The relationship between three eGFR formulas and hospitalization for heart failure in 54 486 individuals with type 2 diabetes.

OBJECTIVE: This study aims to study the association between renal function and hospitalization for heart failure (HF) in individuals with type 2 diabetes. METHODS: Renal function was determined according to three formulas used to estimate glomerular filtration rate (eGFR): Cockcroft-Gault, modified diet in renal disease (MDRD) and chronic kidney disease epidemiology (CKD-EPI). Proportional hazards regression models adjusted for age, sex, HbA1c , blood pressure, smoking and cardiovascular comorbidities were constructed for each eGFR formula to estimate risk of hospitalization for heart failure. Systematic pairwise likelihood ratio tests of nested models were used to compare the predictive power of each eGFR formula. RESULTS: In 54 486 patients, evaluated over a median follow-up of 7.0 years, a total of 5936 (10.9%) developed heart failure, with an excess risk in all eGFR categories below 60 mL/min/1.73 m2 (reference: eGFR >90 mL/min/1.73 m2 ). Hazard ratios ranged from 1.25 to 1.35 for eGFR 45-60 mL/min/1.73 m2 , 1.62 to 1.66 for eGFR 30-45 mL/min/1.73 m2 and 2.18 to 2.52 for eGFR <30 mL/min/1.73 m2 in the three eGFR formulas. In pairwise comparisons, the model with the MDRD variable added significantly more information than the Cockcroft-Gault variable. For the model with the CKD-EPI variable, no clear differences in predictive power for HF hospitalization existed in relation to the other eGFR formulas. CONCLUSION: Patients with type 2 diabetes, with eGFR 45 to 60 mL/min/1.73 m2 , have approximately 25-35% increased risk of hospitalization for HF, increasing with lower eGFR, to 2-2.5 times in those with eGFR <30 mL/min/1.73 m2 . The MDRD formula for calculating eGFR is more predictive of hospitalization for heart failure than the Cockcroft-Gault formula. Copyright © 2016 John Wiley & Sons, Ltd.

The incidence of albuminuria after bariatric surgery and usual care in Swedish Obese Subjects (SOS): a prospective controlled intervention trial.

BACKGROUND: Obesity is associated with increased risk of chronic kidney disease and albuminuria is a predictor of renal impairment. Bariatric surgery reduces body weight in obese subjects, but it is not known whether surgery can prevent development of albuminuria. This study aims to determine the long-term effect of bariatric surgery on the incidence of albuminuria. SUBJECTS: The Swedish Obese Subjects study is a non-randomized, prospective, controlled study conducted at 25 public surgical departments and 480 primary health care centers in Sweden. Between 1 September 1987 and 31 January 2001, 2010 participants who underwent bariatric surgery and 2037 controls were recruited. Inclusion criteria were age 37-60 years and BMI ⩾ 34 in men and BMI ⩾ 38 in women. In this analysis, we included 1498 patients in the surgery group and 1610 controls without albuminuria at baseline. Patients in the bariatric surgery group underwent banding (18%), vertical banded gastroplasty (69%) or gastric bypass (13%); controls received usual obesity care. Date of analysis was 1 January 2011. Median follow-up was 10 years, and the rates of follow-up were 87%, 74 and 52% at 2, 10 and 15 years, respectively. The main outcome of this report is incidence of albuminuria (defined as urinary albumin excretion >30 mg per 24 h) over up to 15 years. RESULTS: During the follow-up, albuminuria developed in 246 participants in the control group and in 126 in the bariatric surgery group, corresponding to incidence rates of 20.4 and 9.4 per 1000 person years, respectively (adjusted hazard ratio, 0.37; 95% confidence interval, 0.30-0.47; P < 0.001). The expected number of surgeries needed to prevent the development of albuminuria in one patient at 10 years was nine. CONCLUSIONS: Bariatric surgery is associated with reduced incidence of albuminuria compared with usual obesity care.

High glucose causes dysfunction of the human glomerular endothelial glycocalyx.

