Carl M. Öberg

Plasma Volume Expansion by 0.9% NaCl During sepsis/SIRS, After Hemorrhage, and During a Normal State.

Objective The objective of this study was to determine the degree of plasma volume expansion by 0.9% NaCl in relation to the infused volume, in sepsis/systemic inflammatory response syndrome (SIRS), after a standardized hemorrhage, and in a normal condition. Design Prospective, randomized animal study. Setting The study was performed at a university hospital laboratory. Subjects Thirty anesthetized adult male rats were included in the study. Interventions The study was performed in three groups: a sepsis/SIRS group (the S group), in which sepsis/SIRS was induced by cecal ligation and incision; a hemorrhage group (the H group), in which the rats were left without intervention for 4 h and bled 8 mL/kg thereafter; and a group that was left without intervention (the N group). Then, 4 h after baseline, all three groups were given an infusion of 0.9% NaCl (32 mL/kg) for 15 min. Baseline was defined as the time point when the surgical preparation was finished. Measurements and Main Results Plasma volumes were measured using 125I-albumin dilution technique at baseline, after 4 h, and 20 min after the end of infusion. The plasma volume–expanding effect 20 min after end of infusion was 0.6% ± 2.9% in the S group, 20% ± 6.4% in the H group, and 12% ± 11% in the N group, compared with just before start of infusion. Conclusions The present study in rats showed that the plasma volume–expanding effect after an infusion of 0.9% NaCl was smaller in a septic/SIRS state than after hemorrhage and in a normal state. This indicates that the plasma volume–expanding effect of a crystalloid is dependent on pathophysiologic changes in sepsis/SIRS.

Is Adapted APD Theoretically More Efficient than Conventional APD

♦ Background: A modified version of automated peritoneal dialysis (APD) using not only variable dwell times but also variable fill volumes has been tested against conventional APD (cAPD) with fixed dwell volumes in a randomized controlled clinical study. The results have indicated that the modified schedule for APD, denoted adapted APD (aAPD), can lead to improved small solute clearances, and, above all, a markedly increased sodium removal (NaR). To theoretically test these results, we have modeled aAPD vs cAPD in computer simulations using the 3-pore model (TPM). ♦ Methods: The TPM, modified by including a transient, initial inflation of small solute mass transfer area coefficients (PS values), was employed. For simulations of osmotic ultrafiltration (UF), the TPM uses a constantly inflated value for PS for glucose and also a reduced value for PS for Na+, setting the peritoneal lymphatic reabsorption term at 0.3 mL/min. The simulations were performed by assuming that increases in intraperitoneal hydrostatic pressure (IPP) are transmitted to the capillary level (via vein compression) and therefore do not significantly affect the Starling balance. Furthermore, the effective peritoneal surface area (A) was set to be variable as a function of intraperitoneal volume (IPV). ♦ Results: The simulations demonstrated a minor improvement of small solute clearances (~0.7 – 1.6%) and a very small improvement of UF and NaR in aAPD compared to cAPD. ♦ Conclusions: Due mainly to the increased fill volumes in 3 out of 5 dwells in aAPD, this modality caused minor increases in small solute clearances and marginal effects on UF and NaR. The computer simulations point to a need for accurate sodium determinations in aAPD, considering all the methodological problems and pitfalls relevant to determining dialysate Na+ concentrations and peritoneal sodium mass balance.

Differential effects of gaseous versus injectable anesthetics on changes in regional cerebral blood flow and metabolism induced by l-DOPA in a rat model of Parkinson's disease

