Computer simulations of peritoneal fluid transport in CAPD

Computer simulations of peritoneal fluid transport in CAPD. To model the changes in intraperitoneal dialysate volume (IPV) occurring over dwell time under various conditions in continuous ambulatory peritoneal dialysis (CAPD), we have, using a personal computer (PC), numerically integrated the phenomenological equations that describe the net ultrafiltration (UF) flow existing across the peritoneal membrane in every moment of a dwell. Computer modelling was performed according to a three-pore model of membrane selectivity as based on current concepts in capillary physiology. This model comprises small “paracellular” pores (radius≍47 Å) and “large” pores (radius ≍250 Å), together accounting for ≍98% of the total UF-coefficient (LpS), and also “transcellular” pores (pore radius ≍4 to 5 Å) accounting for 1.5% of LpS. Simulated curves made a good fit to IPV versus time data obtained experimentally in adult patients, using either 1.36 or 3.86% glucose dialysis solutions, under control conditions; when the peritoneal UF-coefficient was set to 0.082 ml/min/mm Hg, the glucose reflection coefficient was 0.043 and the peritoneal lymph flow was set to 0.3ml/min. Also, theoretical predictions regarding the IPV versus time curves agreed well with the computer simulated results for perturbed values of effective peritoneal surface area, LpS, glucose permeability-surface area product (PS or “MTAC”), intraperitoneal dialysate volume and dialysate glucose concentration. Thus, increasing the peritoneal surface area caused the IPV versus time curves to peak earlier than during control, while the maximal volume ultrafiltered was not markedly affected. However, increasing the glucose PS caused both a reduction in the IPV versus time curve “peak time” and in the “peak height” of the curves. The latter pattern was also seen when the dialysate volume was reduced. It is suggested that computer modelling based on a three-pore model of membrane selectivity may be a useful tool for describing the IPV versus time relationships under various conditions in CAPD

Mass transfer of calcium across the peritoneum at three different peritoneal dialysis fluid Ca2+ and glucose concentrations.

Mass transfer of calcium across the peritoneum at three different peritoneal dialysis fluid Ca2+ and glucose concentrations.BackgroundIn peritoneal dialysis, the rate of ultrafiltration has been predicted to be a major determinant of peritoneal calcium (Ca2+) removal. Hence, dialysis fluid glucose concentration should be an important factor governing the transperitoneal Ca2+ balance. The aim of this study was to test the effect of various dialysate glucose levels and selected dialysate Ca2+ levels on Ca2+ removal in peritoneal dialysis patients.MethodsPatients (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 Ca2+ or 2.5% glucose and 1.6mmol/L Ca2+, or 4% glucose and 2.5mmol/L Ca2+, 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” Ca2+, lactate, glucose, bicarbonate, phosphate, creatinine, and urea.ResultsThere was a clear-cut dependence of peritoneal Ca2+ removal on the rate of ultrafiltration. For large peritoneal to dialysate Ca2+ gradients (2.5mmol/L Ca2+ in 4% glucose) a close fit of measured to simulated data was predicted by the three-pore model using nonelectrolyte equations. For low transperitoneal Ca2+ concentration gradients, however, directly measured Ca2+ data agreed with the simulated ones only when the peritoneal Ca2+ PS was set lower than predicted from pore theory (6mL/min).ConclusionThere was a marked ultrafiltration dependence of transperitoneal Ca2+ transport. Nonelectrolyte equations could be used to simulate peritoneal ion (Ca2+) transport provided that the transperitoneal ion concentration gradients were large. Based on our data 1.38mmol/L Ca2+ in the dialysis fluid would have created zero net Ca2+ gain during a 4-hour dwell for 1.5% glucose, whereas 1.7 and 2.2mmol/L Ca2+ would have been needed to produce zero Ca2+ gain for 2.5% glucose and 3.9% glucose, respectively

Association of muscarinic M(3) receptors and Kir6.1 with caveolae in human detrusor muscle.

