Sodium modeling attenuates rises in whole-blood viscosity during chronic hemodialysis in children with large inter-dialytic weight gain
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- Fathallah-Shaykh, S.A., Brooks, E.R., Langman, C.B. et al. Pediatr Nephrol (2006) 21: 1179. doi:10.1007/s00467-006-0101-y
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Elevated whole-blood viscosity (WBV) is a risk factor for atherosclerosis and thrombosis. We analyzed WBV during hemodialysis (HD) in children and tested the hypothesis that sodium modeling (NaM) attenuates an increase in WBV. Each of six children underwent two control (C) and two NaM HD sessions, B and E. Rapid decline in sodium (Na) concentration occurred at the beginning of HD in B and at the end in E. We measured WBV at different shear rates (SRs) and documented the amount of fluid removed (FR), change in blood volume (BV), and hematocrit (Hct) before, during, and after HD. The percent increase of WBV in control sessions was significantly different at 2 h and 3 h during and after HD from baseline values. The mean percent change in WBV from baseline increased linearly over time during HD (R2>0.90). Hct, FR, and BV correlated with WBV (P<0.05). The effects of NaM on attenuation of WBV were statistically significant in three subjects with >5% inter-dialytic weight gain (IDWG) (P<0.05). WBV increased during HD in children. NaM appears to attenuate the rise in WBV in children with large IDWG.
Children with end stage kidney disease (ESKD) are at a high risk of developing cardiovascular disease . Among those children who die while on maintenance dialysis the cause is cardiovascular in 21% to 57% [1–3]. Factors that may be responsible for the excess cardiovascular mortality in children and young adults with ESKD include hypertension and volume overload, a high calcium-phosphate product, and chronic inflammation .
Whole-blood viscosity (WBV) appears to be a predictor of cardiovascular disease . Elevated WBV is associated with a higher risk of cardiovascular and cerebrovascular disease [6–11] and has been suggested as a risk of vascular thrombosis that may possibly affect hemodialysis access, such as arteriovenous fistula (AVF) [12,13]. Several investigators have measured WBV in adult patients prior to and following conventional hemodialysis (HD) and demonstrated an increase in WBV at HD completion [14, 15]. Thus, maintenance HD produces repetitive or cyclic increases in WBV, contributing to vascular dysfunction.
Sodium (Na) remains the major indicator of blood tonicity and also determines the distribution of water across the intracellular–extracellular boundary . Na modeling is a simplified mathematical method used to describe quantitatively the fluid exchange in the body caused by changes in the extracellular Na concentration . Theoretically, altering the dialysate Na in a step-wise manner permits a more gradual reduction in osmolality, a gradual adjustment in the Na pool, and results in a higher circulating blood volume, lower hematocrit, and avoidance of hypertonicity . Such influences by the use of Na modeling may lower WBV, since WBV is affected by increases in hematocrit and plasma osmolality [5, 7].
In the present study we measured the change in WBV before, during, and after HD in a small group of children to evaluate whether Na modeling (NaM) attenuates the rise in WBV, as we had hypothesized. Additionally, we explored the changes in serum Na and osmolality as an explanation of changing WBV.
Patients and methods
Six children older than 8 years of age, who had been diagnosed with ESKD and on chronic HD for longer than 3 months, were enrolled. The subjects were clinically stable and had exhibited no evidence of additional systemic illness, uncontrolled blood pressure or infection for at least 1 month prior to participation. Informed consents/assents were obtained from all parents and adolescent subjects. Data were collected during visits that coincided with HD treatment sessions. A history and a physical examination were completed, including collection of data on blood pressure, weight, height and body temperature. The medical history included ethnicity, etiology and duration of chronic kidney disease and maintenance hemodialysis therapy.
To limit variations in fluid and electrolytes, all study-related HD sessions were scheduled early in the morning and only mid-week. Blood flow was set at 200–300 ml/min and the dialysate flow at 500 ml/min. A Fresenius hemoflow polysulfone series filter with a hollow fiber size F4–8 was used. Subjects were given heparin based upon a standard protocol. Heparin was stopped 1 h prior to the completion of each HD session. Blood was collected from the arterial port at each data collection interval after subjects had received the heparin.
WBV was measured over different shear rates (1–1,000/s), at 37°C without additional ex vivo anticoagulation, by a capillary scanning viscometer, Rheolog (Rheologics, Exton, Pa., USA), which detects very small changes (less than 5%) in WBV . Scanning capillary viscometer measurements simulate in vivo conditions, at 37°C, and preclude the need for anticoagulation of blood samples. This procedure more accurately characterizes the rheological properties of whole blood, provides WBV data over a wide range of shear rates, and provided data within minutes. The amount of fluid removed during HD was recorded, and the blood volume (BV) and hematocrit were measured with a Crit-line III (Hema Metrics, Kaysville, Utah., USA). In addition, we measured the serum Na and osmolality. WBV, BV, Na, osmolality and Hct were measured at the following five time points in the hemodialysis session; immediately before HD and at hours 1, 2, 3 and within 10 min after HD at the shear rates (SRs) 1/s, 2/s, 5/s, 10/s, 50/s, 100/s, 150/s, 300/s and 1,000/s.
