hypertensive hemodialysis patients without antihypertensive medication. The dry weight was determined with echography of the vena cava. The blood pressure was measured during 2-day and 3-day interdialytic periods using Spacelabs 90207 ambulatory blood pressure monitors. Mean systolic and diastolic blood pressures of the last day of the interdialytic period were compared with mean systolic and diastolic blood pressures of the 1st day of the interdialytic period. Although the interdialytic weight gain in the normotensive and hypertensive patients was greater during the 3-day than during the 2-day interdialytic period, the interdialytic systolic and diastolic blood pressure changes were not greater during the 3-day period. Also, the interdialytic blood pressure rise did not correlate significantly with weight gain, neither in the normotensive nor in hypertensive patients. No significant interdialytic blood pressure changes were found between the normotensive and the hypertensive patients. We conclude that fluid overload does not seem to play a major role in interdialytic blood pressure control in normotensive and hypertensive hemodialysis patients.