Acute and sustained actions of hyperglycaemia on endothelial and glomerular barrier permeability.

Microalbuminuria is an established marker of systemic endothelial dysfunction, which for patients with diabetes signals an increased risk of both diabetic nephropathy and cardiovascular complications. A better understanding of the pathogenesis of microalbuminuria is important in the quest of finding new approaches to treat patients with diabetes. Direct acute effects of episodes of hyperglycaemia (HG) could have implications for the microalbuminuria seen in early diabetes before renal structural alterations have started, especially in those patients with poor glycaemic control. This review summarizes the literature evidence that acute or sustained HG may lead to an increased vascular or glomerular permeability. Special focus is on glomerular barrier permeability. There is evidence in the literature that HG increases systemic capillary and glomerular barrier permeability within 20-30 min in vivo in rats and mice. Furthermore, exposure of monolayers of cultured endothelial cells to HG has been shown to increase monolayer permeability rapidly and transiently (during 60-100 min). Instant cellular changes following F-actin cytoskeleton rearrangements, which could be abrogated by Rho-kinase (ROCK) inhibition, are implicated. Data in this review also suggest that activation of protein kinase C, the polyol pathway, and an increased release of reactive oxygen species (ROS) and cytokines could contribute to the increase in barrier permeability induced by HG. Recent in vitro data from cultured podocyte monolayers also designates a role of insulin in acute podocyte F-actin remodelling, underpinning the complexity of the mechanisms leading to glomerular and endothelial barrier alterations in diabetes mellitus.

A comparison of plasma cystatin C and plasma creatinine for the screening of renal function in lithium-treated patients.

BACKGROUND: Renal insufficiency is a serious complication of lithium treatment. Therefore, regular monitoring of plasma (P) creatinine is always part of lithium treatment safety routines. Recently P-cystatin C-estimated glomerular filtration rate (cystatin C-eGFR) had been launched as a preferable alternative to P-creatinine. AIMS: To find out which of the two alternatives to prefer in the safety routines for lithium-treated patients. MATERIAL: All 201 patients on lithium treatment at the Department of Psychiatry in Lund, Sweden. METHODS: During 14 months P-cystatin C was included in the safety routines besides routine P-creatinine every 4 months. At the end of the study period, 182 patients were eligible for analysis. With iohexol clearance as reference for GFR (performed in 111/182 patients) we calculated positive and negative predictive values (PPV, NPV) for P-creatinine and for creatinine-eGFR and cystatin C-eGFR, obtained by prediction equations. We also calculated the agreement between the measures of GFR (including repeatability). RESULTS: PPV for cystatin C-eGFR (65%) was better than for creatinine-eGFR (48%). Combining the two resulted in a PPV of 56% and marginally increased NPV to 95%. The average of cystatin C-eGFR and creatinine-eGFR yielded PPV 67% and NPV 92%. The agreement between creatinine-eGFR and GFR was better than the agreement between cystatin C-eGFR and GFR, but both were clinically unacceptable. The repeatability of P-creatinine was acceptable for psychiatric purposes. The repeatability of cystatin C-eGFR was inferior to that of P-creatinine. CONCLUSION: Our results do not justify replacing P-creatinine by cystatin C-eGFR in the lithium treatment safety routines.

Similarity of permeabilities for Ficoll, pullulan, charge-modified albumin and native albumin across the rat peritoneal membrane.

