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Background A recent study by Jeloka et al. (Perit Dial Int 2006; 26:336–40) highlighted the high variability in maximum ultrafiltered volume (UFmax) and the corresponding dwell time (tmax) obtained using 7.5% icodextrin solution. We aimed to pinpoint the possible sources of this phenomenon by simulating the icodextrin ultrafiltration (UF) profiles according to the three-pore model of peritoneal transport. Method The individual UF time courses observed in the study by Jeloka et al. ( n = 29) were first characterized by linear and quadratic regression. We were then able to identify four main patterns. These were then adapted to UF profiles generated by the three-pore model by systematically altering the values of some model parameters, namely, the mass transfer area coefficient (MTAC or PS) for icodextrin/glucose, the peritoneal UF coefficient (LpS), the plasma colloid osmotic pressure gradient (ΔΠ), and the macromolecular clearance out of the peritoneal cavity (ClLF). Results Modifications in the PS values caused only marginal variations in UFmax and tmax, while more significant changes were produced by altering LpS and ClLF. However, far more evident was the importance of changes in ΔΠ In fact, lowering ΔΠ to 14 mmHg caused a steady increase in UF with 10 – 14 hour dwells. On the contrary, the UF profiles became nearly “flat” when ΔΠ was increased to 30 mmHg. The parallel shifts induced by altering icodextrin metabolite concentrations did not markedly influence UFmax or tmax. Conclusion The UF pattern in icodextrin dwells seem to be mainly determined by the plasma colloid osmotic pressure, while only moderate changes can be seen with alterations in LpS and ClLF. The result is not completely unexpected considering that icodextrin acts by inducing a strong colloid osmotic gradient. A number of clinical studies would be needed, however, in order to prove this hypothesis.

Background. Poor ultrafiltration is associated with worse outcomes in peritoneal dialysis (PD) patients. This might in part reflect problems associated with salt and water excess. Increasing the diffusive component of peritoneal sodium removal using low-sodium PD fluids might have beneficial effects on blood pressure (BP), thirst and fluid status that could translate into clinical benefits. Methods. Using a multicentre, prospective, baseline controlled (1 month), non-randomized intervention (2 months) design, two novel solutions designed from predictions using the three-pore model were investigated. In group A ([Na+] = 115 mmol/l), the glucose (G) was increased to 2.0% to compensate for reduced osmolality whereas in group B ([Na+] = 102 mmol/l), it was unchanged (2.5%). Both solutions were substituted for one 3- to 5-h exchange per day and no change was made to the rest of the dialysis regime. Results. Ten patients in group A and 15 in group B completed the study. Both solutions resulted in significant increases (30-50 mmol/dwell) in diffusive sodium removal during the test exchanges, P < 0.001. Ultrafiltration was maintained in group A but reduced in group B. Ambulatory nocturnal mean BP fell in group A [93.1 +/- 10.6 mmHg (+/- SD) versus 85.1 +/- 10.2 mmHg, P < 0.05], but was stable in group B (95.4 +/- 9.4 versus 95.1.1 +/- 10.7 mmHg, NS). Thirst reduced independent of appetite and mood in both groups by 2 months, more markedly in group A. Indices of fluid status, including TBW by bioimpedance and D dilution also improved in group A, P < 0.05, whereas weight increased in group B. Conclusions. Increasing the diffusive component of sodium removal whilst maintaining ultrafiltration is associated with improvements in BP, thirst and fluid status. The lack of effect seen with uncompensated low-sodium dialysate suggests that these benefits cannot be achieved by manipulation of dialysate sodium removal alone. These observations provide valuable information of the design of future randomized studies to establish the clinical role for low-sodium dialysis fluids. (Less)

Aim: Polysaccharides and many other non-protein polymers generally have a more open, flexible and asymmetrical structure compared with globular proteins. For a given molecular weight (MW), the Stokes–Einstein radius (ae) of the following polymers increases in the order: Ficoll < dextran ≤ pullulan < polyethylene oxide (PEO). We have tested the hypothesis that such an increase in 'molecular extension' will increase the molecule's glomerular permeability. Thus, we investigated the glomerular sieving coefficients (θ) of the mentioned polymers and of the negatively charged and extended protein bikunin. Methods: In anaesthetized Wistar rats, glomerular sieving curves were generated for each FITC-labelled polymer from their respective concentration in urine and plasma, determined by size exclusion chromatography. The θ for bikunin was measured using a tissue uptake technique. Results: For a molecule of ae = 55 A (cf. IgG), θ increased in the order: Ficoll (0.00035 ± 0.000013) < dextran (0.022 ± 0.0029) < pullulan (0.033 ± 0.0024) < PEO (0.12 ± 0.0055). For ae = 36 A (cf. albumin) the order was: Ficoll (0.076 ± 0.0061) < dextran (0.45 ± 0.037) = pullulan (0.45 ± 0.021) < PEO (0.65 ± 0.0076). θ for bikunin (0.089 ± 0.0045) was 150 times higher than that of albumin, having an equivalent ae and net negative charge. Conclusion: From these results it is concluded that for flexible and asymmetric macromolecules, their degree of glomerular hyperpermeability is proportional to their degree of 'molecular extension'. Thus, compared with globular proteins, the polysaccharides investigated, including Ficoll, were found to be hyperpermeable across the glomerular filter in vivo. (Less)