The endothelial glycocalyx is a gel-like layer which covers the luminal side of blood vessels. The glomerular endothelial cell (GEnC) glycocalyx is composed of proteoglycan core proteins, glycosaminoglycan (GAG) chains, and sialoglycoproteins and has been shown to contribute to the selective sieving action of the glomerular capillary wall. Damage to the systemic endothelial glycocalyx has recently been associated with the onset of albuminuria in diabetics. In this study, we analyze the effects of high glucose on the biochemical structure of the GEnC glycocalyx and quantify functional changes in its protein-restrictive action. We used conditionally immortalized human GEnC. Proteoglycans were analyzed by Western blotting and indirect immunofluorescence. Biosynthesis of GAG was analyzed by radiolabeling and quantified by anion exchange chromatography. FITC-albumin was used to analyze macromolecular passage across GEnC monolayers using an established in vitro model. We observed a marked reduction in the biosynthesis of GAG by the GEnC under high-glucose conditions. Further analysis confirmed specific reduction in heparan sulfate GAG. Expression of proteoglycan core proteins remained unchanged. There was also a significant increase in the passage of albumin across GEnC monolayers under high-glucose conditions without affecting interendothelial junctions. These results reproduce changes in GEnC barrier properties caused by enzymatic removal of heparan sulfate from the GEnC glycocalyx. They provide direct evidence of high glucose-induced alterations in the GEnC glycocalyx and demonstrate changes to its function as a protein-restrictive layer, thus implicating glycocalyx damage in the pathogenesis of proteinuria in diabetes.

Corticosteroid administration alters the mechanical properties of isolated collagen fascicles in rat-tail tendon.

Overload tendon injuries are frequent in recreational and elite sports. The optimal treatment strategy remains unknown, but local administration of corticosteroids is one common treatment option. The direct effects of the corticosteroid administration on the tissue are not fully understood. The present study examined the biomechanical effects of intratendinous corticosteroid injections on healthy rat-tail tendon collagen fascicles. A total of 24 Wistar male rats were divided into (A) a corticosteroid group where the animals were injected in the tail tendon with methylprednisolone acetate, 1.0 mL of 40 mg/mL mixed with 1.0 mL 9% saline (n=12), and (B) a control group that was injected with 9% saline (n=12). Three days after the injections, the animals were sacrificed and single individual collagen fascicles were collected and underwent displacement to failure. Corticosteroid administration significantly reduced tensile fascicle yield strength by 16% and Young's modulus by 14% compared with sham treatment (10.5+/-0.8 vs 12.4+/-0.5 MPa, P< or =0.05, and 537+/-27 vs 641+/-30 MPa, P<0.05, respectively), while the strain properties were unaffected. Peak stress was similar between the two groups. There was no difference in fascicle diameter between the two groups.

Changes in muscarinic receptors in the toad urothelial cell line TBM-54 following acrolein treatment.

1. In cyclophosphamide-induced cystitis in the rat, cholinergic function of the bladder and muscarinic receptor expression are altered. In the present study, we investigated whether the toad urothelial cell line TBM-54 expresses functional muscarinic receptors and whether changes in muscarinic receptors can be induced in vitro by treating cells with acrolein, a metabolite of cyclophosphamide causing cystitis. 2. The occurrence of muscarinic receptors on cells was assessed by microphysiometry, a method analysing receptor function by measuring changes in the extracellular acidity rate (ECAR) in response to receptor stimulation. 3. Challenging untreated cells with the muscarinic receptor agonist carbachol gave rise to a concentration-dependent increase in changes in ECAR, with a maximal response at 1 mmol/L carbachol of 51 +/- 6%. Pre-incubating cells with different muscarinic receptor antagonists (i.e. pirenzepine (M(1) receptor selective), methoctramine (M(2)/M(4) receptor selective) and 4-diphenylacetoxy-N-methylpiperidine methobromide (4-DAMP; M(3)/M(1)/M(5) receptor selective)), gave rise to a concentration-dependent decrease in the effects of carbachol (0.5 mmol/L) on changes in ECAR. 4. Western blot analysis was used to determine the expression of all muscarinic receptor subtypes (M(1)-M(5)) by the cell line. Following acrolein treatment, cells were markedly less sensitive to carbachol and the expression of muscarinic M(2) receptors was decreased, whereas the expression of muscarinic M(3) receptors was increased. 5. In conclusion, the urothelial cell line TBM-54 expresses functional muscarinic receptors and exposure to acrolein leads to a modulation in the expression of muscarinic receptors. Consequently, acrolein may have direct effects on muscarinic receptor function and expression that contribute to the pathogenesis of cyclophosphamide-induced cystitis.

Novel methods for tendon investigations.

