Diffusive-convective mass transfer rates for solutes present on both sides of a dialyzer membrane

The transport (J) of waste products across dialyzer membranes is known to be proportional to the blood inlet concentration (Cbi) according to J = KCbi, where K is the clearance. For solutes present on both sides of the membrane, like sodium chloride, it has been shown that under certain conditions the transport rate will depend linearly also upon the dialysis fluid inlet concentration Cdi according to J = KbCbi -KdCdi. Kb and Kd are generalized clearances, which depend upon flow rates and membrane permeability but are independent of the concentrations. We have extended the results of Ross et al. in three ways. First, they only considered ultrafiltration (UF) that is equally distributed along the dialyzer. This is an unrealistic assumption, especially in hemodiafiltration and hemofiltration treatments with large UF rates (Quf) leading to large pressure drops along the dialyzer. Our approach allows for an arbitrary UF distribution. Second, it was possible to incorporate the more realistic model of Villaroel et al. for the local combination of diffusion and convection. Finally, we allow an arbitrary distribution of blood among the different fibers. All of these results are valid in both cocurrent and countercurrent configurations. With a sieving coefficient of 1, a good approximation for small solutes, we were also able to show that Kd = Kb - Quf, irrespective of the UF distribution along the dialyzer. This is an important result that, for example, provides a theoretical foundation for allowing a nonzero Quf in conductivity based clearance measurements.     

Hyperphospholipasemia A2 in human volunteers challenged with intravenous endotoxin

Phospholipase A₂ (PLA₂) activity was measured in the serum of 23 individuals infused intravenously with endotoxin (EN) at a dose of 4 ng/kg body weight. A marked increase in PLA₂ was noted 3 h after EN challenge (mean 828 ± 513 units/ml), reached its maximum at 24 h after the challenge (mean 2667 ± 2442 units/ ml), and was still evident at 48 h (mean 763 ± 366 units/ml). In contrast, TNF levels were maximal (mean 712 ± 375 pg/ml) 90 min after the EN challenge and subsided to very low values (5 ± 5 pg/ml) 5 h after the challenge. There was a positive correlation between the maximum response of TNF and that of PLA₂ (r = 0.82,P < 0.01). Administration of ibuprofen or pentoxifylline did not alter the PLA₂ response. EN challenge did not affect serum pancreatic PLA₂ concentration or that of the lysosomal cationic enzyme, lysozyme. Neutralizing antibody against human recombinant (synovial type) PLA₂ completely abolished PLA₂ activity in the sera tested. We conclude that EN infusions cause marked intravascular release of nonpancreatic secretory PLA₂ and that the magnitude of this response seems to be related to the prior generation of TNF.     

Pancreatic growth after pancreatico-biliary diversion does not increase the capacity to secrete amylase

BACKGROUND/AIM: Cholecystokinin (CCK) stimulates secretion and evokes a hyperplastic response in the rat pancreas. The aims of this study were to measure the effect of chronic hyperCCKemia induced by pancreatico-biliary diversion (PBD) on pancreatic enzyme concentrations, on amylase secretion by dispersed acinar cells, and on the CCK-stimulated secretion of pancreatic juice in PBD-operated rats. MATERIAL AND METHODS: Forty-five Sprague-Dawley male rats had either PBD or sham operation 4 weeks before sacrifice or additional experiments. In the first study, 25 rats (13 PBD and 12 sham-operated rats) were either freely fed or fasted overnight before sacrifice. The pancreas was dissected out, weighed and analyzed. In the second study, the rats (6 PBD and 7 sham-operated rats) were fasted overnight before pancreatic acini were prepared. Secretion of amylase during stimulation of acini with CCK-8S and carbachol was measured. In the third study (5 sham-operated and 4 PBD rats), the rats were fasted overnight before basal and CCK-stimulated secretion was measured in vivo. RESULTS: PBD-operated rats showed a threefold increase in pancreatic wet weight with increased contents of DNA, protein and water. The concentration of pancreatic amylase was 7-12% of that found in control animals. The concentrations of trypsin and lipase were also lowered. Stimulation of dispersed pancreatic acini with CCK-8S or carbachol resulted in secretion of amylase to a similar extent in PBD and sham-operated rats. There was no difference in the secretion of pancreatic juice in response to CCK, but although the output of amylase from PBD-operated rats increased with CCK, it remained at a low level throughout the study period. CONCLUSION: PBD evoked hyperplastic changes in the rat pancreas and decreased the concentrations of amylase, trypsin and lipase. However, the capacity of acinar cells to secrete amylase remained intact. The stimulated pancreatic secretion was not changed in volume, but the output of amylase was low in PBD-operated rats. The findings are consistent with the idea that the enlargement of the pancreas following PBD does not improve the secretory capacity.     