It is established that the glomerular filter sieves macromolecules based on their size, shape, and charge. Anionic proteins are thus retarded compared with their neutral or cationic counterparts. However, recent studies have indicated that charge effects are small, or even "anomalous," for polysaccharides. We therefore investigated the impact of charge on the glomerular permeability to polysaccharides by comparing sieving coefficients (theta; primary urine-to-plasma concentration ratio) for negatively charged, carboxymethylated (CM) FITC-Ficoll and FITC-dextran with their neutral counterparts. For these probes, theta were determined in anesthetized Wistar rats [269 +/- 2.7 g (+/-SE; n = 36)], whose ureters were cannulated for urine sampling. The glomerular filtration rate was assessed using FITC-inulin. Polysaccharides were constantly infused, and after equilibration, urine was collected and a midpoint plasma sample was taken. Size and concentration determinations of the FITC-labeled polysaccharides were achieved by size-exclusion HPLC (HPSEC). For CM-Ficoll, theta was significantly increased (32 times at 55 A) compared with that of uncharged Ficoll. A small increase in theta for CM-dextran compared with neutral dextran was also observed (1.8 times at 55 A). In conclusion, negatively charged Ficoll relative to neutral Ficoll was found to be markedly hyperpermeable across the glomerular filter. Furthermore, negatively charged Ficoll was observed to be larger on HPSEC compared with its neutral counterpart of the same molecular weight. It is proposed that the introduction of negative charges in the "dendrimeric," cross-linked Ficoll molecule may alter its configuration, so as to make it more extended, and conceivably, more flexible, thereby increasing its glomerular permeability.

Caveolae are Ω-shaped vesicular structures postulated to play a role in transvascular protein transport. Studies on mice lacking endothelial caveolae, caveolin-1 knockout (Cav-1-KO) mice, indicate increased macromolecular transport rates. This was postulated to be due to the appearance of an alternative pathway. The present study tested whether an alternative pathway had appeared in Cav-1-KO mice. Male Cav-1-KO ( n = 12) and male control mice ( n = 13) were intubated and anesthetized using 2% isoflurane.125I-labeled albumin,131I-labeled immunoglobulin M (IgM), and polydisperse FITC-Ficoll were administered intravenously. During tracer administration, a 90-min peritoneal dialysis dwell was performed. Clearance of tracers to dialysate and permeability-surface area product for glucose were assessed. Transvascular protein transport was higher in Cav-1-KO compared with control mice. Albumin clearance from plasma to peritoneum was 0.088 ± 0.008 μl/min in control and 0.179 ± 0.012 μl/min in Cav-1-KO ( P = 0.001) mice. IgM clearance was 0.049 ± 0.003 and 0.083 ± 0.010 μl/min in control and Cav-1-KO mice, respectively ( P = 0.016). Ficoll clearance was increased in Cav-1-KO mice. In conclusion, the lack of caveolae in Cav-1-KO mice resulted in a marked increase in macromolecular transport. A two-pore analysis of the Ficoll clearance data revealed that the higher transport rate in Cav-1-KO mice was not compatible with the appearance of an alternative pathway for macromolecular transport. In contrast, the higher transperitoneal protein and Ficoll clearance is consistent with passive porous transport through an unperturbed two-pore system, presumably at an elevated capillary hydraulic pressure. Alternatively, the data may be explained by reductions in the selectivity of the endothelial glycocalyx, leading to an increased capillary hydraulic conductivity and large solute filtration.