ABSTRACT Preclinical imaging of brain activity requires the use of anesthesia. In this study, we have compared the effects of two widely used anesthetics, inhaled isoflurane and ketamine/xylazine cocktail, on cerebral blood flow and metabolism in a rat model of Parkinsons disease and l‐DOPA‐induced dyskinesia. Specific tracers were used to estimate regional cerebral blood flow (rCBF ‐ [14C]‐iodoantipyrine) and regional cerebral metabolic rate (rCMR ‐ [14C]‐2‐deoxyglucose) with a highly sensitive autoradiographic method. The two types of anesthetics had quite distinct effects on l‐DOPA‐induced changes in rCBF and rCMR. Isoflurane did not affect either the absolute rCBF values or the increases in rCBF in the basal ganglia after l‐DOPA administration. On the contrary, rats anesthetized with ketamine/xylazine showed lower absolute rCBF values, and the rCBF increases induced by l‐DOPA were masked. We developed a novel improved model to calculate rCMR, and found lower metabolic activities in rats anesthetized with isoflurane compared to animals anesthetized with ketamine/xylazine. Both anesthetics prevented changes in rCMR upon l‐DOPA administration. Pharmacological challenges in isoflurane‐anesthetized rats indicated that drugs mimicking the actions of ketamine/xylazine on adrenergic or glutamate receptors reproduced distinct effects of the injectable anesthetics on rCBF and rCMR. Our results highlight the importance of anesthesia in studies of cerebral flow and metabolism, and provide novel insights into mechanisms mediating abnormal neurovascular responses to l‐DOPA in Parkinsons disease. HIGHLIGHTSIsoflurane does not affect basal rCBF values or L‐DOPA‐induced increases in rCBFKetamine/xylazine reduces basal rCBF values and masks the L‐DOPA‐induced hemodynamic effectsA novel, improved model for calculation of rCMR is describedIsoflurane reduces rCMR, and both anesthetics prevent L‐DOPA‐induced changes in rCMRKetamine/xylazine effects on rCBF and on rCMR are mediated through adrenergic and glutamate receptors.

Nitric oxide synthase inhibition causes acute increases in glomerular permeability in vivo, dependent upon reactive oxygen species

There is increasing evidence that the permeability of the glomerular filtration barrier (GFB) is partly regulated by a balance between the bioavailability of nitric oxide (NO) and that of reactive oxygen species (ROS). It has been postulated that normal or moderately elevated NO levels protect the GFB from permeability increases, whereas ROS, through reducing the bioavailability of NO, have the opposite effect. We tested the tentative antagonism between NO and ROS on glomerular permeability in anaesthetized Wistar rats, in which the left ureter was cannulated for urine collection while simultaneously blood access was achieved. Rats were systemically infused with either l-NAME or l-NAME together with the superoxide scavenger Tempol, or together with l-arginine or the NO-donor DEA-NONOate, or the cGMP agonist 8-bromo-cGMP. To measure glomerular sieving coefficients (theta, θ) to Ficoll, rats were infused with FITC-Ficoll 70/400 (mol/radius 10-80 Å). Plasma and urine samples were analyzed by high-performance size-exclusion chromatography (HPSEC) for determination of θ for Ficoll repeatedly during up to 2 h. l-NAME increased θ for Ficoll70Å from 2.27 ± 1.30 × 10-5 to 8.46 ± 2.06 × 10-5 (n = 6, P < 0.001) in 15 min. Tempol abrogated these increases in glomerular permeability and an inhibition was also observed with l-arginine and with 8-bromo-cGMP. In conclusion, acute NO synthase inhibition in vivo by l-NAME caused rapid increases in glomerular permeability, which could be reversed by either an ROS antagonist or by activating the guanylyl cyclase-cGMP pathway. The data strongly suggest a protective effect of NO in maintaining normal glomerular permeability in vivo.

Counterpoint: Defending Pore Theory.

The paradigm of a charge-selective glomerular filtration barrier (GFB) was established in the 1970s when Brenner and colleagues published their seminal data on glomerular sieving coefficients (θ; primary urine-to-plasma concentration ratios) of differently charged dextran species across the rat GFB (1). Negatively charged, sulphated dextran molecules exhibited much lower θ than neutral and cationic dextran species (Figure 1B). However, recently, several authors have questioned these results (2,3). This is due to the fact that some fractions of sulphated dextran can bind to plasma proteins and to glomerular cells, leading to an underestimation of their θ (3,4). In addition, it has been shown that polysaccharides (cf. dextran) exhibit a flexible molecular conformation, making them hyperpermeable compared to more rigid solutes, such as proteins (5,6). Ficoll, a co-polymer of sucrose and epichlorohydrine, apparently shows glomerular sieving characteristics somewhere in between those of dextran and proteins, at least for molecular radii (ae) approaching the pore radius (rp) (5). However, for certain ranges of molecular radii (ae/rp < 0.65), Ficoll and proteins have actually been found to have similar glomerular permeation characteristics (7,8). High molecular weight Ficoll, passing through “large pores” (see below; ae/rp < 0.65), like albumin (7), has therefore been frequently used for assessments of glomerular permeability (9–12).