Caveolae are 50-100nm large membrane invaginations that play a role in cellular signaling. The aim of the present study was to assess whether muscarinic M(3) receptors and the K(ATP) channel subunit Kir6.1 are associated with human detrusor caveolae, and to pharmacologically assess the relevance of this organization for contractility. Detrusor strips were dissected and used in ultrastructural, biochemical and mechanical studies. Caveolae were manipulated by cholesterol desorption using mβcd (methyl-β-cyclodextrin). Mβcd disrupted caveolae and caused a cholesterol-dependent ~3-fold rightward shift of the concentration-response curve for the muscarinic receptor agonist carbachol. The effect of mβcd was inhibited by the K(ATP) blockers glibenclamide, repaglinide and PNU-37883, and it was mimicked by the K(ATP) activator levcromakalim. Immunoelectron microscopy showed muscarinic M(3) receptors and Kir6.1 to be enriched in caveolae. In conclusion, pharmacological K(ATP) channel inhibition antagonizes the effect of caveolae disruption on muscarinic contractility in the human detrusor, and the K(ATP) channel subunit Kir6.1 co-localizes with M(3) receptors in caveolae

Reduction in glomerular pore size is not restricted to pregnant women. Evidence for a new syndrome: 'Shrunken pore syndrome'.

The plasma levels of cystatin C, β2-microglobulin, beta-trace protein, retinol binding protein (RBP) and creatinine were determined in plasma samples from 111 randomly selected patients with eGFRcystatin C ≤ 60% of eGFRcreatinine and from 55 control patients with 0.9eGFRcreatinine ≤ eGFRcystatin C ≤ 1.1eGFRcreatinine (eGFRcystatin C ≈ eGFRcreatinine). The concentration ratios of cystatin C/creatinine, β2-microglobulin/creatinine, beta-trace protein/creatinine and RBP/creatinine were significantly higher in patients with eGFRcystatin C ≤ 60% of eGFRcreatinine than in patients with eGFRcystatin C ≈ eGFRcreatinine. When the patients were divided into three groups with different estimated GFR intervals (≤ 40, 40-60 and ≥ 60 mL/min/1.73m(2)) the concentration ratios of cystatin C/creatinine, β2-microglobulin/creatinine, and beta-trace protein/creatinine were significantly higher in patients with eGFRcystatin C ≤ 60% of eGFRcreatinine than in patients with eGFRcystatin C ≈ eGFRcreatinine for all GFR intervals. Similar results were obtained when the population without pregnant women was studied as well as the subpopulations of men or of non-pregnant women. Populations of pre-eclamptic women and pregnant women in the third trimester display similar results. Since the production of these four proteins with sizes similar to that of cystatin C is not co-regulated, the most likely explanation for the simultaneous increase of their creatinine-ratios in patients with eGFRcystatin C ≤ 60% of eGFRcreatinine is that their elimination by glomerular filtration is decreased. We suggest that this is due to a reduction in pore diameter of the glomerular membrane and propose the designation 'Shrunken pore syndrome' for this pathophysiological state

Increased urine IgM excretion predicts cardiovascular events in patients with type 1 diabetes nephropathy

<p>Abstract</p> <p>Background</p> <p>Diabetic nephropathy, a major complication of diabetes, is characterized by progressive renal injury and increased cardiovascular mortality. An increased urinary albumin excretion due dysfunction of the glomerular barrier is an early sign of diabetic nephropathy. An increased urinary excretion of higher molecular weight proteins such as IgM appears with progression of glomerular injury. We aim here to study the prognostic significance of urine IgM excretion in patients with type 1 diabetes mellitus (type 1 diabetic nephropathy).</p> <p>Methods</p> <p>This is an observational study of 139 patients with type1 diabetes mellitus (79 males and 60 females) under routine care at the diabetic outpatient clinic at the Lund University Hospital. The median follow-up time was 18 years (1 to 22) years. Urine albumin and urine IgM concentration were measured at time of recruitment.</p> <p>Results</p> <p>Overall 32 (14 male and 18 female) patients died in a cardiovascular event and 20 (11 male and 9 female) patients reached end-stage renal disease. Univariate analysis indicated that patient survival and renal survival were inversely associated with urine albumin excretion (RR = 2.9 and 5.8, respectively) and urine IgM excretion (RR = 4.6 and 5.7, respectively). Stratified analysis demonstrated that in patients with different degrees of albuminuria, the cardiovascular mortality rate and the incidence of end-stage renal disease was approximately three times higher in patients with increased urine IgM excretion.</p> <p>Conclusion</p> <p>An increase in urinary IgM excretion in patients with type 1 diabetes is associated with an increased risk for cardiovascular mortality and renal failure, regardless of the degree of albuminuria.</p