PURPOSE: Tendon structures have been studied for decades, but over the last decade, methodological development and renewed interest for metabolic, circulatory and tissue protein turnover in tendon tissue has resulted in a rising amount of investigations. METHOD: This paper will detail the various modern investigative techniques available to study tendons. RESULTS: There are a variety of investigative methods available to study the correlations between mechanics and biology in tendons. CONCLUSION: The available methodologies not only allow for potential insight into physiological and pathophysiological mechanisms in tendon tissue, but also, to some extent, allow for more elaborate studies of the intact human tendon.

Massage for mechanical neck disorders.

BACKGROUND: Mechanical neck disorders (MND) are common, disabling and costly. Massage is a commonly used modality for the treatment of neck pain. OBJECTIVES: To assess the effects of massage on pain, function, patient satisfaction and cost of care in adults with neck pain. To document adverse effects of treatment. SEARCH STRATEGY: Cochrane CENTRAL, MEDLINE, EMBASE, MANTIS, CINAHL, and ICL databases were electronically searched, without language restriction, from their inception to September 2004 SELECTION CRITERIA: Studies using random or quasi-random assignment were included. DATA COLLECTION AND ANALYSIS: Two reviewers independently conducted citation identification, study selection, data abstraction and methodological quality assessment. Using a random-effects model, we calculated the relative risk and standardized mean difference. MAIN RESULTS: Nineteen trials met the inclusion criteria. Overall, the methodological quality was low, with 12/19 assessed as low-quality studies. Trials could not be statistically pooled because of heterogeneity in treatment and control groups. Therefore, a levels-of-evidence approach was used to synthesize results. Assessment of the clinical applicability of the trials showed that the participant characteristics were well reported, but neither the descriptions of the massage intervention nor the credentials or experience of the massage professionals were well reported. Six trials examined massage as a stand-alone treatment. The results were inconsistent. Of the 14 trials that used massage as part of a multimodal intervention, none were designed such that the relative contribution of massage could be ascertained. Therefore, the role of massage in multimodal treatments remains unclear. AUTHORS' CONCLUSIONS: No recommendations for practice can be made at this time because the effectiveness of massage for neck pain remains uncertain. Pilot studies are needed to characterize massage treatment (frequency, duration, number of sessions, and massage technique) and establish the optimal treatment to be used in subsequent larger trials that examine the effect of massage as either a stand-alone treatment or part of a multimodal intervention. For multimodal interventions, factorial designs are needed to determine the relative contribution of massage. Future reports of trials should improve reporting of the concealment of allocation, blinding of outcome assessor, adverse events and massage characteristics. Standards of reporting for massage interventions, similar to CONSORT, are needed. Both short- and long-term follow-up are needed.

Region-specific mechanical properties of the human patella tendon.

The present study investigated the mechanical properties of tendon fascicles from the anterior and posterior human patellar tendon. Collagen fascicles from the anterior and posterior human patellar tendon in healthy young men (mean +/- SD, 29.0 +/- 4.6 yr, n = 6) were tested in a mechanical rig. A stereoscopic microscope equipped with a digital camera recorded elongation. The fascicles were preconditioned five cycles before the failure test based on pilot data on rat tendon fascicle. Human fascicle length increased with repeated cycles (P < 0.05); cycle 5 differed from cycle 1 (P < 0.05), but not cycles 2-4. Peak stress and yield stress were greater for anterior (76.0 +/- 9.5 and 56.6 +/- 10.4 MPa, respectively) than posterior fascicles (38.5 +/- 3.9 and 31.6 +/- 2.9 MPa, respectively), P < 0.05, while yield strain was similar (anterior 6.8 +/- 1.0%, posterior 8.7 +/- 1.4%). Tangent modulus was greater for the anterior (1,231 +/- 188 MPa) than the posterior (583 +/- 122 MPa) fascicles, P < 0.05. In conclusion, tendon fascicles from the anterior portion of the human patellar tendon in young men displayed considerably greater peak and yield stress and tangent modulus compared with the posterior portion of the tendon, indicating region-specific material properties.

Optimization of peritoneal dialysis prescription using computer models of peritoneal transport.

Computer models are valuable clinical tools in the effort to improve quality of life for dialysis patients. At present, two software programs have been validated clinically in adult and pediatric populations. They are the Personal Dialysis Capacity (PDC: Gambro Lundia AB, Lund, Sweden) and PD Adequest (Baxter Healthcare Corporation, Deerfield, IL, U.S.A.). Both programs seem to give accurate predictions of small-solute clearance, but the PDC seems to be superior in predicting ultrafiltration volumes. Indeed, the software programs have several important differences that affect their accuracy and, hence, their clinical value. The PDC software introduces the concepts of capillary physiology to the field of peritoneal dialysis. It gives a functional description of the peritoneal membrane of the individual patient. Recently, its "new" area parameter (A0/delta x) was shown to be superior to the peritoneal equilibration test (PET) in predicting transperitoneal exchange.

