Renal Division, Department of Internal Medicine, University Hospital, Gent, Belgium
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Abstract |
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Methods. In this study, 56 equilibrated haemodialysis patients were evaluated by radioisotopic examination for gastric emptying time. These data were correlated to anthropometrical as well as biochemical parameters.
Results. The half-life time for gastric emptying was 83±34 min in the overall population, compared to 50±15 min in a normal reference population. Prealbumin, mean fibular nerve-conduction velocity and intra- as well as extracorpuscular folic acid were significantly different between patients with the lowest and highest gastric emptying times. Linear correlation analysis between the half-life for residual radioactivity and the remaining parameters yielded a significant correlation for blood urea nitrogen, serum folic acid, intracorpuscular folic acid, serum vitamin B12, serum C-reactive protein, serum prealbumin and mean fibular nerve-conduction velocity.
Conclusions. This study demonstrates that gastric emptying is significantly delayed in end-stage renal disease patients. The delay is associated with changes in biochemical indicators of nutritional status such as serum albumin and prealbumin.
Keywords: end-stage renal disease; gastroparesis; nerve conduction velocity; nutritional status; vitamin B12
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Introduction |
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Experience with other conditions complicated by malnutrition, such as diabetes mellitus [5], critical illness [6], and hepatic cirrhosis [7] suggest that alterations in gastric emptying might play a crucial role. In addition, gastric emptying is at least in part dependent on nerve function [8], which is known to be disturbed in renal failure.
The issue of gastric emptying in ESRD has been considered in a limited number of studies, each with substantial shortcomings. One study was conducted on rats [9], another in children [10], while some investigated exclusively Asian patients [11,12], allowing no direct extrapolation of the results to an adult Caucasian population. In addition, many studies were based on a limited number of subjects [10,1320] and did not allow definitive conclusions. Different methods for measuring gastric emptying time were used, ranging from radio-isotopic investigation to echography and electrogastrography. Hence, results obtained and cut-off values were not always comparable.
In the present study, gastric emptying was evaluated in 56 haemodialysis patients and compared with that of a healthy control group. The obtained results are correlated to a set of anthropometric, clinical, and biochemical patient characteristics.
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Subjects and methods |
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Patient recruitment
Patients, older than 18 years, on a regular haemodialysis schedule for at least 3 months before their enrolment, who had given signed or oral witnessed informed consent before the start of the trial were included. Excluded were patients with mechanical obstruction of the GI tract and with known GI cancer or active ulcer disease. Patients who could become pregnant during the study period (i.e. not being post-menopausal or not using adequate contraceptive measures), with alcoholism (defined as a daily intake of >4 units of alcohol), who started with parenteral hyperalimentation within 4 weeks before the study, who were unable to adequately express their subjective complaints or with a history of major GI surgery (except for appendectomy, cholecystectomy and herniotomy) were also excluded. Medications that could influence GI motility and function (e.g. dopamine agonists, tricyclic antidepressants, anticholinergics, H2 antagonists, proton-pump blockers, prokinetics, spasmolytics, opiates, and macrolide antibiotics) were discontinued at least 2 weeks prior to the study start. Applied to the patient population of the dialysis centre in the University Hospital of Gent, these criteria resulted in the selection of 56 patients who were submitted to an initial screening.
Haemodialysis characteristics
All patients were dialysed three times weekly for 34 h with bicarbonate as a dialysate buffer and with non-complement-activating membranes. The composition of the dialysate was Na+ 137 mEq/l, K+ 12 mEq/l, Cl- 97 mEq/l, CH3COO- 5 mEq/l and HCO3- 36 mEq/l. Blood flows and dialysate flows of >250 ml/min and 500 ml/min were pursued. Adequacy of dialysis was evaluated by monthly controls of the ratio of total urea clearance over its distribution volume (Kt/V), using a single-pool kinetic model (post-dialysis blood sample collected 15 min after the end of the dialysis session). The target value per session was 1.3.
Vitamin B complex was administered monthly by routine intravenous injection in the bubble trap chamber (thiamine, pyridoxine, and cyanocobalaminNeurobion®, Merck-Belgolabo NV, Overijse, Belgium) in a dose of 1 ampoule monthly at the end of a dialysis session. In patients with prominent motor and sensory nerve conduction disturbances and/or low serum levels of vitamin B12, the frequency of administration was increased to once weekly.