The purpose of the present study was to assess the role of diffusion and convection during filtration of Ficoll across the glomerular filter by comparing glomerular sieving coefficients (theta) to neutral fluorescein isothiocyanate (FITC)-Ficoll 70/400 obtained at low (hydropenic) vs raised (normal) glomerular filtration rates (GFRs). The theta for FITC-Ficoll was determined in anesthetized Wistar rats (304 +/- 18 g) following laparotomy and cannulation of the ureters, used for urine sampling. After surgery, GFR was 1.2 +/- 0.16 ml/min (+/- s.e.), assessed using the plasma to urine clearance of FITC-inulin and (51)Cr-ethylenediaminetetraacetic acid. FITC-Ficoll 70/400 was infused intravenously (i.v.) following an initial bolus dose. To raise GFR, to an average of approximately 2 ml/min, 5 ml of serum together with glucagon (3 microg/min) was given i.v. FITC-inulin and FITC-Ficoll were determined in plasma and urine using size-exclusion high-performance liquid chromatography. The theta for Ficoll as a function of Stokes-Einstein radius was significantly reduced in the range of 13-43 A when GFR was raised. The maximal theta lowering effect, in relative terms, of raising GFR was obtained for a Ficoll a(e) of approximately 32 A. For Ficoll(36 A) (cf. albumin), theta was reduced from 0.111+/- 0.009 to 0.081+/- 0.012 (P0.05; n = 7) for the GFR increment imposed. The reduction in theta for Ficoll after raising GFR indicates the presence of a high diffusive component of glomerular Ficoll filtration in rats in vivo and contradicts the notion of a significant concentration polarization effect in the glomerular filter upon Ficoll molecules50 A in radius.

Background. The development of fluid and salt retention is a potential problem for all peritoneal dialysis (PD) patients. Sodium removal by the peritoneum is predominantly determined by convective fluid loss but influenced by diffusion and sieving due to free water transport as predicted by the three-pore model (TPM). The aim of the study was to establish the effect of transport status, dwell length and glucose concentration on observed ultrafiltration (UF), dialysate sodium concentration ([Na+](D)) and removal, and compare this with that predicted by a computer program based on the principles of the TPM. Methods. This was a cross-sectional study of UF and [Na+](D) collected prospectively from dwells classified by length, glucose concentration and membrane transport characteristics. Solute transport, converted to area parameter and UF capacity, was measured on each occasion by the peritoneal equilibration test. These parameters, along with plasma [Na+], were entered into the computer model. Fixed values for other parameters, e.g. hydraulic conductance and lymphatic absorption and sump volume, were used. Results. A total of 1853 dwells from 182 patients [10% were on automated PD (APD)] were analysed. There was a high degree of correlation (r=0.83-95, P

Background In peritoneal dialysis, approximately 40% of the total osmotic ultrafiltration (UF) induced by glucose can be predicted to be due to “free” water transport across aquaporin-1 (APQ-1). Theoretically, it would be possible to assess the fraction of free water transport in the early phase of a hypertonic dwell, when UF rate is high and the relative contribution of Na+ diffusion is low. La Milia et al. [La Milia V. et al. Fast-fast peritoneal equilibration test (FAST-FAST-PET): a simple method for peritoneal hydraulic permeability study [Abstract]. Nephrol Dial Transplant 2002; 17 (Suppl 1):17–18] suggested a technique to assess sodium-associated water transport based on sodium removal (Na+R) divided by the plasma Na+ concentration during a “fast-fast” (60 minute) peritoneal equilibration test (PET) for 3.86% glucose, yielding an estimate of the UF passing through the small pores (UFSP). Free water transport (UF through ultrasmall pores; UFUSP) was obtained by subtracting UFSP from total UF. Although peritoneal Na+ transport is almost totally convective, this technique will slightly overestimate small-pore UF due to the presence of some small-pore Na+ diffusion from the circulation during the dwell. A way of dealing with this problem was presented recently by Smit (Smit W. et al. Quantification of free water transport in peritoneal dialysis. Kidney Int 2004; 66:849–854). Methods In the present study we used the three-pore model of peritoneal transport to predict the degree of overestimation of UFSP for the technique presented by La Milia et al., and any potential deviations from theory for the technique presented by Smit et al. Simulations were performed under ordinary conditions and during simulated UF failure for 3.86% glucose. The fractional UF coefficient accounted for by APQ-1 was set at 2%. Results Estimating the UFSP from the sodium-associated water transport according to the method by La Milia et al. consistently overestimated UFSP and underestimated UFUSP. These errors were, however, minimal for dwells lasting between 30 and 80 minutes. The technique by Smit et al. to calculate aquaporin-mediated water flow (UFUSP), using an elaborate correction for Na+ diffusion from the circulation during the dwell, seemed accurate in most situations but, in general, tended to moderately overestimate UFUSP at early dwell times (Conclusions The technique presented by La Milia et al. to calculate free water transport during a fast-fast PET was found to be surprisingly accurate, although the procedure would further improve by the introduction of a correction algorithm. The technique by Smit is even more accurate for dwells up to 4 hours’ duration. However, since the Smit technique is elaborate, it is less practical for routine determinations of aquaporin-mediated water transport in peritoneal dialysis.