CAPD in patients with autosomal dominant polycystic kidney disease.

OBJECTIVE: To investigate whether there are specific complications to continuous ambulatory peritoneal dialysis (CAPD) in patients with autosomal dominant polycystic kidney disease (ADPKD) due to defects in various wall structures--causing hernia and diverticulitis--and to enlarged kidneys. DESIGN: The clinical experience of CAPD in 26 patients with ADPKD, treated for 11+/-6 months, was studied in retrospect and compared with that of 26 contemporary controls. Medical records were reviewed with respect to survival in this treatment form and any complication. Peritoneal dialysis capacity (PDC), as measured in 21 ADPKD patients and 20 controls, was also evaluated. SETTING: University Hospital. RESULTS: Before initiation of CAPD, enlarged kidneys necessitated nephrectomy in 2 of 26 ADPKD patients; both cases were registered as preparation for transplantation, not for CAPD. Survival in CAPD was similar in ADPKD patients and controls. Hernia was present in 4 ADPKD patients and 2 controls, and required transfer to hemodialysis in 1 patient from each group, temporarily. The incidence of peritonitis was 1 per 20 months in ADPKD patients versus 1 in 27 months in the controls, not significantly different. Peritonitis was caused by colonic bacteria in similar numbers. Residual renal function was 1.9 2.1 mL/min per 1.73 m2 in ADPKD patients versus 1.9+/-1.4 mL/min per 1.73 m2 in the controls. No difference was detected in any of the variables measured by PDC. CONCLUSION: There were no specific problems related to ADPKD.

Dyslipidemia in peritoneal dialysis--relation to dialytic variables.

OBJECTIVE: To investigate whether the specific lipoprotein (LP) abnormalities of peritoneal dialysis (PD) are associated with functional variables of this mode of dialysis. DESIGN: A survey of the LP profile in relation to peritoneal dialysis capacity (PDC) variables. The LP profile was compared to that of a group of age- and sex-matched controls. SETTING: The Peritoneal Dialysis Unit at Sahlgrenska University Hospital in Gothenburg, Sweden. PATIENTS: Twenty-two nondiabetic PD patients (5 women, 17 men) who had been on PD for at least 6 months. MAIN OUTCOME MEASURES: The LP profile included plasma lipids, apolipoproteins (Apo), and individual ApoA- and ApoB-containing LP. The PDC measurement determined peritoneal glucose uptake, protein losses, effective peritoneal surface area, and total weekly creatinine clearance. RESULTS: The patients had been on PD for 6 to 48 months (mean 15.3 months) and had a total weekly creatinine clearance of 69.7+/-13.3 L/1.73 m2 body surface area, an average peritoneal glucose uptake corresponding to 446+/-162 kcal/24 hour, and a protein loss of 8.1+/-2.5 g/24 hr. The patients had significantly higher total cholesterol (7.1 mmol/L),VLDL-cholesterol (1.0 mmol/L), LDL-cholesterol (4.7 mmol/L), and triglyceride levels (2.5 mmol/L); whereas the HDL-cholesterol level (1.2 mmol/L) was significantly lower than in controls. The PD patients had increased levels of ApoB-containing LPs, both of the cholesterol-rich LP-B and of the triglyceride-rich LP-B complex, reflected in higher plasma concentrations of ApoB, ApoC-III, and ApoE. Furthermore, they had significantly lower levels of LP-A-I:A-II, as well as of ApoA-I and ApoA-II. The LP-A-I:A-II and ApoA-II levels correlated inversely with the duration of PD treatment (r = 0.54, p < 0.01 and r = 0.52, p < 0.05, respectively). The ApoA-II level was inversely correlated with the peritoneal surface area (r = 0.53, p < 0.05). There were no other correlations between LP variables and PDC variables, nor did any of the LP variables correlate with peritoneal glucose uptake or protein losses. CONCLUSION: The proatherogenic lipoprotein profile of patients on PD is characterized by increased concentrations of cholesterol-rich and triglyceride-rich ApoB-containing LPs. While the duration of treatment appears to have some influence on the development of this type of dyslipidemia, the pathophysiological links to the dialysis mode must be further explored.