AIM: Compared to neutral globular proteins, neutral polysaccharides, such as dextran, pullulan and Ficoll, appear hyperpermeable across the glomerular filtration barrier. This has been attributed to an increased flexibility and/or asymmetry of polysaccharides. The present study investigates whether polysaccharides are hyperpermeable also across the continuous capillaries in the rat peritoneum. METHODS: In anaesthetized Wistar rats, FITC-Ficoll or FITC-pullulan together with (125)I-human serum albumin (RISA) or neutralized (125)I-bovine serum albumin (nBSA) were given intravenously, after which peritoneal dialysis (PD) using conventional PD fluid (Gambrosol 1.5%) was performed for 120 min. Concentrations of FITC-polysaccharides and radioactive albumin species in plasma and dialysis fluid were analysed with high-performance size exclusion chromatography and a gamma counter respectively. Transperitoneal clearance values were calculated for polysaccharides in the molecular radius range 36-150 A, and for RISA and nBSA. RESULTS: Ficoll and pullulan showed more or less identical permeabilities, compared to RISA and nBSA, across the peritoneal membrane. Although RISA-clearance, 5.50 +/- 0.28 (microL min(-1); +/-SEM), tended to be lower than the clearances of Ficoll(36A) (6.55 +/- 0.25), pullulan(36A) (6.08 +/- 0.22) and nBSA (6.56 +/- 0.23), the difference was not statistically significant. This is in contrast to the hyperpermeability exhibited by polysaccharides across the glomerular filtration barrier and also contrasts with the charge selectivity of the latter. CONCLUSION: The phenomenon of molecular flexibility is more important for a macromolecule's permeability through the glomerular filter than across the continuous peritoneal capillary endothelium. Furthermore, it seems that charge plays a subordinate role in the steady-state transport across the combined peritoneal capillary-interstitial barrier.

Inaccuracy of GFR predictions by plasma cystatin C in patients without kidney dysfunction and in advanced kidney disease.

BACKGROUND: In clinical practice there is need for a simple and reliable test for determination of impaired renal function. With reductions in GFR, the plasma cystatin C concentration (C, mg/l) will increase earlier than serum creatinine, and it is generally agreed that plasma cystatin C is only little affected by body weight, age or sex. However, some reports indicate that cystatin C may be influenced not only by GFR, but also by malignancy, inflammation and high doses of corticosteroids. The aim of the present study was to investigate how plasma cystatin C predicts GFR in distinct subcategories of patients with various disorders as well as in organ transplant patients. METHODS: Plasma cystatin C was measured in 536 patients (age range 0.3-96 years, 262 females, 274 males), consecutively referred to our hospital for determination of GFR by iohexol clearance. Correlations of log GFR vs. log cystatin C were used to compare plasma cystatin C and measured GFR for the following categories: individuals with no known kidney disease (No-KD), malignant patients with (mostly) normal GFR, solid organ-transplanted patients, and patients with native chronic kidney disease (CKD). RESULTS: In patients with normal kidney function and cystatin C level GFR>30 ml/min(-1) (1.73 m2)(-1)) or solid organ transplantation (GFR=84.55 C(1.7666) and GFR=83.95(C-1.5968), respectively). CONCLUSION: Therefore, for these categories, a common equation for all patients with increased cystatin C, irrespective of cause of renal impairment, could be used, namely that presented by Grubb et al. [2005] (GFR=83.93(C-1.676)). However, at marked reductions of renal function (GFR<30 or cystatin C>2), i.e. for CKD Stages 4 and 5, the Grubb prediction equation is less accurate. Based on our data, we suggest the equation GFR=50.52 C(-1.26) for this category of patients.

Fluid loss from the peritoneal cavity by back-filtration through the small pores of the three-pore model.

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.

Glomerular sieving of three neutral polysaccharides, polyethylene oxide and bikunin in rat. Effects of molecular size and conformation.

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 (a(e)) of the following polymers increases in the order: Ficoll < dextran

Controversies in nephrology: renal albumin handling, facts, and artifacts!

In this article, we discuss and contradict a recent publication by Russo et al., which suggests that the filtration of large amounts of albumin followed by transtubular transport of intact albumin is a physiological phenomenon.

Is there an increased long-term risk of hypertension and renal impairment after Puumala virus-induced nephropathy?

Nephropathia epidemica (NE) is a mild form of hemorrhagic fever with renal syndrome, assumed to have a favorable prognosis. NE patients who manifested a higher glomerular filtration rate and mean systolic blood pressure, and more proteinuria, versus controls at 5 years of follow-up demonstrated no major abnormalities after 10 years. Antihypertensive treatment was, however, more common. Could NE predispose some patients to develop hypertension after all?

Aquaporin-1 plays an essential role in water permeability and ultrafiltration during peritoneal dialysis.