The size and charge-selective properties of the glomerular barrier are partly controversial. Glomerular sieving coefficients (θ) for proteins have rarely been determined noninvasively before in vivo. Therefore, θ was assessed vs. glomerular filtration rate (GFR;51Cr-EDTA clearance) in intact rats for radiolabeled myoglobin, κ-dimer, neutral horseradish peroxidase (nHRP), neutral human serum albumin (nHSA), and native albumin (HSA). To obtain θ, glomerular tracer clearance, assessed from the 7- to 8-min kidney uptake of protein, was divided by the GFR. The data were fitted with a two-pore model of glomerular permeability, where the small-pore radius was 37.35 ± 1.11 (SE) Å, and the “unrestricted pore area over diffusion path length” ( A0/Δ X) 1.84 ± 0.43 · 106cm. Although seemingly horizontal for nHRP and nHSA, the log θ vs. GFR curves showed slightly negative slopes for the proteins investigated in the GFR interval of 2–4.5 ml/min. Strong negative (linear) correlations between (log) θ and GFR were obtained for myoglobin ( P = 0.002) and HSA ( P = 0.006), whereas they were relatively weak for nHRP and nHSA and nonsignificant for κ-dimer. θ for nHSA was markedly higher than that for HSA. In conclusion, there were no indications of increases in θ vs. GFR, as indicative of concentration polarization, for the proteins investigated at high GFRs. Furthermore, the glomerular small-pore radius assessed from endogenous (neutral) protein sieving data was found to be smaller than previously determined using dextran or Ficoll as test molecules.

The relative contribution of transcytosis vs. large pore transport to the passage of macromolecules across microvascular endothelia has been a controversial issue for nearly half a century. To separate transcytosis from ‘porous’ transport, the transcytosis inhibitors N-ethylmaleimide (NEM) and filipin have been tested in in situ or ex vivo perfused organs with highly conflicting results. In continually weighed isolated perfused organs, where measurements of pre- and post-capillary resistances, capillary pressure and capillary filtration coefficients can be repeatedly performed, high doses of NEM and filipin increased the bulk transport of macromolecules from blood to tissue, despite producing vasoconstriction. By contrast, in in situ perfused organs, marked reductions in the tissue uptake of albumin tracer have been observed after NEM and filipin. When tissue cooling has been employed as a means of inhibiting (active) transcytosis, results have invariably shown a low cooling sensitivity of albumin transport, compatible with passive transendothelial passage of albumin. This observation is further strengthened by the commonly observed dependence of albumin transport upon the capillary pressure and the rate of transcapillary convection. For low-density lipoprotein (LDL), a cooling-sensitive, non-selective transport component has been discovered, which may be represented by filtration through paracellular gaps, lateral diffusion through transendothelial channels formed by fused vesicles, or by transcytosis. From a physiological standpoint there is little evidence supporting active transendothelial transport of most plasma macromolecules. This seems to be supported by studies on caveolin-1-deficient mice lacking plasmalemmal vesicles (caveolae), in which there are no obvious abnormalities in the transendothelial transport of albumin, immunoglobulins or lipoproteins. Nevertheless, specific transport in peripheral capillaries of several hormones and other specific substances, similar to that existing across the blood-brain barrier, still remains as a possibility.

The permselectivity of the parietal pleura was determined in spontaneously breathing anesthetized rabbits and dogs. In rabbits, we injected intrapleurally 5 ml of 1-g/dl albumin solution containing 100 microCi of 131I-labeled albumin plus 100 microCi of either lactate dehydrogenase (LDH) or alpha 2–125I-macroglobulin. Dogs received 100 ml of 1-g/dl albumin solution containing 100 microCi of 131I-albumin plus 100 microCi of alpha 2–125I-macroglobulin. A transpleural pressure gradient was set, lowering the intracapsular pressure to -30 cmH2O. The solvent drag reflection coefficients (sigma f) were calculated as the ratio between tracer concentrations in capsular and pleural liquid collected at 60–180 min. In rabbits sigma f was 0.44 +/- 0.2 (SD) for albumin, 0.84 +/- 0.1 for LDH, and 0.93 +/- 0.05 for alpha 2-macroglobulin. In dogs sigma f was 0.30 +/- 0.19 for albumin and 0.53 +/- 0.15 for alpha 2-macroglobulin. The hydraulic conductivity of the parietal pleura was 2.18 +/- 1.54 microliters.h-1.cmH2O-1.cm-2 in rabbits and 1.22 +/- 1.13 microliters.h-1.cmH2O-1.cm-2 in dogs. The parietal pleura could be modeled by two pore populations with radii of 83–89 and 156-222 A. The permeability coefficient averaged 0.08–0.21 x 10(-6) cm/s for albumin, 0.06–0.09 x 10(-6) cm/s for LDH, and 0.01-0.03 x 10(-6) cm/s for alpha 2-macroglobulin.

