RESUMO
The recently discovered selective glomerular hypofiltration syndromes have increased interest in the actual elimination of molecules in the human kidney. In the present study, a novel human model was introduced to directly measure the single-pass renal elimination of molecules of increasing size. Plasma concentrations of urea, creatinine, C-peptide, insulin, pro-BNP, ß2-microglobulin, cystatin C, troponin-T, orosomucoid, albumin, and IgG were analysed in arterial and renal venous blood from 45 patients undergoing Transcatheter Aortic Valve Implantation (TAVI). The renal elimination ratio (RER) was calculated as the arteriovenous concentration difference divided by the arterial concentration. Estimated glomerular filtration rate (eGFR) was calculated by the CKD-EPI equations for both creatinine and cystatin C. Creatinine (0.11 kDa) showed the highest RER (21.0 ± 6.3%). With increasing molecular size, the RER gradually decreased, where the RER of cystatin C (13 kDa) was 14.4 ± 5.3% and troponin-T (36 kDa) was 11.3 ± 4.6%. The renal elimination threshold was found between 36 and 44 kDa as the RER of orosomucoid (44 kDa) was -0.2 ± 4.7%. The RER of creatinine and cystatin C showed a significant and moderate positive linear relationship with eGFR (r = 0.48 and 0.40). In conclusion, a novel human model was employed to demonstrate a decline in renal elimination with increasing molecular size. Moreover, RERs of creatinine and cystatin C were found to correlate with eGFR, suggesting the potential of this model to study selective glomerular hypofiltration syndromes.
Assuntos
Creatinina , Cistatina C , Taxa de Filtração Glomerular , Rim , Humanos , Cistatina C/sangue , Masculino , Creatinina/sangue , Feminino , Idoso , Rim/metabolismo , Idoso de 80 Anos ou mais , Troponina T/sangue , Microglobulina beta-2/sangue , Ureia/sangue , Peptídeo Natriurético Encefálico/sangue , Peptídeo C/sangue , Insulina/sangue , Modelos Biológicos , Imunoglobulina G/sangueRESUMO
BACKGROUND: Harmful glucose exposure and absorption remain major limitations of peritoneal dialysis (PD). We previously showed that inhibition of sodium glucose cotransporter 2 did not affect glucose transport during PD in rats. However, more recently, we found that phlorizin, a dual blocker of sodium glucose cotransporters 1 and 2, reduces glucose diffusion in PD. Therefore, either inhibiting sodium glucose cotransporter 1 or blocking facilitative glucose channels by phlorizin metabolite phloretin would reduce glucose transport in PD. METHODS: We tested a selective blocker of sodium glucose cotransporter 1, mizagliflozin, as well as phloretin, a nonselective blocker of facilitative glucose channels, in an anesthetized Sprague-Dawley rat model of PD. RESULTS: Intraperitoneal phloretin treatment reduced glucose absorption by >30% and resulted in a >50% higher ultrafiltration rate compared with control animals. Sodium removal and sodium clearances were similarly improved, whereas the amount of ultrafiltration per millimole of sodium removed did not differ. Mizagliflozin did not influence glucose transport or osmotic water transport. CONCLUSIONS: Taken together, our results and previous results indicate that blockers of facilitative glucose channels may be a promising target for reducing glucose absorption and improving ultrafiltration efficiency in PD.