The water channel aquaporin-1 (AQP1) is considered as the molecular counterpart of the ultrasmall pore predicted by the three-pore model of fluid transport across the peritoneal membrane. However, the definitive proof of the implication of AQP1 in solute-free water transport, sodium sieving, and ultrafiltration (UF) during peritoneal dialysis (PD) is lacking, and the effects of its deletion on the structure of the membrane are unknown. Using real-time reverse transcriptase-polymerase chain reaction and immunogold electron microscopy, we showed that AQP1 is the most abundant member of the AQP gene family expressed in the mouse peritoneum, and the only one located in the capillary endothelium. Transport studies during a 2-h dwell demonstrated that, in comparison with Aqp1(+/+) littermates, Aqp1(-/-) mice had no sodium sieving; an approximately 70% decrease in the initial, solute-free UF; and an approximately 50% decrease in cumulative UF. These modifications occurred despite unchanged osmotic gradient and transport of small solutes in the Aqp1(-/-) mice. Heterozygous Aqp1(+/-) mice showed intermediate values in sodium sieving and initial UF, whereas cumulative UF was similar to Aqp1(+/+) mice. The deletion of AQP1 had no effect on the expression of other AQPs and on the density, structure, or diameter of peritoneal capillaries. These data provide direct evidence for the role of AQP1 during PD. They validate essential predictions of the three-pore model: (i) the ultrasmall pores account for the sodium sieving, and (ii) they mediate 50% of UF during a hypertonic dwell.

Effects of glomerular filtration rate on Ficoll sieving coefficients (theta) in rats.

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 (P < 0.05; 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 molecules < 50 A in radius.

Renal function in proteinuric glomerular diseases correlates to the changes in urine IgM excretion but not to the changes in the degree of albuminuria.

UNLABELLED: Renal function in proteinuric glomerular diseases correlates to the changes in urine IgM but not to the changes in the degree of albuminuria. BACKGROUND: Albuminuria is believed to correlate to the progression of renal failure in glomerular diseases. Nevertheless, many patients with glomerular disorders maintain their renal function despite persistent albuminuria. In previous studies, we found that the baseline urine excretion of IgM, rather than the degree of albuminuria, predicts the renal outcome in glomerulopathies. In the present study, we examine correlations between changes in the content and in the amount of urine proteins and renal survival during a follow-up time of 3.5 years. METHODS: An observational study of a mean of 44 (+/- 3.6) months was conducted in 37 proteinuric patients (21 males and 16 females) with biopsy-verified primary glomerular disease. The patients were subdivided, according to the findings at the end of the study, into 3 groups, 1 group with decreasing albuminuria (by more than 50%), 1 group with persisting albuminuria and low (< 0.04 mg/mmol creatinine) urinary IgM excretion and 1 group with persisting albuminuria and with high (> or = 0.04 mg/mmol) urinary IgM excretion. RESULTS: All patients that showed remission of albuminuria had also low IgM excretion at the end of the study. All these patients, except 1, maintained their renal function. Patients with persistent albuminuria and high urinary IgM excretion showed a decrease in the glomerular filtration rate (GFR) of a mean of 9.6 ml/min/year compared to a mean GFR increase by 1.5 ml/min/year in patients with low IgM excretion and the same degree of albuminuria (p < 0.01). Seven out of the 9 patients in the former group fall in GFR by more than 5 ml/min/year compared to only 1 of the 10 patients in the latter group. Furthermore, the GFR alterations that occurred during follow-up time correlated in a higher degree to the changes in urinary IgM excretion (r = 0.6, p < 0.01) than to the changes in the degree of albuminuria, (r = 0.4, p < 0.05). A stepwise regression analysis indicated that increased urine IgM excretion is a strong predictor of the GFR decline (r = 0.73, p < 0.001). CONCLUSION: High urinary IgM excretion correlates to decreased GFR in primary glomerular diseases regardless of the degree of albuminuria. In parallel, low urinary IgM excretion indicates beneficial prognosis in these diseases. Since IgM passes the glomerular barrier entirely through large shunts or defects in the glomerular capillary wall, decreased urine content of IgM might be considered as a sign of recovery in the glomerular damage.