Albumin Turnover in Peritoneal and Hemodialysis.

The turnover of albumin is increased in both peritoneal dialysis (PD) and hemodialysis (HD) due to increased external losses, normally leading to compensatory increases in the hepatic albumin synthesis. The normal rate of albumin synthesis is on the order of 12 g/day corresponding to an equally large albumin fractional catabolic rate of ~4% daily. Most albumin catabolism is assumed to occur in the endothelium, but there is also renal and hepatic catabolism and leakage into the gastrointestinal tract. In PD the daily losses are on the order of 5 g/day. There are also external albumin losses in HD, particularly when high‐performance membranes are used, the losses per session ranging between 1 and 8 g (or more). The dialytic albumin losses cannot be detected by assessing the transcapillary escape rate of albumin from the plasma compartment to the interstitium. In PD, tracer albumin that has been injected into the peritoneal fluid is absorbed to the tissues surrounding the peritoneal cavity without much edema formation, due to the process of “volume recirculation”. A small fraction of the dialysate albumin tracer (0.2–0.3 ml/minute) is directly reabsorbed to the plasma via the lymphatics. A significant portion of dialysis patients are affected by chronic inflammation, such as in the malnutrition inflammation and atherosclerosis syndrome, which is also associated with cardiovascular mortality and fluid overload. These patients usually have a reduced ability to compensate for external losses of albumin, which may result in hypoalbuminemia. Reduced plasma albumin levels in dialysis patients may thus be regarded as a sign of chronic inflammation rather than reflecting malnutrition.

Inhibition of mammalian target of rapamycin decreases intrarenal oxygen availability and alters glomerular permeability

An increased kidney oxygen consumption causing tissue hypoxia has been suggested to be a common pathway toward chronic kidney disease. The mammalian target of rapamycin (mTOR) regulates cell proliferation and mitochondrial function. mTOR inhibitors (e.g., rapamycin) are used clinically to prevent graft rejection. mTOR has been identified as a key player in diabetes, which has stimulated the use of mTOR inhibitors to counter diabetic nephropathy. However, the effect of mTOR inhibition on kidney oxygen consumption is unknown. Therefore, we investigated the effects of mTOR inhibition on in vivo kidney function, oxygen homeostasis, and glomerular permeability. Control and streptozotocin-induced diabetic rats were chronically treated with rapamycin, and the functional consequences were studied 14 days thereafter. In both groups, mTOR inhibition induced mitochondrial uncoupling, resulting in increased total kidney oxygen consumption and decreased intrarenal oxygen availability. Concomitantly, mTOR inhibition induced tubular injury, as estimated from urinary excretion of kidney injury molecule-1 (KIM-1) and reduced urinary protein excretion. The latter corresponded to reduced sieving coefficient for large molecules. In conclusion, mTOR inhibition induces mitochondrial dysfunction leading to decreased oxygen availability in normal and diabetic kidneys, which translates into increased KIM-1 in the urine. Reduced proteinuria after mTOR inhibition is an effect of reduced glomerular permeability for large molecules. Since hypoxia has been suggested as a common pathway in the development of chronic kidney disease, mTOR inhibition to patients with preexisting nephropathy should be used with caution, since it may accelerate the progression of the disease.