Carboxyl ester lipase in human tissues and in acute pancreatitis

Carboxyl ester lipase was purified from human pancreatic juice. Antisera were raised in rabbits and the monospecificity of the antibody was verified by immunoblotting. The enzyme was present in zymogen granules of acinar cells, in occasional duct cells, and in secretory material in normal pancreas in immunohistochemistry. Also, occasional cells in the epithelium of small intestinal villi but not the granules of Paneth cells, were stained. Decreased and evenly dispersed staining was observed in necrotic acinar cells in acute pancreatitis, whereas the reaction was intensive in plugs in acinar lumina. Interstitial staining was seen around necrotic pancreatic lobules and in areas of fat necrosis. This staining pattern is similar to that obtained with antisera against other lipolytic pancreatic proteins, but differed from that with antisera against trypsin and pancreatic secretory trypsin inhibitor. We conclude that carboxyl ester lipase behaves similarly to the other lipolytic enzymes during acute pancreatitis and that interstitial localization of secretory lipolytic enzymes is characteristic of the necrotizing inflammatory process in pancreas.     

Pancreatic lipolytic enzymes in human duodenal contents. Radioimmunoassay compared with enzyme activity.

The total pancreatic lipolytic capacity was determined in duodenal contents in healthy humans 10-120 min after a liquid test meal, by estimating the amount of pancreatic lipase, colipase, carboxyl ester lipase, and phospholipase A2 by means of radioimmunoassays and enzymatic assays. The molar concentrations of the different proteins were of the same order of magnitude. The relative specific activity (enzyme activity/milligram immunoreactive protein expressed as a percentage of the specific activity of the respective pure protein) amounted to 75-120% for lipase, 45-80% for colipase, 30-70% for carboxyl ester lipase, and 45-120% for phospholipase A2. These varied, and sometimes low values can be explained by the fact that the enzymes are inhibited or partly inactivated in the duodenal contents by surface denaturation, in which cases the products are still immunoreactive. Also, the proforms of colipase and phospholipase A2 may not always be completely activated. Furthermore, the specific activities of the pure enzymes (and thus the relative specific activities) are related to the methods used, which are not specific enough to distinguish completely the three enzymes and the cofactor in duodenal contents.     

Cephalic phase of lipolysis is impaired in pancreatic insufficiency: role of gastric lipase

BACKGROUND: Gastric lipase contributes significantly to overall lipolysis and is regulated by interacting neuro-hormonal mechanisms. Patients with alcoholic chronic pancreatitis (ACP) have low, or even absent, activity of pancreatic lipases. In that state the secretion of gastric lipase could be essential and compensate for the pancreatic defect. However, conflicting studies have not resolved the order of magnitude of gastric lipase secretion in these patients. This could be explained by differences in regulatory mechanisms, gastric mucosal changes, and abdominal vagal tone. METHODS: Nasogastric intubation with modified sham feeding and upper endoscopy including biopsies for histologic classification and Helicobacter pylori infection status were performed in eight ACP patients, and eight healthy volunteers were studied on separate occasions. Vagal nerve function was assessed by calculation of heart rate variability in ACP patients. Gastric lipase was measured in aspirates by means of enzyme-linked immunosorbent assay and an enzyme kinetic assay. Plasma concentrations of gastrin, secretin, cholecystokinin, and pancreatic polypeptide were measured throughout the study. RESULTS: Sham feeding rapidly and significantly increased gastric lipase secretion in healthy volunteers, whereas ACP patients did not respond to sham feeding. Two of eight patients were infected with H. pylori and had mucosal changes accordingly. The lack of lipase response could not be ascribed to dysfunction of the abdominal vagus. CONCLUSIONS: The cephalic phase of gastric lipase secretion is impaired in ACP patients. Although their fundic cells continue to secrete gastric lipase, they are not subject to normal neuro-hormonal regulation.     

Clinical implications for the management of acute thromboembolic occlusion of the superior mesenteric artery: autopsy findings in 213 patients

OBJECTIVE: To study findings at autopsy in patients with fatal acute thromboembolic occlusion of the superior mesenteric artery (SMA). SUMMARY BACKGROUND DATA: Acute occlusion of the SMA is difficult to diagnose and mortality remains high. In Malmo, Sweden, the autopsy rate between 1970 and 1982 was 87%, creating possibilities for a population-based study. METHODS: Among 23,496 clinical autopsies and 7569 forensic autopsies, 213 cases with acute thromboembolic occlusion of the SMA and intestinal infarction were identified. RESULTS: A clinical suspicion of intestinal infarction was documented in 32% of the patients, only 35% being in the care of surgeons. The embolus/thrombus ratio was 1.4 to 1. Thrombotic occlusions were located more proximally than embolic occlusions (P < 0.001), intestinal infarction was more extensive (P = 0.025) and thrombotic occlusions were associated with old brain infarction (P = 0.048), aortic wall thrombosis (P = 0.080), and disseminated cancer (P = 0.079). Patients with embolic occlusions (n = 122) had a higher frequency of acute myocardial infarction (AMI) than patients with thrombotic occlusions (P = 0.049). The embolic source was identified in 80%. In 115 (94%), synchronous embolism and/or source of embolus were present. There were findings of remaining cardiac thrombi in 58 (48%) and synchronous emboli affected 273 other arterial segments in 83 (68%). CONCLUSIONS: Early recognition and revascularization would have been a prerequisite for survival in at least half of the patients, since the jejunum, ileum, and colon were affected by infarction. A minority of all patients were under surgical care. AMI, cardiac thrombi, and synchronous emboli were common findings among patients with embolic occlusions.     