Urine excretion of protein HC in proteinuric glomerular diseases correlates to urine IgG but not to albuminuria.

BACKGROUND: Proteinuric glomerular diseases often are associated with tubulointerstitial injury, which imposes on the progression of renal failure. Tubular damage is partly referable to toxic effects on the tubular epithelial cells induced by filtered plasma proteins. Patients with nonselective proteinuria, that is, increased urine excretion of high-molecular-weight plasma proteins such as IgG in comparison to albumin, often have poor renal outcome. The present observational study examined correlations between the degree of tubular damage, measured by urine concentration of protein HC, and the levels of urine IgG and albuminuria. METHODS: Measurements of urine concentrations of IgG, albumin, and protein HC were performed in 56 proteinuric patients (33 males and 23 females) with nondiabetic glomerular diseases at the time of the diagnostic renal biopsy and at a mean of 49 follow-up months. RESULTS: A highly significant correlation between the urine IgG excretion and the urine protein HC concentration was found both at the start and at the end of the observational time (r = 0.74 and 0.65, respectively, P < 0.001). Furthermore, alterations in the urinary excretion of the two proteins in single patients correlated significantly to each other (r = 0.84, P < 0.001). The correlation between the degree of albuminuria and the protein HC excretion was significant at the time of kidney biopsy, but ceased to exist during the follow-up time. Stepwise linear regression analysis showed that in comparison with the creatinine clearance and albuminuria, only the changes in urinary IgG excretion were related to the corresponding changes in urinary protein HC excretion (r = 0.84 and r2 = 0.7, P < 0.001). CONCLUSION: The findings of the study suggest that the urinary protein HC concentration correlates to the degree of IgG-uria but not to the degree of albuminuria during the course of proteinuric glomerular disease. Whether this correlation is to be explained by an intrinsic toxic effect on tubular cells executed by IgG or perhaps by some other high molecular weight proteins, needs to be investigated further. However, the results contribute to the understanding of the poor renal survival in patients with glomerular diseases and nonselective proteinuria.

The peritoneal microcirculation in peritoneal dialysis.

This paper deals with the peritoneal microcirculation and with peritoneal exchange occurring in peritoneal dialysis (PD). The capillary wall is a major barrier to solute and water exchange across the peritoneal membrane. There is a bimodal size-selectivity of solute transport between blood and the peritoneal cavity, through pores of radius approximately 40-50 A as well as through a very low number of large pores of radius approximately 250 A. Furthermore, during glucose-induced osmosis during PD, nearly 40% of the total osmotic water flow occurs through molecular water channels, termed "aquaporin-1." This causes an inequality between 1 - sigma and the sieving coefficient for small solutes, which is a key feature of the "three-pore model" of peritoneal transport. The peritoneal interstitium, coupled in series with the capillary walls, markedly modifies small-solute transport and makes large-solute transport asymmetric. Thus, although severely restricted in the blood-to-peritoneal direction, the absorption of large solutes from the peritoneal cavity occurs at a high clearance rate ( approximately 1 mL/min), largely independent of molecular radius. True absorption of macromolecules to the blood via lymphatics, however, seems to be occurring at a rate of approximately 0.2 mL/min. Several controversial issues regarding transcapillary and transperitoneal exchange mechanisms are discussed in this paper.

Transcytosis inhibitor N-ethylmaleimide increases microvascular permeability in rat muscle.