Assuntos
Diálise Peritoneal , Transportador 1 de Glucose-Sódio , Ratos , Animais , Transportador 1 de Glucose-Sódio/metabolismo , Soluções para Diálise/farmacologia , Soluções para Diálise/metabolismo , Glucose/metabolismo , Ratos Sprague-Dawley , Ultrafiltração , Floretina/farmacologia , Floretina/metabolismo , Florizina/farmacologia , Florizina/metabolismo , Diálise Peritoneal/métodos , Transporte Biológico , Sódio/metabolismo , Peritônio/metabolismoRESUMO
Emerging evidence indicates that endogenous production of endothelin (ET)-1, a 21-amino acid peptide vasoconstrictor, plays an important role in proteinuric kidney disease. Previous studies in rats have shown that chronic administration of ET-1 leads to increased glomerular albumin leakage. The underlying mechanisms are, however, currently not known. Here, we used size-exclusion chromatography to measure glomerular sieving coefficients for neutral FITC-Ficoll (molecular Stokes-Einstein radius: 15-80 Å, molecular weight: 70 kDa/400 kDa) in anesthetized male Sprague-Dawley rats (n = 12) at baseline and at 5, 15, 30, and 60 min after intravenous administration of ET-1. In separate experiments, ET-1 was given together with the selective ET type A (ETA) or ET type B (ETB) receptor antagonists JKC-301 and BQ-788, respectively. At both 15 and 30 min postadministration, the glomerular sieving coefficient for macromolecular Ficoll (70 Å) was significantly increased to 4.4 × 10-5 ± 0.7 × 10-5 (P = 0.024) and 4.5 × 10-5 ± 0.8 × 10-5 (P = 0.007), respectively, compared with baseline (2.2 × 10-5 ± 0.4 ×10-5). Decreased urine production after ET-1 prevented the use of higher doses of ET-1. Data analysis using the two-pore model indicated changes in large-pore permeability after ET-1, with no changes in the small-pore pathway. Administration of ETA blocker abrogated the permeability changes induced by ET-1 at 30 min, whereas blockade of ETB receptors was ineffective. Mean arterial pressure was only significantly increased at 60 min, being 123 ± 4 mmHg compared with 111 ± 2 mmHg at baseline (P = 0.02). We conclude that ET-1 evoked small, delayed, and sustained increases in glomerular permeability, mediated via the ETA receptor.
Assuntos
Endotelina-1/administração & dosagem , Taxa de Filtração Glomerular/efeitos dos fármacos , Glomérulos Renais/efeitos dos fármacos , Receptor de Endotelina A/agonistas , Animais , Hemodinâmica/efeitos dos fármacos , Infusões Intravenosas , Glomérulos Renais/metabolismo , Masculino , Modelos Biológicos , Permeabilidade , Ratos Sprague-Dawley , Receptor de Endotelina A/metabolismo , Transdução de Sinais , Fatores de TempoRESUMO
BACKGROUND: Optimal infusion rate of colloids in patients with suspected hypovolemia is unknown, and the primary objective of the present study was to test if plasma volume expansion by 5% albumin is greater if fluid is administered slowly rather than rapidly. METHODS: Patients with signs of hypoperfusion after major abdominal surgery were randomized to intravenous infusion of 5% albumin at a dose of 10 ml/kg (ideal body weight) either rapidly (30 min) or slowly (180 min). Plasma volume was measured using radiolabeled albumin at baseline, at 30 min, and at 180 min after the start of infusion. Primary outcome was change in plasma volume from the start of infusion to 180 min after the start of infusion. Secondary outcomes included the change in the area under the plasma volume curve and transcapillary escape rate (TER) for albumin from 180 to 240 min after the start of albumin infusion. RESULTS: A total of 33 and 31 patients were included in the analysis in the slow and rapid groups, respectively. The change in plasma volume from the start of infusion to 180 min did not differ between the slow and rapid infusion groups (7.4 ± 2.6 vs. 6.5 ± 4.1 ml/kg; absolute difference, 0.9 ml/kg [95%CI, - 0.8 to 2.6], P = 0.301). Change in the area under the plasma volume curve was smaller in the slow than in the rapid infusion group and was 866 ± 341 and 1226 ± 419 min ml/kg, respectively, P < 0.001. TER for albumin did not differ and was 5.3 ± 3.1%/h and 5.4 ± 3%/h in the slow and in the rapid infusion groups, respectively, P = 0.931. CONCLUSIONS: This study does not support our hypothesis that a slow infusion of colloid results in a greater plasma volume expansion than a rapid infusion. Instead, our result of a smaller change in the area under the plasma volume curve indicates that a slow infusion results in a less efficient plasma volume expansion, but further studies are required to confirm this finding. A rapid infusion has no effect on vascular leak as measured after completion of the infusion. TRIAL REGISTRATION: EudraCT2013-004446-42 registered December 23, 2014.