Vitamin D supplementation was titrated according to serum PTH levels whereby a threshold serum PTH concentration of 100200 pg/ml was implemented for the initiation of the therapy. If PTH levels rose above this level, alfacalcidol (One-alpha Leo®, Leo Pharmaceutical Products Trading Ltd, Ballerup, Denmark) was orally administered in three weekly pulsed doses (0.54.0 mg/pulse). Serum PTH and 1,25(OH)2 vitamin D3 levels were checked bi-monthly and alfacalcidol doses were adjusted accordingly.
Haematocrit levels were determined every 2 weeks and target values of 3235% were pursued. If the observed value was lower, recombinant human erythropoietin was administered three times weekly at the end of each dialysis session. Both intravenous (Recormon®, BoehringerMannheim GmbH, Mannheim, Germany or Eprex®, JanssenCilag, Schaffhausen, Switzerland) as well as subcutaneous administrations (Recormon®, Boehringer) were applied.
Serum ferritin was targeted at 200 ng/ml and transferrin saturation at 20% or more. If these conditions were not met, intravenous iron supplements (Venofer®, Vifor Inc., St Gallen, Switzerland) were administered weekly.
Test procedure and data analysis
Trans-sectional analysis
A determination of gastric emptying was performed in all patients (n=56). For this measurement a radioisotopic evaluation was used, whereby a standardized solid meal of ±260 g (one scrambled egg, well done and labelled with 500 mCi of Technetium-99m-sulphur colloid, two slices of white bread (±50 g each), and 150 ml of water), with a caloric content of 231 kcal (47% carbohydrate, 18% protein, 35% fat) was presented to each patient. The test was performed on a dialysis-free day, and patients were instructed to fast overnight. Smoking was not allowed during 12 h preceding the test. The total meal consumption time was limited to 10 min, and the moment at which the meal had been ingested completely was labelled as time 0. After ingestion of the meal, anterior and posterior images were acquired with the patient in sitting position using a double-headed gamma camera equipped with a low-energy high-resolution collimator and interfaced to a nuclear medicine computer system. Twenty-per cent energy windows were set with peaks at 140 keV. The anterior and posterior images were acquired for 1 min in both energy windows at 0, 10, and 20 min and from then every 20 min. Patients remained seated between acquisitions. If 50% of the meal had not been emptied from the stomach after 120 min, acquisition was continued until 50% of the meal had emptied. Data was stored on an on-line computer.
The gastric counts were determined for each image in the marked region of interest, and corrected for background, scatter, and radioactive decay. Values for relative residual radioactivity (RAA) for the solid component of the meal, using the activity at time 0 as 100%, were calculated at each time point. Results were then presented graphically and curve-fitting was applied in order to determine the values for the time by which half of the gastric content had been evacuated (T½) and the area under the curve (AUC0120 min) of the RAA vs time plot. The normal value±standard deviation of T½ obtained for a solid meal in healthy subjects, using the above procedures, by a Working Party of the Belgian Association for Nuclear Medicine, of which the unit where the examinations were performed is a member, was 50±15 min (i.e. T½+2 SD=80).
Patient characteristics and biochemical parameters
Additionally, anthropometric as well as biochemical data were collected for each patient at the time of the gastric emptying test. The following patient characteristics were registered: gender, age, time since start of haemodialysis, and the primary renal diagnosis. As biochemical data, serum haemoglobin (Hgb), ferritin, transferrin, Na+, K+, Ca2+ corrected for plasma protein, P3-, Mg2+, predialysis blood urea nitrogen (BUN), serum creatinine, red blood cell count (RBC), white blood cell count (WBC), serum albumin, arterial pH, intact parathyroid hormone (iPTH), intracellular and extracellular folic acid, vitamin B12, 1,25(OH)2 vitamin D3, cholesterol (CH), red-cell sedimentation rate (ESR), serum C-reactive protein (CRP), prealbumin, residual creatinine clearance, protein catabolic rate (PCR), and Kt/V were included.
Aluminium accumulation was evaluated by performing a desferrioxamine test. Desferrioxamine (Desferal®, CibaGeigy, Basel, Switzerland) 1500 mg was administered intravenously through the arteriovenous fistula or central venous access catheter during the last 30 min of the haemodialysis session. Serum aluminium levels were measured immediately before and 44 h after the desferrioxamine administration.