N-ethylmaleimide (NEM) has been claimed to markedly inhibit the transvascular passage of small proteins and albumin by interacting with the docking and fusion of plasmalemmal vesicles with their target membranes. To investigate the role of transcytosis in the transcapillary passage of albumin, we assessed the effects of NEM on (125)I-labeled radioiodinated serum albumin clearance (RISA-Cl) from blood to muscle in isolated and maximally vasodilated perfused rat hindquarters, in which vascular pressures, pre- and postcapillary resistances, and the capillary filtration coefficient (CFC) were continuously monitored. NEM (0.3-0.5 mM) caused a marked increase mainly in precapillary vascular resistance. Thus the arterial-to-venous resistance ratio in NEM-treated animals was 3.12 +/- 0.56 versus 1.66 +/- 0.17 during the control period (P < 0.05). Despite that, there was a doubling of both CFC from 0.0363 +/- 0.0028 to 0.0778 +/- 0.0101 ml x min(-1) x mmHg(-1) x 100 g(-1) (P < 0.01) and RISA-Cl, compared with the control situation, signaling markedly increased microvascular permeability. Our results strongly suggest that NEM, besides producing marked vasoconstriction, also causes damage to the capillary endothelium. Thus, instead of inhibiting transvascular transport, NEM may induce increases in the bulk transport of albumin from blood to tissue.

Insulin insensitivity and delayed transcapillary delivery of insulin in oophorectomized rats treated with testosterone.

The importance of transcapillary insulin delivery as a regulated step was explored in an insulin resistant rat model. Oophorectomized female rats were exposed to testosterone (OVX + T) for 8 weeks and examined with insulin clamps, muscle microdialysis, and analyses of insulin distribution kinetics. The results were compared with those obtained in sham-operated control rats. After OVX + T, onset of glucose uptake in skeletal muscle was significantly (P < 0.001-0.05) delayed compared with controls as measured by the glucose infusion rate (GIR) during a euglycaemic, hyperinsulinaemic clamp (5 mU kg-1 min-1). The increase in interstitial insulin concentrations was also significantly (P < 0.05) delayed (15-20% lower) in OVX + T treated rats compared with control rats, but to such a small magnitude that this alone could not explain the late onset of the insulin effect. Skeletal muscle capillary density, examined histochemically, was diminished (P < 0.01-0.001) by 20-25% after treatment with OVX + T compared with control animals, as was the peripheral blood flow (P < 0.05) by 40-45%, measured with the microsphere technique. Insulin binding was reduced in proportion to the reduced (P < 0.01) vascular surface area by OVX + T treatment. Transcapillary transport rate of insulin, measured by comparisons of the kinetics of inulin and insulin spaces in muscle with time, tended (ns) to be lower after OVX + T compared with control rats (30-40%) as a reflection of the lower capillary surface area. The data suggest that the delayed onset of insulin action after OVX + T results from combined defects in the muscle cell at a postreceptor level and, to a lesser extent, from retarded transcapillary delivery of insulin.

High proteinuria selectivity index based upon IgM is a strong predictor of poor renal survival in glomerular diseases.

BACKGROUND: The transport of large proteins across the glomerular capillary wall (GCW) may increase several fold in glomerular diseases. The occurrence of IgM in urine is a consequence of the presence of large defects or shunts in the GCW, whereas albuminuria is probably a result of an altered charge- and size-selectivity of the GCW. In order to examine whether patho-morphological differences influence the renal outcome in proteinuric glomerulopathies, we examined urinary excretion of IgM and albumin as prognostic markers of glomerular disease. METHODS: An observational study over a median of 41 (+/-3) months was conducted in 84 patients with biopsy-verified glomerular disease. The patients were subdivided into groups with low (< or =0.002) and high (>0.002) proteinuria selectivity index based upon IgM (IgM-SI), and into groups with low (< or =200 mg/mmol) and high (>200 mg/mmol) albumin creatinine index (ACI). RESULTS: In the high IgM-SI group, the median creatinine clearance (Ccr) decreased by 26%, and 62% of the patients decreased in Ccr by >5 ml/ min/year during the follow-up time. In comparison, the median Ccr decreased by 8% in the low IgM-SI group (P<0.001) and only 18% of the patients in this group deteriorated by >5 ml/min/year in the Ccr. Eleven (21%) of the 51 patients in the high IgM-SI group developed end-stage renal failure compared with none of the 33 patients in the low IgM-SI group. All the patients that progressed to uraemia had decreased Ccr (<60 ml/min) at entry into the study. However, among all these patients, only those with high IgM-SI, and none with low IgM-SI, developed end stage renal failure. The fall in Ccr did not differ significantly between the patients in high (12%) and low (16%) ACI groups. CONCLUSION: The results of this study indicate that an increased IgM-SI value is a stronger predictor of clinical outcome in proteinuric glomerulopathies than baseline albuminuria. This finding may reflect different patho-histological mechanisms influencing renal survival in glomerular diseases.