Assuntos
Albuminas/administração & dosagem , Infusões Intravenosas/estatística & dados numéricos , Idoso , Albuminas/uso terapêutico , Análise de Variância , Procedimentos Cirúrgicos do Sistema Digestório/efeitos adversos , Procedimentos Cirúrgicos do Sistema Digestório/métodos , Feminino , Procedimentos Cirúrgicos em Ginecologia/efeitos adversos , Procedimentos Cirúrgicos em Ginecologia/métodos , Humanos , Infusões Intravenosas/métodos , Masculino , Pessoa de Meia-Idade , Substitutos do Plasma/administração & dosagem , Substitutos do Plasma/uso terapêutico , Volume Plasmático/efeitos dos fármacos , Volume Plasmático/fisiologia , Complicações Pós-Operatórias/prevenção & controle , Estudos Prospectivos , Estatísticas não Paramétricas , SuéciaRESUMO
Background Osmosis drives transcapillary ultrafiltration and water removal in patients treated with peritoneal dialysis. Crystalloid osmosis, typically induced by glucose, relies on dialysate tonicity and occurs through endothelial aquaporin-1 water channels and interendothelial clefts. In contrast, the mechanisms mediating water flow driven by colloidal agents, such as icodextrin, and combinations of osmotic agents have not been evaluated.Methods We used experimental models of peritoneal dialysis in mouse and biophysical studies combined with mathematical modeling to evaluate the mechanisms of colloid versus crystalloid osmosis across the peritoneal membrane and to investigate the pathways mediating water flow generated by the glucose polymer icodextrin.ResultsIn silico modeling and in vivo studies showed that deletion of aquaporin-1 did not influence osmotic water transport induced by icodextrin but did affect that induced by crystalloid agents. Water flow induced by icodextrin was dependent upon the presence of large, colloidal fractions, with a reflection coefficient close to unity, a low diffusion capacity, and a minimal effect on dialysate osmolality. Combining crystalloid and colloid osmotic agents in the same dialysis solution strikingly enhanced water and sodium transport across the peritoneal membrane, improving ultrafiltration efficiency over that obtained with either type of agent alone.Conclusions These data cast light on the molecular mechanisms involved in colloid versus crystalloid osmosis and characterize novel osmotic agents. Dialysis solutions combining crystalloid and colloid particles may help restore fluid balance in patients treated with peritoneal dialysis.
Assuntos
Soluções Cristaloides/farmacocinética , Soluções para Diálise/farmacocinética , Icodextrina/farmacocinética , Peritônio/metabolismo , Água/metabolismo , Animais , Aquaporina 1/genética , Transporte Biológico , Coloides , Simulação por Computador , Soluções para Diálise/metabolismo , Genótipo , Glucose/metabolismo , Icodextrina/metabolismo , Camundongos , Modelos Teóricos , Osmose , Diálise PeritonealRESUMO
It is well known that proteinuria following urinary tract obstruction is mainly of a tubular nature. However, it is unknown whether there are also changes in glomerular permeability. In this study, we compared glomerular sieving coefficients (θ) of polydisperse fluorescein isothiocyanate (FITC)-Ficoll 70/400 following a 120- or 180-min unilateral ureteral obstruction (UUO) in anesthetized Sprague-Dawley rats. Samples were collected from the obstructed kidney at 5, 15, and 30 min postrelease and analyzed by means of high-pressure size-exclusion chromatography. After 120-min UUO, mean θ for Ficoll70Å was increased ( P < 0.01) from 2.2 ± 0.5 × 10-5 (baseline) to 10.6 ± 10 × 10-5 15 min postrelease (highest value). After 180-min UUO, mean θ for Ficoll70Å was further increased ( P < 0.001) from 1.4 ± 0.5 × 10-5 (baseline) to 40 ± 10 × 10-5 at 5 min postrelease (highest value). Administration of a reactive oxygen species (ROS) scavenger (Tempol; 1 mg·kg-1·min-1) partly abrogated the permeability effects following 120-min UUO but not after 180 min. Moreover, administration of the RhoA kinase inhibitor Y-27632, the nitric oxide synthase inhibitor NG-nitro-l-arginine methyl ester, or Rac-1 inhibition did not ameliorate glomerular hyperpermeability following 180-min UUO. We show, for the first time, that acute UUO results in marked elevations in glomerular permeability. In addition, our data suggest a time-dependent pathophysiology of UUO-induced hyperpermeability, where reactive oxygen species generation may play an important role in the early stages.