Reflectance spectrophotometry from 400 to 800 nm on different cutaneous pigmented lesions, including primary and metastatic malignant melanoma, pigmented nevi, lentigo and seborrhoeic keratosis, has been performed by using an external integrating sphere coupled to a spectrophotometer. Measurements show that reflectance spectra of the different lesions manifest dissimilar patterns, particularly in the near IR region. Comparison of reflectance of nevi with that of malignant melanomas results in a highly significant difference (P less than 10(-6)) between the two samples. Though interpretation of the spectra remains difficult as a result of the complexity of the optical processes of scattering and absorption, our results suggest that a detailed analysis of the reflectance spectrum may give clinically useful information, and could be utilized as an aid in clinical diagnosis of cutaneous pigmented lesions, especially where malignant melanoma is concerned.

This study was performed to investigate the glomerular permeability alterations responsible for the microalbuminuria occurring in endotoxemia and during anaphylactic shock. In anesthetized Wistar rats, the left ureter was catheterized for urine collection while, simultaneously, blood access was achieved. Endotoxemia was induced by lipopolysaccharide (LPS) from Escherichia coli, and glomerular permeability was assessed at 60 and 90 ( n = 7) and 120 ( n = 7) min. Anaphylaxis was induced by a bolus dose of Dextran-70, and glomerular permeability assessed at 5 min ( n = 8) and 40 min ( n = 9). Sham animals were followed for either 5 or 120 min. The glomerular sieving coefficients (θ) to fluorescein isothiocyanate-Ficoll (70/400) were determined from plasma and urine samples and assessed using size-exclusion chromatography (HPLC). After start of the LPS infusion (2 h), but not at 60 or 90 min, θ for Ficoll70Åhad increased markedly [from 2.91 × 10−5± 6.33 × 10−6to 7.78 × 10−5± 6.21 × 10−6( P < 0.001)]. In anaphylaxis, there was a large increase in θ for Ficolls >60 Å in molecular radius already at 5 min, but the glomerular permeability was completely restored at 40 min. In conclusion, there was a transient, immediate increment of glomerular permeability in dextran-induced anaphylaxis, which was completely reversible within 40 min. By contrast, endotoxemia caused an increase in glomerular permeability that was manifest first after 2 h. In both cases, θ to large Ficoll molecules were markedly increased, reflecting an increase in the number of large pores in the glomerular filter.

In patients undergoing peritoneal dialysis (PD) for end-stage renal failure, the optimum electrolyte composition of a dialysis solution is that which best serves the homeostatic needs of the body. Comparing the trans-peritoneal removal of electrolytes by conventional PD solutions (CPDSs) with that by normal kidneys, it is evident that peritoneal removal is in the lower range of what can be considered “normal.” Given the electrolyte composition of CPDSs and a total dwell volume of 4 exchanges of 2 L each, approximately 90 mmol NaCl, 40 mmol K+, 10 – 15 mmol HPO4- and 1 – 2 mmol Ca2+ can be removed daily [plus 1 L ultrafiltration (UF)]. Na+, Ca2+, and Mg2+ are supplied in CPDSs in concentrations close to their plasma concentrations, which makes their removal almost entirely dependent on UF. In UF failure (UFF), plasma levels of the foregoing ions will tend to rise, producing a higher diffusion gradient to compensate for their defective UF removal. Peritoneal removal of HCO3-, HPO4-, and K+ are usually quite efficient because of the zero CPDS concentrations of these ions. Approximately 150 mmol HCO3- is lost daily with CPDSs, compensated for by the addition of 30 – 40 mmol/L lactate, or, with the use of multi-compartment bags, bicarbonate instead. However, a mixture of bicarbonate and lactate should be preferred as a buffer, to avoid intracellular acidosis from high levels of pCO2 in the dialysis fluid. For patients on continuous ambulatory peritoneal dialysis (CAPD) without UFF and with some residual renal function, PD fluid concentrations of Na+ 130 – 133 mmol/L, Ca2+ 1.25 – 1.35 mmol/L, and Mg2+ 0.25 – 0.3 mmol/L seem appropriate. With reduced UF after a few years of PD, the removal of fluid and electrolytes often becomes deficient. Dietary salt restriction can be prescribed, but it is hard to implement. The use of low-Na+ solution (LNa) is a potential alternative. The reduction in osmolality resulting from Na+ removal in LNa should preferably be compensated by the addition of glucose (G). In a recent study, a regimen including 1 LNa exchange daily (Na+ 115 mmol/L) in a G-compensated solution showed very promising effects on blood pressure and fluid status. However, large-scale randomized controlled studies have to be performed to definitively settle the role of LNa in volume-overloaded patients.