Impact of fill volume changes on peritoneal dialysis tolerance and effectiveness in children.

In the last decade, it has became apparent that the prescribed fill volume (IPV) in children on peritoneal dialysis (PD) should be expressed per body surface area (BSA in square meters) to avoid a false perception of peritoneal hyperpermeability as determined during a peritoneal equilibration test [PET, dialysate-to-plasma (D/P) ratio]. Nevertheless, the optimal IPV in terms of both tolerance and effectiveness remains under discussion. An individual approach to IPV prescription might balance the measurement of the intraperitoneal pressure, the use of the mass transfer coefficient despite the D/P ratio, and a determination of the effective peritoneal area available for exchanges. Considering these parameters, we usually found the individual optimal fill volume to be less than 1400 mL/m2.

Functional and molecular alterations of the glomerular barrier in long-term diabetes in mice.

AIMS/HYPOTHESIS: Despite the fact that diabetic nephropathy is an increasingly common disorder that may lead to uraemia, the underlying mechanisms are still poorly understood and there is no specific therapy. To clarify whether long-term diabetes alters glomerular size- or charge-selectivity or both, we studied non-obese diabetic mice for up to 40 weeks. MATERIALS AND METHODS: During the study period, spot urine was collected and blood pressure measured. At weeks 10 and 40, the right kidney was isolated and perfused at 8 degrees C to inhibit tubular function, allowing for analysis of glomerular selectivity with albumin and Ficoll clearance. The left kidney was removed for further investigation using electron microscopy and molecular biology. Real-time PCR with low-density arrays was done to evaluate renal cortex mRNA expression of proteoglycans and other components in the glomerular barrier. After 40 weeks of diabetes, kidneys showed morphological changes typical of diabetic complications. RESULTS: At 40 weeks, the fractional clearance for negatively charged albumin was three times higher in the diabetic animals (0.0160) than in controls (0.0051, p<0.001), while fractional clearance for neutral Ficoll 35.5 A with a Stokes Einstein radius similar to that of albumin was unaffected. In addition, protein and mRNA levels for versican and decorin were downregulated after 40 weeks of diabetes. CONCLUSIONS/INTERPRETATION: We conclude that glomerular charge- but not size-selectivity was impaired in the diabetic animals with proteinuria. Also, glomerular components such as versican, decorin and fibromodulin were found to be downregulated after 40 weeks of diabetes.

Podocyte proteoglycan synthesis is involved in the development of nephrotic syndrome.

Proteoglycans (PGs) are important for the glomerular barrier, for cell signaling, and for the anchorage of cells to the glomerular basement membrane. They are, however, complex macromolecules, and their production has not yet been thoroughly investigated in podocytes. In the present study, we studied the biosynthesis of PGs by highly differentiated human podocytes and in rats. The cells were treated with puromycin aminonucleoside (PAN; a nephrosis-inducing agent), steroids (used as primary treatment for nephrotic syndrome), or both. Analysis was made by TaqMan real-time PCR, Western blotting, and by metabolic labeling with (35)S and (3)H. We found that podocytes produce versican, syndecan-1, decorin, and biglycan together with the previously known PG syndecan-4, glypican, and perlecan. PAN treatment downregulated the mRNA and the protein expression of both versican (by 24 +/- 6%, P < 0.01, for mRNA and by 50% for protein) and perlecan (by 14 +/- 5%, P < 0.05, for mRNA and by 50% for protein). The decreased expression was confirmed by studying the glomerular gene expression in rats treated with PAN during a time course study. In addition, puromycin decreased the expression of enzymes involved in the glycosaminoglycan biosynthesis. Steroid treatment decreased perlecan (by 24 +/- 3%, P < 0.01) and syndecan-1 expression (by 30 +/- 4%, P < 0.01) but increased the expression of decorin 2.5-fold. The observed alterations of PG synthesis induced by PAN may lead to decreased glomerular anionic charge and disturbed podocyte morphology, factors that are important for the development of a nephrotic syndrome.

Peritoneal dialysis in children: consider the membrane for optimal prescription.