Assuntos
Antioxidantes/farmacologia , Óxidos N-Cíclicos/farmacologia , Inibidores Enzimáticos/farmacologia , Taxa de Filtração Glomerular/efeitos dos fármacos , Glomérulos Renais/efeitos dos fármacos , Óxido Nítrico Sintase Tipo III/antagonistas & inibidores , Estresse Oxidativo/efeitos dos fármacos , Obstrução Ureteral/tratamento farmacológico , Proteínas rac1 de Ligação ao GTP/antagonistas & inibidores , Proteínas rho de Ligação ao GTP/antagonistas & inibidores , Amidas/farmacologia , Aminoquinolinas/farmacologia , Animais , Pressão Arterial/efeitos dos fármacos , Modelos Animais de Doenças , Frequência Cardíaca/efeitos dos fármacos , Glomérulos Renais/enzimologia , Glomérulos Renais/fisiopatologia , Masculino , NG-Nitroarginina Metil Éster/farmacologia , Óxido Nítrico Sintase Tipo III/metabolismo , Proteinúria/tratamento farmacológico , Proteinúria/enzimologia , Proteinúria/fisiopatologia , Piridinas/farmacologia , Pirimidinas/farmacologia , Ratos Sprague-Dawley , Espécies Reativas de Oxigênio/metabolismo , Marcadores de Spin , Fatores de Tempo , Obstrução Ureteral/enzimologia , Obstrução Ureteral/fisiopatologia , Proteínas rac1 de Ligação ao GTP/metabolismo , Proteínas rho de Ligação ao GTP/metabolismo , Quinases Associadas a rho/antagonistas & inibidores , Quinases Associadas a rho/metabolismoRESUMO
One of the many unresolved questions regarding the permeability of the glomerular filtration barrier is the reason behind the marked difference in permeability between albumin and polysaccharide probe molecules such as Ficoll and dextran of the same molecular size. Although the differences in permeability have been mainly attributed to charge effects, we have previously shown that this would require a highly charged filtration barrier, having a charge density that is ~10 times more than that on the albumin molecule. In this article, the classic two-pore model was extended by introducing size distributions on the solute molecules, making them conformationally flexible. Experimental sieving data for Ficoll from the rat glomerulus and from precision-made silicon nanopore membranes were analyzed using the model. For the rat glomerulus a small-pore radius of 36.2 Å and a geometric standard deviation (gSD) for the Ficoll size-distribution of 1.16 were obtained. For the nanopore membranes, a gSD of 1.24 and a small-pore radius of 43 Å were found. Interestingly, a variation of only ~16% in the size of the polysaccharide molecule is sufficient to explain the difference in permeability between albumin and Ficoll. Also, in line with previous data, the effects of applying a size distribution on the solute molecule are only evident when the molecular size is close to the pore size. Surely there is at least some variation in the pore radii, and, likely, the gSD obtained in the current study is an overestimation of the "true" variation in the size of the Ficoll molecule.
Assuntos
Ficoll/metabolismo , Taxa de Filtração Glomerular , Glomérulos Renais/metabolismo , Modelos Biológicos , Albuminas/química , Albuminas/metabolismo , Animais , Transporte Biológico , Simulação por Computador , Ficoll/química , Barreira de Filtração Glomerular/metabolismo , Membranas Artificiais , Peso Molecular , Nanoporos , Permeabilidade , Porosidade , Ratos , Silicones/químicaRESUMO
An increased kidney oxygen consumption causing tissue hypoxia has been suggested to be a common pathway toward chronic kidney disease. The mammalian target of rapamycin (mTOR) regulates cell proliferation and mitochondrial function. mTOR inhibitors (e.g., rapamycin) are used clinically to prevent graft rejection. mTOR has been identified as a key player in diabetes, which has stimulated the use of mTOR inhibitors to counter diabetic nephropathy. However, the effect of mTOR inhibition on kidney oxygen consumption is unknown. Therefore, we investigated the effects of mTOR inhibition on in vivo kidney function, oxygen homeostasis, and glomerular permeability. Control and streptozotocin-induced diabetic rats were chronically treated with rapamycin, and the functional consequences were studied 14 days thereafter. In both groups, mTOR inhibition induced mitochondrial uncoupling, resulting in increased total kidney oxygen consumption and decreased intrarenal oxygen availability. Concomitantly, mTOR inhibition induced tubular injury, as estimated from urinary excretion of kidney injury molecule-1 (KIM-1) and reduced urinary protein excretion. The latter corresponded to reduced sieving coefficient for large molecules. In conclusion, mTOR inhibition induces mitochondrial dysfunction leading to decreased oxygen availability in normal and diabetic kidneys, which translates into increased KIM-1 in the urine. Reduced proteinuria after mTOR inhibition is an effect of reduced glomerular permeability for large molecules. Since hypoxia has been suggested as a common pathway in the development of chronic kidney disease, mTOR inhibition to patients with preexisting nephropathy should be used with caution, since it may accelerate the progression of the disease.