Polydisperse mixtures of dextran or Ficoll have been frequently used as molecular probes for studies of glomerular permselectivity because they are largely inert and not processed (reabsorbed) by the proximal tubules. However, dextrans are linear, flexible molecules, which apparently are hyperpermeable across the glomerular barrier. By contrast, the Ficoll molecule is almost spherical. Still, there is ample evidence that Ficoll fractional clearances (sieving coefficients) across the glomerular capillary wall (GCW) are markedly higher than those for neutral globular proteins of an equivalent in vitro Stokes-Einstein (SE) radius. Physical data, obtained by “crowding” experiments or measurements of intrinsic viscosity, suggest that the Ficoll molecule exhibits a rather open, deformable structure and thus deviates from an ideally hard sphere. This is also indicated from the relationship between (log) in vitro SE radius and (log) molecular weight (MW). Whereas globular proteins seem to behave in a way similar to hydrated hard spheres, polydisperse dextran and Ficoll exhibit in vitro SE radii that are much larger than those for compact spherical molecules of equivalent MW. For dextran, this can be partially explained by a high-molecular-size asymmetry. However, for Ficoll the explanation may be that the Ficoll molecule is more flexible (deformable) than are globular proteins. An increased compressibility of Ficoll and an increased deformability and size asymmetry for dextran may be the explanation for the fact that the permeability of the GCW is significantly higher when assessed using polysaccharides such as Ficoll or dextran compared with that obtained using globular proteins as molecular size probes. We suggest that molecular deformability, besides molecular size, shape, and charge, plays a crucial role in determining the glomerular permeability to molecules of different species.

During the last decades there has been a debate regarding whether transvascular protein transport is an active (transcytosis) or a passive (porous) process. To separate cooling-sensitive transcytosis from passive transport processes between blood and peritoneal fluid, we induced hypothermia in rats in vivo, reducing their body temperature to 19°C. Control rats were kept at 37°C. Either human albumin, or IgG, or IgM, or LDL, radiolabeled with 125I, was given intra-arterially together with 51Cr-EDTA. During tracer administration, a 2-hour peritoneal dialysis dwell was performed. Clearance of the tracers to dialysate, and the permeability-surface area coefficient (PS) for 51Cr-EDTA and glucose were assessed. During cooling, mean arterial blood pressure (MAP) was reduced to 40% of control and plasma viscosity increased by 48.5%, while peritoneal blood flow was reduced to 10%. At 19°C, clearance of albumin to dialysate fell from 9.30 ± 1.62 (SEM) to 3.13 ± 0.28 µl/min (p < 0.05), clearance of IgG from 6.33 ± 0.42 to 2.54 ± 0.12 µl/min (p < 0.05), clearance of IgM from 3.65 ± 0.33 to 1.10 ± 0.12 µl/min (p < 0.05), and clearance of LDL from 3.54 ± 0.20 to 0.73 ± 0.06 µl/min (p < 0.05). The fall in PS for 51Cr-EDTA was from 0.320 ± 0.01 to 0.075 ± 0.003 ml/min (p < 0.05), and that for glucose from 0.438 ± 0.02 to 0.105 ± 0.01 ml/min (p < 0.05). Tissue cooling reduced large solute transport largely in proportion to the cooling-induced reductions of MAP (to 40%), and the concomitant increase in viscosity (to 67%), i.e. to ≈20–30% (0.40 × 0.67) of control, though LDL clearance was reduced further. The fall in small solute PS, in excess of the viscosity effect, mirrored the fall in peritoneal blood flow occurring during hypothermia. In conclusion, the good correlation of predicted to calculated changes suggests that the overall transendothelial macromolecular passage in vivo occurs passively, and not due to active processes.