Hyaluronan and peritoneal ultrafiltration: a test of the "filter-cake" hypothesis.

Adding hyaluronan (HA) to the dialysis fluid seems to improve the efficiency of peritoneal dialysis (PD). This effect may be explained by the gradual formation of a HA "filter-cake" that decreases the tissue hydraulic conductivity. A filter cake (concentration hyperpolarization layer) can be formed when a large, slowly diffusible molecule, such as HA, is partly sieved by the pores of a membrane during the process of transmembrane ultrafiltration. The filter cake then forms at the "uphill" membrane-fluid interface, thereby increasing the resistance to fluid flow across the membrane. To test the filter-cake hypothesis, we investigated the effects of intraperitoneal (IP) HA on peritoneal small solute and water transport by administering HA either during the dwells or as incubations before PD dwells in rats. In the first set of experiments, HA, 0.01% (n = 7), 0.05% (n = 6), and 0.1% (n = 7) was given in 20 mL dialysis fluid (3.86% Dianeal). Control group was instilled with 20 mL of dialysis fluid. Evans Blue (EB) albumin was given as an intra-arterial (IA) bolus and (51)Cr-EDTA as an intravenous (IV) infusion. Plasma and dialysate were sampled up to 240 minutes to determine total peritoneal clearance (Cl), clearance from dialysate to plasma (Cl-->P) of (125)I-albumin (RISA), clearance from plasma to dialysate (Cl-->D) of EB-albumin, and mass transfer area coefficients (MTAC or permeability-surface area products, PS) of (51)Cr-EDTA and glucose. Peritoneal ultrafiltration (UF) was determined from RISA dilution. In the second set of experiments, rats were first incubated with 4 mL of phosphate-buffered saline (PBS) or PBS containing 0.1% HA for 120 minutes. Rats were then dialyzed with HA-free PD fluid, and sampling of plasma and dialysate was performed for 60 minutes. For HA concentrations exceeding 0.01%, UF volumes increased with increasing doses of HA. Small solute MTACs and initial UF were unaffected when HA was either given during the dwell or as a preincubation. Compared with control, there was a significant decrease in RISA-Cl for 0.05% HA and 0.1% HA. Also, Cl-->P decreased significantly compared with control for 0.1% HA. In conclusion, the present data clearly demonstrate that small solute MTACs and the glucose-induced osmotic water transport occurring early in the dwell are not affected by HA. Only the back-filtration of fluid from peritoneum to plasma was affected.

Transport asymmetry in peritoneal dialysis: application of a serial heteroporous peritoneal membrane model.

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 (r(s)) approximately 45 A], large [radius of the large pore (r(L)) approximately 250 A], and transcellular pores accounting for 90, 8, and 2% to the hydraulic conductance, respectively, and with a corresponding pore area over diffusion distance (A(0)/Delta 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 (a(e)) approximately 5 A] to alpha(2)-macroglobulin (molecular weight = 820,000, a(e) approximately 90 A). The results describe a second two-pore membrane with very large pores (r(L) approximately 2,300 A) accounting for 95% of the hydraulic conductance, minor populations of small (r(s) approximately 67 A) and transcellular pores (3 and 2%, respectively), and an A(0)/Delta x approximately 65,000 cm. The estimated peritoneal lymph flow is approximately 0.3 ml/min. The two membranes can be identified as the capillary endothelium and an extracellular interstitium lumped with the peritoneal mesothelium.

Very high daily intraperitoneal doses of carbonyl compounds affect the morphology, but not the exchange characteristics, of rat peritoneum.