Finally, mean conductive velocity in the fibular nerve, as measured by needle electromyography, was also submitted to analysis.
Statistical analysis
After comparison with the control group, the entire ESRD population was divided into three equal groups based on the value obtained from the gastric emptying test. The two outermost groups (i.e. those with the highest and lowest values) were then compared for all anthropometric and biochemical parameters.
In addition, a linear regression analysis was performed for all patients, between the T½ and the anthropometric and biochemical parameters. Parameters rendering a P value 0.05 were grouped and further submitted to a stepwise multifactorial regression.
The same test procedure was repeated with the area under the curve (AUC) as dependent variable.
Statistical methods
Data are given as mean±standard deviation. To compare different groups intermutually, analyses were performed by the ANOVA, the Fisher exact, the Wilcoxon signed rank and the MannWhitney U-test where appropriate. Significance was accepted for P0.05. Linear correlation analysis was performed using the GraphPad PrismTM statistical package version 1.00, GraphPad® Software. In addition, a stepwise multifactorial regression was executed using the Unistat® Statistical Package version 3.0a, Unistat© Ltd 19841995.
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Results |
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After division of the entire population into three groups according to their gastric emptying (as measured by T½ for RAA and AUC), no significant differences could be observed in gender, age, and time on dialysis (Table 1). The primary diagnosis was not significantly different between groups.
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Discussion |
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Although the issue of gastric emptying has frequently been studied in other conditions, studies in adults suffering from uraemia are scant and of limited size [10,1322]. In the present study, comparing 56 haemodialysed patients with a control group, it is clear that a substantial number of these patients suffer from severe gastric emptying disturbances. In 20 patients, gastric emptying time is at least doubled compared to the normal value of T½ as defined by a Working Party of the Belgian Association for Nuclear Medicine. These alterations occurred in spite of haemodialysis conforming to the current standards of adequate treatment (Kt/V 1.3, dialysis time
3x4 h a week, with non-complement-activating dialysers and bicarbonate dialysate).
The gastric emptying data obtained in the present study were correlated with various parameters (Table 3). A significant correlation was found with some parameters of nutritional status and of nerve conduction. Regarding nutritional status, gastric emptying was significantly correlated with serum prealbumin and to a lesser extent also to serum albumin. Both parameters are considered to be indices of nutritional status [3]. Also the correlation with blood urea should be considered in the same context: a direct positive relationship was found, meaning that urea was higher in patients with the better gastric emptying times. Urea concentrations both depend on dialysis adequacy and protein intake. In this regard, it is of note that, except for extremely high values, an inverse relationship between urea and survival on dialysis has been observed, indicating that a high urea in this context should rather be considered as a beneficial index related to adequate nutrition than to a negative indicator related to inadequate dialysis [23]. All these data together suggest that adequate gastric emptying in dialysis patients leads to a better nutritional status.
Another group of parameters to which gastric emptying seems to be linked is nerve conduction. A direct correlation is found with fibular nerve motor velocity. Although intestinal motility is predominantly dependent on the splanchnic nerve system, it can be assumed that motor nerve function correlates well with autonomic nerve function in ESRD. Evaluation of the autonomic nervous system, by performing a power spectral analysis of the blood pressure and heart frequency could even result in stronger correlation and might be an even more appropriate study method in this regard; this should be considered for further evaluation.
The peculiar negative correlation with vitamin B12 can be explained by the fact that patients with the most compromised nerve function, and consequently the slowest gastric emptying, receive the highest doses of vitamin B12 [24,25]. In contrast, it is reported in at least one publication that vitamin B12 itself can be nocuous to nerve function [24]. In that way, our data might offer suggestion for a more careful administration of vitamin B12 in patient populations with motor nerve dysfunction. It is of interest to note that the vitamin B preparations that our patients receive on a regular basis do not contain folic acid. A positive correlation was found between folic acid and gastric emptying. Therefore the possibility should be considered that folic acid deficiency is somehow involved in the process of gastric dysmotility. No direct data are available to confirm this hypothesis. It has, however, been demonstrated that folic acid is involved in nervous function [25].
In conclusion, this study demonstrates that gastric emptying is significantly delayed in ESRD, affecting biochemical parameters of nutritional status and thus presumably leading to malnutrition.
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Notes |
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References |
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