Mass transfer of calcium across the peritoneum at three different peritoneal dialysis fluid Ca 2+ and glucose concentrations. Background In peritoneal dialysis, the rate of ultrafiltration has been predicted to be a major determinant of peritoneal calcium (Ca 2+ ) removal. Hence, dialysis fluid glucose concentration should be an important factor governing the transperitoneal Ca 2+ balance. The aim of this study was to test the effect of various dialysate glucose levels and selected dialysate Ca 2+ levels on Ca 2+ removal in peritoneal dialysis patients. Methods Patients ( N = 8) received, during a 7-week period, 2L of lactate (30mmol/L)/bicarbonate (10mmol/L)–buffered peritoneal dialysis solutions containing either 1.5% glucose and 1.0mmol/L Ca 2+ or 2.5% glucose and 1.6mmol/L Ca 2+ , or 4% glucose and 2.5mmol/L Ca 2+ , respectively, provided in a three-compartment bag (trio system). Patients underwent standardized (4-hour) dwells, one for each of the three dialysates to assess permeability-surface area product (PS) or mass transfer area coefficients (MTAC) for ionized and "freely diffusible" Ca 2+ , lactate, glucose, bicarbonate, phosphate, creatinine, and urea. Results There was a clear-cut dependence of peritoneal Ca 2+ removal on the rate of ultrafiltration. For large peritoneal to dialysate Ca 2+ gradients (2.5mmol/L Ca 2+ in 4% glucose) a close fit of measured to simulated data was predicted by the three-pore model using nonelectrolyte equations. For low transperitoneal Ca 2+ concentration gradients, however, directly measured Ca 2+ data agreed with the simulated ones only when the peritoneal Ca 2+ PS was set lower than predicted from pore theory (6mL/min). Conclusion There was a marked ultrafiltration dependence of transperitoneal Ca 2+ transport. Nonelectrolyte equations could be used to simulate peritoneal ion (Ca 2+ ) transport provided that the transperitoneal ion concentration gradients were large. Based on our data 1.38mmol/L Ca 2+ in the dialysis fluid would have created zero net Ca 2+ gain during a 4-hour dwell for 1.5% glucose, whereas 1.7 and 2.2mmol/L Ca 2+ would have been needed to produce zero Ca 2+ gain for 2.5% glucose and 3.9% glucose, respectively.

The transport of macromolecules during peritoneal dialysis is highly selective when they move from blood to dialysate but nearly completely unselective in the opposite direction. Aiming at describing this asymmetry, we modeled the peritoneal barrier as a series arrangement of two heteroporous membranes. First a three-pore membrane was considered, crossed by small [radius of the small pore ( rs) ≈ 45 Å], large [radius of the large pore ( rL) ≈ 250 Å], and transcellular pores accounting for 90, 8, and 2% to the hydraulic conductance, respectively, and with a corresponding pore area over diffusion distance ( A0/Δ x) set to 50,000 cm. We calculated the second membrane parameters by fitting simultaneously the bidirectional clearance of molecules ranging from sucrose [molecular weight = 360, permeating solute radius ( ae) ≈ 5 Å] to α2-macroglobulin (molecular weight = 820,000, ae≈ 90 Å). The results describe a second two-pore membrane with very large pores ( rL≈ 2,300 Å) accounting for 95% of the hydraulic conductance, minor populations of small ( rs≈ 67 Å) and transcellular pores (3 and 2%, respectively), and an A0/Δ x≈ 65,000 cm. The estimated peritoneal lymph flow is ≈0.3 ml/min. The two membranes can be identified as the capillary endothelium and an extracellular interstitium lumped with the peritoneal mesothelium.

Considering fluid and protein fluxes, the human microvascular exchange system can be viewed as a two-compartment system, the circulation and the interstitium, and one draining pathway, through the interstitial lymphatics. The serous spaces (pleural space, peritoneal space, pericardium) represent a more complicated case of anatomical disposition in that the serous cavity itself is an intermediate compartment that can exchange with the surrounding interstitial spaces on the parietal and visceral side. In addition, the serous cavity is served by a private draining route, the parietal serosal lymphatics. The aim of this work was to investigate the distribution of these lymphatics in the parietal pleura in order to gain some insight into their fluid dynamics properties.