Glucose degradation products (GDP) are carbonyl compounds, that are formed by heat sterilization of conventional peritoneal dialysis (PD) fluids. Carbonyl compounds are known to be toxic in vitro and potentially toxic also in vivo. The aim of this study was to evaluate the effects of daily, short-term exposure of the peritoneum to very high concentrations of GDP in vivo on peritoneal transport parameters and on peritoneal morphology in a well-established rat model of PD. Rats were exposed to three daily intraperitoneal (IP) injections (10 ml) for 9 days of a largely neutral (pH 7.2) PD fluid containing 1.5% glucose and sterilized by filtration, with (n = 8) or without (n = 8) the presence of different carbonyl compounds in concentrations 100 times higher than those reported in commercial PD fluids. Seven rats, not subjected to any exposure, served as controls. After the exposure, the rats were subjected to acute PD in 4-hour dwells. Twenty milliliters of 4% glucose dialysis fluid were instilled into the rat peritoneal cavity. Blood and dialysate samples were taken during the dwell for measurements of dialysate sodium, and for assessments of the mass transfer area coefficient (PS) for glucose and 51Cr-EDTA and of transperitoneal clearance (Cl) or radiolabelled albumin (RISA). At the end of the dwell, parts of the liver, diaphragm and peritoneum were removed for measurements of tissue cell density and thickness of the submesothelial peritoneal tissue. The exposure of the peritoneum to very high doses of carbonyl compounds did not affect the peritoneal transport of fluid and small solutes significantly, but seemed to slightly reduce lymph flow and albumin clearance out of the peritoneal cavity. Assessed after a hypertonic dwell, and compared to the situation in nontreated rats after the same kind of dwell, there was a significant thinning of the submesothelial tissue, but no difference in tissue cell density. It is concluded that short-term exposure of the peritoneum in vivo to very high doses of GDP resulted in almost no signs of acute toxicity.

Long-term clinical effects of a peritoneal dialysis fluid with less glucose degradation products.

BACKGROUND: Glucose degradation products (GDPs) are cytotoxic in vitro and potentially toxic in vivo during peritoneal dialysis (PD). We are presenting the results of a two-year randomized clinical trial of a new PD fluid, produced in a two-compartment bag and designed to minimize heat-induced glucose degradation while producing a near neutral pH. The effects of the new fluid over two years of treatment on membrane transport characteristics, ultrafiltration (UF) capacity, and effluent markers of peritoneal membrane integrity were investigated and compared with those obtained during treatment with a standard solution. DESIGN: A two-group parallel design with 80 continuous ambulatory peritoneal dialysis patients was used. The patients were randomly assigned to either the new fluid (N = 40) or to a conventional one (N = 40), and were stratified with respect to age, diabetes, and time on PD. Peritoneal transport characteristics were assessed by the Personal Dialysis Capacity (PDCtrade mark) test at 1, 6, 12, 18, and 24 months after inclusion and by weighing the overnight bag daily. Infusion pain and handling were evaluated using a questionnaire. Peritoneal mesothelial and interstitial integrity were evaluated by analyzing overnight effluent dialysate concentrations of CA 125, hyaluronan (HA), procollagen-1-C-terminal peptide (PICP), and procollagen-3-N-terminal peptide (PIIINP) at 1, 6, 12, 18, and 24 months. RESULTS: The handling of the new two-compartment bag was considered easy, and there were no indications of increased discomfort with the new system. Furthermore, no changes in peritoneal fluid or solute transport characteristics were observed during the study period for either fluid, and neither were there any differences with regard to peritonitis incidence. However, significantly higher dialysate CA 125 (73 +/- 41 vs. 25 +/- 18 U/mL), PICP (387 +/- 163 vs. 244 +/- 81 ng/mL), and PIIINP (50 +/- 24 vs. 29 +/- 13 ng/mL) and significantly lower concentrations of HA (395 +/- 185 vs. 530 +/- 298 ng/mL) were observed in the overnight effluent during treatment with the new fluid. CONCLUSIONS: We conclude that the new fluid with a higher pH and less GDPs is safe and easy to use and has no negative effects on either the frequency of peritonitis or peritoneal transport characteristics as compared with conventional ones. Our results indicate that the new solution causes less mesothelial and interstitial damage than conventional ones; that is, it may be considered more biocompatible than a number of conventional PD solutions currently in use.