Infusion fluids contain harmful glucose degradation products

PURPOSE: Glucose degradation products (GDPs) are precursors of advanced glycation end products (AGEs) that cause cellular damage and inflammation. We examined the content of GDPs in commercially available glucose-containing infusion fluids and investigated whether GDPs are found in patients' blood. METHODS: The content of GDPs was examined in infusion fluids by high-performance liquid chromatography (HPLC) analysis. To investigate whether GDPs also are found in patients, we included 11 patients who received glucose fluids (standard group) during and after their surgery and 11 control patients receiving buffered saline (control group). Blood samples were analyzed for GDP content and carboxymethyllysine (CML), as a measure of AGE formation. The influence of heat-sterilized fluids on cell viability and cell function upon infection was investigated. RESULTS: All investigated fluids contained high concentrations of GDPs, such as 3-deoxyglucosone (3-DG). Serum concentration of 3-DG increased rapidly by a factor of eight in patients receiving standard therapy. Serum CML levels increased significantly and showed linear correlation with the amount of infused 3-DG. There was no increase in serum 3-DG or CML concentrations in the control group. The concentration of GDPs in most of the tested fluids damaged neutrophils, reducing their cytokine secretion, and inhibited microbial killing. CONCLUSIONS: These findings indicate that normal standard fluid therapy involves unwanted infusion of GDPs. Reduction of the content of GDPs in commonly used infusion fluids may improve cell function, and possibly also organ function, in intensive-care patients

Size and charge selectivity of the glomerular filter in early experimental diabetes mellitus in rats.

Abstract Microalbuminuria is an early sign of diabetic nephropathy. The aim of the present study was to investigate whether the changes of the glomerular filtration barrier in early experimental diabetes are due to size- or charge-selective alterations. Wistar rats, made diabetic by streptozotocin (STZ) and having their blood glucose maintained at approximately 20 mM for 3 or 9 wk, were compared with age-matched controls. Glomerular clearances of native albumin (Cl-HSA) and neutralized albumin (Cl-nHSA) were assessed using a renal uptake technique. Glomerular filtration rate and renal plasma flow were assessed using (51)Cr-EDTA and [125I]iodohippurate, respectively. In a separate set of animals, diabetic for 9 wk, and in controls, glomerular sieving coefficients (theta) for neutral FITC-Ficoll (molecular radius: 15-90 A) were assessed using size exclusion chromatography. At 3 wk of diabetes, Cl-HSA and Cl-nHSA remained unchanged, indicating no alteration in either size or charge selectivity. By contrast, at 9 wk of diabetes, there was a twofold increase of Cl-HSA, whereas Cl-nHSA remained largely unchanged, at first suggesting a glomerular charge defect. However, according to a two-pore model, the number of large pores, assessed from both Ficoll and Cl-HSA, increased twofold. In addition, a small reduction in proximal tubular reabsorption was observed at 3 wk, which was further reduced at 9 wk. In conclusion, no functional changes were observed in the glomerular filtration barrier at 3 wk of STZ-induced diabetes, whereas at 9 wk there was a decrease in size selectivity due to an increased number of large glomerular pores

Nature of glomerular capillary permeability changes following acute renal ischemia/reperfusion (I/R) injury in rats.

This study was performed to evaluate the alterations of glomerular filtration barrier characteristics following acute renal ischemia-reperfusion (I/R). Ischemia was induced in anesthetized rats by unilateral renal artery occlusion for either 20 or 60 min, followed by reperfusion during 20 or 60 min, respectively, with the contralateral kidney serving as control. Sieving coefficients (theta) were obtained by analyzing Ficoll [mol.radius (a(e)) 13-85 angstrom] in urine and plasma after 20 and 60 min I/R. Furthermore, theta for human serum albumin (HSA) was estimated using a tissue uptake technique after 20 and 60 min of I/R, while clearance of HSA compared with that for neutralized HSA (nHSA) was assessed after 20 min of I/R only. Glomerular filtration rate (GFR) was measured by [Cr-51] EDTA and inulin. I/R reduced GFR and increased theta for Ficoll molecules of a(e) > 55 angstrom and theta for albumin. theta for Ficoll vs. a(e), analysed using a two-pore model, demonstrated that, despite increases in theta, the large-pore fractional ultrafiltration coefficient (alpha(L)) was unchanged after 20 min of I/R, owing to the decline in GFR, but increased after 60 min of I/R. However, the apparent alpha(L) for albumin increased already after 20 min of I/R (P < 0.005) and the nHSA/HSA clearance ratio was slightly reduced, possibly reflecting a diminished negative charge barrier. In conclusion, after 20 min of I/R, indications of a reduced charge selectivity were noted, while after 60 min of I/R, there was mainly a reduction in size selectivity, compatible with an increased formation of large pores