The peritoneal dialysis prescription was, for a long time, based on clinical experience and very empirical, especially for patients on continuous ambulatory peritoneal dialysis (CAPD). Better comprehension of the peritoneal membrane as a dynamic dialysis surface allows an individualized prescription, especially for children on automated peritoneal dialysis (APD). Fill volume prescription should be scaled for body surface area (mL/m(2)) and not in a too low amount to avoid a hyperpermeable exchange. Fill volume enhancement should be done under clinical control and is best secured by intraperitoneal pressure measurement (IPP; cm H2O). A peak fill volume of 1400-1500 mL/m(2) could be prescribed both in terms of tolerance and of efficiency. The dwell times should be determined individually with respect to two opposite parameters namely: short dwell times which provide adequate small solute clearance and maintain ultrafiltration capacity and long dwell times which enhance phosphate clearance but can contribute to dialysate reabsorption. The new peritoneal dialysis fluids which are free of GPD's, have neutral pH and are not exclusively lactate buffered, appear as the best choice in the context of peritoneal exchange membrane recruitment and of peritoneal vascular hyperperfusion preservation.

Diffusional transport of albumin from interstitium to blood across small pores in the capillary walls of rat skeletal muscle.

The transport of radiolabelled albumin from tissue to blood was measured with an external detection technique in isolated, maximally vasodilated rat skeletal muscles. Initially, rat hindlimbs were perfused with albumin-serum solutions containing [99mTc]albumin for at least 2 h, during which time the tracer accumulated interstitially. The accumulated tracer albumin was then washed out over a period of 1 h, using a tracer-free, otherwise identical, perfusate. The wash-out curve was multi-exponential and the last 30-min period was used to calculate the turnover rate constant (k), which was 7.5 x 10(-4) min-1, (+/- 0.7 x 10(-4), n = 5). Moreover, if albumin was assumed to be distributed homogeneously within the interstitium, with a distribution volume (Vi) of 10 ml 100 g-1, a tissue-to-blood clearance of albumin (ClT-B) of 0.0075 ml min-1 100 g-1 could be calculated. By this approach ClT-B is probably slightly overestimated, but is still only 30% of the clearance from blood to tissue (ClB-T), as determined in several previous studies under similar conditions. Thus, transcapillary passage of albumin is highly asymmetrical, being at least three times greater from blood to tissue than in the opposite direction. This is in agreement with the concept of the capillary walls being composed of two populations of functional pores, where macromolecules are transported from blood to tissue mainly by convection through large pores, even at low filtration rates.

Physiological studies of macromolecular transport across capillary walls. Studies on continuous capillaries in rat skeletal muscle.

Studies of the transcapillary exchange of fluid and solutes have provided experimental evidence for the following description of the capillary wall: Transport can be adequately described by passive phenomena such as filtration and diffusion across the permeable structures of the capillary barrier. Hydrophilic solutes are progressively restricted in their transcapillary passage with increasing molecular radius in a bimodal manner. The simplest membrane model compatible with these properties is the two-pore model (Grotte 1956), for which there now is massive documentation (Taylor & Granger 1984). Thus, small hydrophilic solutes (radius less than 30A) are transported mainly by diffusion through small equivalent pores (40-65A), which also represent almost 90% of the hydraulic conductivity. Moreover, larger solutes pass mainly through large equivalent pores (250-350A) by convection. Hence, diffusion is of minor importance for macromolecular transport also during conditions of no net fluid flux across the capillary walls, when there is a circulation of fluid between small and large pores and a net filtration of macromolecules at the large pores. The functional small pores are most probably identical to the interendothelial junctions, while the large pore system is more difficult to define. In addition, solutes are subjected to electrostatic charge interactions at the capillary wall. Thus, there is overwhelming evidence of the presence of high densities of negative charges at the capillary endothelium (glycocalyx), the basement membrane and in the interstitium. This suggests the presence of a negative capillary charge barrier restricting anionic solutes, which also could be experimentally verified (study I & II), but the importance of this barrier is not yet fully clear. A simplistic theoretical two-pore model including effects of charge (Munch et al. 1979) was found to describe our experimental data. According to this model, the charge effect will be most important for solutes with molecular radii of 20-40 A, while charges probably are of no importance for the transport of larger solutes. For anionic macromolecules, e.g. albumin, the effective pore radius will be 40-45A, but the steric small pore radius (i.e. for neutral solutes) will be around 65A. Hereby, the area of diffusion calculated from CFC and the small pore radius (64A) will be lower and it will actually approach the values determined by indicator dilution technique (cf. Haraldsson & Rippe 1986).(ABSTRACT TRUNCATED AT 400 WORDS)