A model of pleural fluid turnover, based on mass conservation law, was developed from experimental evidence that 1) pleural fluid filters through the parietal pleura and is drained by parietal lymphatics and 2) lymph flow increases after an increase in pleural liquid volume, attaining a maximum value 10 times greater than control. From the differential equation describing the time evolution of pleural liquid pressure, we obtained the equation for the steady-state condition ("set point") of pleural liquid pressure: Pss = (KfPi*+KlPzf)/Kf+Kl), where Kf is parietal pleura filtration coefficient, Kl is initial lymphatic conductance, Pzf is lymphatic potential absorption pressure, and Pi* is a factor accounting for the protein reflection coefficient of parietal mesothelium and hydraulic and colloid osmotic pressure of parietal interstitium and pleural liquid. Lymphatics act as a passive negative-feedback control tending to offset increases in pleural liquid volume. Some features of this control are summarized here: 1) lymphatics exert a tight control on pleural liquid volume or pressure so that the set point is maintained close to the potential absorption pressure of lymphatics; 2) a 10-fold increase in Kf would cause only a 2- and 5-fold increase in pleural liquid volume with normal (1.8 g/dl) and increased (3.4 g/dl) protein concentration of the pleural fluid, respectively; and 3) the reduction in maximum lymph flow greatly reduces the range of operation of the control with increased filtration and/or protein concentration of pleural fluid.

In 31 anesthetized rabbits, after removal of superficial tissues, glass micropipettes filled with 0.5 M NaCl solution and connected to an electrohydraulic servo-null system were used to measure extraperitoneal interstitial fluid pressure (Pi,per) and peritoneal liquid pressure (Pliq,per) at various heights. Linear regressions relating pressure to recording height (H) were Pi,per = 1.07 – 0.27H and Pliq,per = 0.9 – 0.64H, respectively. Protein concentration (Cp;g/dl) and colloid osmotic pressure (II; cmH2O) of plasma and of peritoneal and pleural liquids were 5.48 +/- 0.38 and 24.61 +/- 3.23, 3.07 +/- 0.5 and 13.29 +/- 1.87, and 1.76 +/- 0.42 and 8.45 +/- 2, respectively. The equation relating II to Cp was II = 4.64Cp + 0.0027Cp2. Tissue fluid samples were collected with saline-soaked wicks implanted in vivo or dry wicks inserted postmortem in extraperitoneal and extrapleural interstitial spaces. After 60 and 15 min, respectively, wicks were withdrawn and centrifuged; wick fluid was analyzed in colloid osmometer for small samples. Average extraperitoneal and extrapleural II values were 14.2 +/- 2.49 and 11.94 +/- 1.52 cmH2O, corresponding to Cp of 3.07 and 2.57 g/dl, respectively. The average net pressure gradient, assuming reflection coefficient and hydraulic conductivity (Negrini et al. J. Appl. Physiol. 69: 625–630, 1990; 71: 2543–2547, 1991), was 1.18 and 0.98 cmH2O for parietal peritoneal and pleural mesothelia, respectively, favoring filtration from the extraserosal interstitia into the serosal cavities. Total parietal peritoneal filtration was 1.49 ml.kg-1.h-1, approximately 15-fold higher than that for pleural mesothelium.

We injected technetium-labeled albumin (at a concentration similar to that of the pleural fluid) in the costal region of anesthetized dogs (n = 13) either breathing spontaneously or apneic. The decay rate of labeled activity at the injection site was studied with a gamma camera placed either in the anteroposterior (AP) or laterolateral (LL) projection. In breathing animals (respiratory frequency approximately 10 cycles/min), 10 min after the injection the activity decreased by approximately 50% on AP and approximately 20% on LL imaging; in apneic animals the corresponding decrease in activity was reduced to approximately 15 and approximately 3%, respectively. We considered label translocation from AP and LL imaging as a result of bulk flows of liquid along the costomediastinal and gravity-dependent direction, respectively. We related intrapleural flows to the hydraulic pressure gradients existing along these two directions and to the geometry of the pleural space. The pleural space was considered as a porous medium partially occupied by the mesh of microvilli protruding from mesothelial cells. Solution of the Kozeny-Carman equation for the observed flow velocities and pressure gradients yielded a mean hydraulic radius of the pathways followed by the liquid ranging from 2 to 4 microns. The hydraulic resistivity of the pleural space was estimated at approximately 8.5 x 10(5) dyn.s.cm-4, five orders of magnitude lower than that of interstitial tissue.

The partitioning of fluid flows among small and ultrasmall pores of the three-pore model in peritoneal dialysis has been traditionally assessed using 4-hour dwells with 3.86% glucose solutions. Under these conditions, however, back-filtration through small pores has been hard to demonstrate. As nicely shown by Asghar and Davies, however, the use of low-concentration (1.36%) glucose-based solutions allows accurate studies of the partitioning of fluid flows from the peritoneal cavity under conditions of fluid loss.