Inhibition of Human Gastric Lipase Secretion by Glucagon-like Peptide-1

Glucagon-like peptide-1 (GLP-1) may be one ofthe enterogastrone hormones of the ileal brakemechanism. We therefore studied its effects on gastriclipase secretion in healthy volunteers and vagotomized patients during infusion of pentagastrin. Theintestinal incretin hormone GLP-1 (glucagon-likepeptide-1, 7-36 amide) was investigated because of itsinhibitory effects on gastric acid secretion andmotility. GLP-1 infused intravenously in amountscorresponding to the postprandial release significantlyinhibited pentagastrinstimulated gastric lipasesecretion and lipolytic activity. The inhibitory effectof GLP-1 persisted in vagotomized patients,suggesting that fundic chief cells, from which gastriclipase is released, or neighboring inhibitory cellscould be equipped with GLP-1 receptors. Vagotomizedpatients had significantly higher plasma concentrationsof gastrin and secretin. No significant changes ofgastrin, secretin, and CCK secretion were seen duringGLP-1 infusion in the vagotomized patients, whereas secretin decreased significantly in the healthyvolunteers. GLP-1 seems to be a naturally occurringinhibitor of gastric lipase secretion acting via anonvagal mechanism. Our results indicate that gastric lipase secretion is subject to hormonalstimulatory as well as inhibitory mechanisms.     

The Measurement of Hemodialysis Access Blood Flow by a Conductivity Step Method

Background and objectives: Measurement of blood flow rate (Qa) is used to monitor dialysis access, AV fistulas, and grafts. Indicator dilution measurements of the recirculation (R) induced by reversal of hemodialysis blood lines are commonly used. This plus the dialysis circuit flow (Qb) allows calculation of Qa. R also changes the conductivity, which can be measured by a conductivity cell in the spent dialysate. The change in conductivity caused by line reversal should vary with Qa. A methodology for Qa measurement utilizing this conductivity step is proposed. This study compares conductivity step methodology against the reference method of ultrasound dilution (Qa-Trans).Design, setting, participants, & measurements: This was an open diagnostic test study in a single academic hospital setting involving 15 hemodialysis-dependent patients. Each was studied over four hemodialysis treatments. During each treatment, two pairs of Qa measurements (conductivity step and Trans) were made. Pre- and postdialysis sodium levels were also measured.Results: Average Qa-conductivity step was 1040 ml/min. Average Qa-Trans was 1030 ml/min. The difference was NS. The data pairs showed mean difference of 1.3 ± 17% (SD). The SD indicates a relatively large variation between data pairs. There was significant linear correlation between the Qa-conductivity step and Qa-Trans results (r = 0.91, P < 0.001). Serum sodium rose slightly but significantly over dialysis (P < 0.001).Conclusions: Qa measurement by conductivity step may be an acceptable alternative to ultrasound dilution methodology. Care must be taken to prevent salt loading when the conductivity step is used.The measurement of hemodialysis blood access flow rate (Qa, ml/min) in arteriovenous (AV) fistulas and grafts is common. Reduced or falling levels of Qa indicate access dysfunction and predict thrombosis (1). Most Qa measurements use indicator dilution techniques to measure the amount of recirculation induced by reversal of blood lines. This plus the dialysis circuit flow rate (Qb, ml/min) allows for the calculation of Qa (1). One methodology for Qa measurement involves ultrasound velocity measurements of flowing blood and their dilution by saline using the Transonics hemodialysis monitor (Transonics, Inc., Ithaca, NY). Details of this and other technologies are given elsewhere (2). Because access recirculation is inversely related to Qa (3) and because it will lead to a decreased dialyzer urea clearance, we hypothesized that needle reversal can measure Qa by observing the effect on dialysate urea concentrations. This hypothesis was proven and the results have been published (4). Mercadal et al. (5) and Gotch et al. (6) have shown that the change in effective ionic dialysance (EID) values induced by line reversal can be used to measure Qa. As pointed out in our Discussion (4), Fresenius Medical Care (www.fmc-ag.com) had incorporated propriety software into their dialysis machine (2008K) to measure Qa utilizing EID. At that time, there was no published work regarding the accuracy and validity of this methodology beyond the original theory validation (5). Subsequently, Lacson et al. (7) of Fresenius Medical Care and Whittier et al. (8) have separately published validation data for EID incorporated into the Fresenius 2008K machine using ultrasound velocity measurements as the “gold standard” comparator. Their results showed good agreement between the methodologies. The EID-based measurements rely on two separate determinations of ionic dialysance obtained many minutes apart. Knowing the effect of line reversal on dialysate urea concentrations, we examined the possibility to directly measure Qa from the conductivity change induced by the reversal of lines (conductivity step method).