Subjects’ characteristics (H Hispanic, B Black, F female, M male, MPGN membranoproliferative glomerulonephritis, DK dysplastic kidney, OU obstructive uropathy, reflux reflux nephropathy. IJ tunneled internal jugular catheter, Qb blood flow during HD, IDWG % average weight gain from baseline dry weight, Hb hemoglobin measurement at enrollment)
MPGN type I
Time on dialysis (years)
Whole-blood viscosity increased linearly during conventional dialysis
For control sessions (C), the percent increases of WBV from pre-HD baseline (PI) at hours 2 and 3 and after HD were significant for SRs 50–1,000/s (multiple comparison test of the means P<0.001, Fig. 2a–c). Furthermore, the mean percent increase (MPI) from before HD of WBV correlated linearly with length of the HD sessions at all SRs (r2>0.97; Fig. 2d–f). Figure 2d–f demonstrates that WBV MPI decreased within 10 min after completion of HD, because the measurement was obtained after the subjects had received 200 ml of 0.9% saline solution.
Higher WBV is positively correlated with increase in Hct, fluid loss and decrease in BV
To determine the contributing factors to the rise of WBV during HD, we computed the Pearson’s correlation coefficients between WBV and Hct, amount of fluid loss, and BV. In all subjects the increase in WBV was positively associated with a rise in Hct at all SRs (r=0.60–0.75; P<0.001). Increase in WBV was also positively correlated with the amount of fluid removed in all subjects at SRs of 50–1,000/s (r=0.26–0.4; P<0.05). In addition, an increase in WBV was inversely correlated with the BV in all patients at SRs of 150–1,000/s (r=0.5–0.8; P<0.05 for all).
Sodium modeling and WBV
Na and osmolality. Na values are given as mean ± SD mEq/l and osmolality values are mean ± SD mosmol/kg H2O. % Uf percentage of ultrafiltrate removed during dialysis from the actual dry weight
Our results describe the changes in WBV during and after HD in children over a wide range of blood shear rates and with differing dialysate Na gradients. Others have previously reported an increase in WBV after HD in adults [14, 15]. We demonstrate that WBV increased linearly over the HD sessions in children too. We observed a significant correlation between increased WBV and hematocrit, the quantity of fluid removed, and decline in blood volume.
Importantly, we observed no changes in serum Na and osmolality by our experimental procedures for Na modeling when compared with absence of Na gradient modeling (control period).
To date, intra-dialytic viscosity changes have not been evaluated in children or adults, and studies in adults have tended to look at “before” and “after” hemodialysis values. Based on our limited data, we would suggest that inclusion of such observations gives a more accurate appraisal of the WBV changes that occur.
Thus, our results are consistent with previous data from adults demonstrating higher WBV and plasma viscosity after HD, which were correlated with an increased hematocrit and the degree of ultrafiltration (weight loss) [15, 20]. However, additional factors that may contribute, in part, to our observed changes WBV during HD include changes in plasma proteins, white blood cell (WBC) count, red blood cell (RBC) aggregability and deformability [5, 7, 21, 22].
Hemodialysis access failure is a major cause of morbidity in patients on hemodialysis. Various reports indicate that a high percentage of ESKD patient hospitalization is due to vascular access complications [23–25]. The United States Renal Data System (USRDS) reports that hemodialysis access failure is the most frequent cause of hospitalization among ESKD patients, and, in some centers, it accounts for the largest number of hospital days . In addition, vascular changes progress rapidly in adults receiving renal replacement therapy . Atherosclerosis is exacerbated in ESKD in both young and older adults [28–30]. WBV has been suggested as a risk factor in vascular thrombosis in patients with deep venous thrombosis . Moreover, enhanced red blood cell aggregation has been shown to affect nitric oxide synthesis and thus control vascular smooth muscle tone and thereby vascular resistance . Higher WBV during HD may contribute to thrombosis of the HD access and the atherosclerotic process, thereby producing ischemic heart disease [11, 13].
Sodium modeling has been shown to decrease both intra-dialytic and inter-dialytic morbidity in adolescent and adult hemodialysis patients, with no increase in adverse events when used over a period of a few weeks . Benefits of NaM include reduction in the incidence of muscle cramps, improved sodium removal, and improved vascular stability. In our study NaM appears to have the additional benefit of reduction in WBV in children with large IDWG.
By decreasing dialysate Na to counteract the consequences of rapid removal of solutes, we suggest NaM maintains a stable plasma osmolality during the course of HD ultrafiltration. A stepwise decline in Na may have an advantage over linear and logarithmic modeling . It is not uncommon for children with large IDWG to have large ultrafiltration. Thus, we expect a large increase in WBV. However, model E attenuated this increase to some degree. This should have long-term consequences if studied in a large group of children. Although the mechanism of the effect remains unknown and is not related to changes in serum Na or osmolality, we are continuing our study to look at other variables that affect WBV.
Our study has some limitations. These include a small sample size, which limits our ability to generalize the results. We also were not able to measure all variables that may affect WBV because of limited ability to withdraw larger volumes of blood in these children. Lastly, we could not predict IDWG but used the random nature of its magnitude to our advantage in the analyses presented.
In this pilot study, NaM attenuated the increase in WBV in subjects with large IDWG (>5%) but not in subjects with smaller IDWG (<5%). Such attenuation may benefit the children in the long term by decreasing their risk of access thrombosis and atherosclerotic events.
This study was supported in part by a grant from Rheologics, Inc., Exton, Pa., USA, and from the Zell Family and McNulty Family Foundations. We thank the research participants, their families, and the nursing staff of DaVita Children’s Dialysis Center for their kind assistance in this study.