Optimizing Automated Peritoneal Dialysis Using an Extended 3-Pore Model

Introduction In the current study, an extended 3-pore model (TPM) is presented and applied to the problem of optimizing automated peritoneal dialysis (APD) with regard to osmotic water transport (UF), small/middle-molecule clearance, and glucose absorption. Methods Simulations were performed for either intermittent APD (IPD) or tidal APD (TPD). IPD was simulated for fill and drain volumes of 2 L, whereas TPD was simulated using a tidal volume of 0.5 L, 1 L, or 1.5 L with full drains and subsequent fills (2 L) occurring after every fifth dwell. A total of 25 cycles for a large number of different dialysate flow rates (DFR) were simulated using 3 different glucose concentrations (1.36%, 2.27%, and 3.86%) and 3 different peritoneal transport types: slow (peritoneal equilibrium test D/Pcrea < 0.6), fast (peritoneal equilibrium test D/Pcrea > 0.8), and average. Solute clearance and UF were simulated to occur during the entire dwell, including both fill and drain periods. Results It is demonstrated that DFRs exceeding ∼ 3 L/h are of little benefit both for UF and small-solute transport, whereas middle-molecule clearance is enhanced at higher DFRs. The simulations predict that large reductions (> 20%) in glucose absorption are possible by using moderately higher DFRs than a standard 6 × 2 L prescription and by using shorter optimized “bi-modal” APD regimens that alternate between a glucose-free solution and a glucose-containing solution. Discussion Reductions in glucose absorption appear to be significant with the proposed regimens for APD; however, further research is needed to assess the feasibility and safety of these regimens.

Reduced glomerular size selectivity in late streptozotocin‐induced diabetes in rats: application of a distributed two‐pore model

Microalbuminuria is an early manifestation of diabetic nephropathy. Potential contributors to this condition are reduced glomerular filtration barrier (GFB) size‐ and charge selectivity, and impaired tubular reabsorption of filtered proteins. However, it was recently reported that no significant alterations in charge selectivity of the GFB occur in early experimental diabetic nephropathy. We here aimed at investigating the functional changes in the GFB in long‐term type‐1 diabetes in rats, applying a novel distributed two‐pore model. We examined glomerular permeability in 15 male Wistar rats with at least 3 months of streptozotocin (STZ)‐induced diabetes (blood glucose ∼20 mmol/L) and in age‐matched control rats. The changes in glomerular permeability were assessed by determining the glomerular sieving coefficients (θ) for FITC‐Ficoll (molecular radius 20–90 Å) using size exclusion HPLC. The values of θ for FITC‐Ficoll of radius >50 Å were significantly increased in STZ‐diabetic rats compared to age‐matched controls (θ for 50–69 Å = 0.001 vs. 0.0002, and θ for 70–90 Å = 0.0007 vs. 0.00006, P < 0.001), while θ for FITC‐Ficoll <50 Å tended to be lower in diabetic rats than in controls (θ for 36–49 Å = 0.013 vs. 0.016, ns). According to the distributed two‐pore model, there was primarily an increase in macromolecular transport through large pores in the glomerular filter of diabetic rats associated with a loss of small‐pore area. Deterioration in the glomerular size selectivity due to an increase in the number and size‐spread of large pores, with no changes in the permeability of the small‐pore system, represent the major functional changes observed after 3 months of induced experimental diabetes.

Swedish and English word ratings of imageability, familiarity and age of acquisition are highly correlated

At present, there is no comprehensive psycholinguistic database containing Swedish words with ratings of word properties such as e.g. imageability, although researchers carrying out psycholinguistic studies in Swedish face the need to be able to control for and systematically vary such properties. The present study addressed this issue by investigating the possibility of transferring English word ratings to Swedish. Imageability, familiarity and age of acquisition (AoA) ratings were obtained for a sample of Swedish words (N = 99). These ratings were then compared with the corresponding English ratings from the Medical Research Council (MRC) Psycholinguistic Database (Coltheart 1981) using Spearman correlation. Swedish and English word ratings were found to be highly correlated for imageability and AoA, and moderately correlated for familiarity. Following these results, we suggest that, in general, ratings of these variables can be reliably transferred between the two languages, although some caution should be taken, since for some individual words, some ratings might differ substantially for their Swedish and English translations. (Less)