Assuntos
Permeabilidade Capilar/efeitos dos fármacos , Nefropatias Diabéticas/complicações , Taxa de Filtração Glomerular/efeitos dos fármacos , Glomérulos Renais/efeitos dos fármacos , Mitocôndrias/efeitos dos fármacos , Consumo de Oxigênio/efeitos dos fármacos , Inibidores de Proteínas Quinases/toxicidade , Insuficiência Renal Crônica/induzido quimicamente , Sirolimo/toxicidade , Serina-Treonina Quinases TOR/antagonistas & inibidores , Animais , Moléculas de Adesão Celular/metabolismo , Hipóxia Celular , Nefropatias Diabéticas/enzimologia , Nefropatias Diabéticas/patologia , Nefropatias Diabéticas/fisiopatologia , Progressão da Doença , Glomérulos Renais/enzimologia , Glomérulos Renais/patologia , Glomérulos Renais/fisiopatologia , Túbulos Renais/efeitos dos fármacos , Túbulos Renais/enzimologia , Túbulos Renais/patologia , Masculino , Mitocôndrias/enzimologia , Estresse Oxidativo/efeitos dos fármacos , Ratos Sprague-Dawley , Insuficiência Renal Crônica/enzimologia , Insuficiência Renal Crônica/patologia , Insuficiência Renal Crônica/fisiopatologia , Transdução de Sinais , Serina-Treonina Quinases TOR/metabolismoRESUMO
There is increasing evidence that the permeability of the glomerular filtration barrier (GFB) is partly regulated by a balance between the bioavailability of nitric oxide (NO) and that of reactive oxygen species (ROS). It has been postulated that normal or moderately elevated NO levels protect the GFB from permeability increases, whereas ROS, through reducing the bioavailability of NO, have the opposite effect. We tested the tentative antagonism between NO and ROS on glomerular permeability in anaesthetized Wistar rats, in which the left ureter was cannulated for urine collection while simultaneously blood access was achieved. Rats were systemically infused with either l-NAME or l-NAME together with the superoxide scavenger Tempol, or together with l-arginine or the NO-donor DEA-NONOate, or the cGMP agonist 8-bromo-cGMP. To measure glomerular sieving coefficients (theta, θ) to Ficoll, rats were infused with FITC-Ficoll 70/400 (mol/radius 10-80 Å). Plasma and urine samples were analyzed by high-performance size-exclusion chromatography (HPSEC) for determination of θ for Ficoll repeatedly during up to 2 h. l-NAME increased θ for Ficoll70Å from 2.27 ± 1.30 × 10-5 to 8.46 ± 2.06 × 10-5 (n = 6, P < 0.001) in 15 min. Tempol abrogated these increases in glomerular permeability and an inhibition was also observed with l-arginine and with 8-bromo-cGMP. In conclusion, acute NO synthase inhibition in vivo by l-NAME caused rapid increases in glomerular permeability, which could be reversed by either an ROS antagonist or by activating the guanylyl cyclase-cGMP pathway. The data strongly suggest a protective effect of NO in maintaining normal glomerular permeability in vivo.
Assuntos
Glomérulos Renais/metabolismo , Óxido Nítrico Sintase/antagonistas & inibidores , Espécies Reativas de Oxigênio/metabolismo , Animais , GMP Cíclico/análogos & derivados , GMP Cíclico/farmacologia , Inibidores Enzimáticos/farmacologia , Taxa de Filtração Glomerular/efeitos dos fármacos , Hidrazinas/farmacologia , Glomérulos Renais/efeitos dos fármacos , Masculino , NG-Nitroarginina Metil Éster/farmacologia , Permeabilidade/efeitos dos fármacos , Ratos , Ratos WistarRESUMO
The turnover of albumin is increased in both peritoneal dialysis (PD) and hemodialysis (HD) due to increased external losses, normally leading to compensatory increases in the hepatic albumin synthesis. The normal rate of albumin synthesis is on the order of 12 g/day corresponding to an equally large albumin fractional catabolic rate of ~4% daily. Most albumin catabolism is assumed to occur in the endothelium, but there is also renal and hepatic catabolism and leakage into the gastrointestinal tract. In PD the daily losses are on the order of 5 g/day. There are also external albumin losses in HD, particularly when high-performance membranes are used, the losses per session ranging between 1 and 8 g (or more). The dialytic albumin losses cannot be detected by assessing the transcapillary escape rate of albumin from the plasma compartment to the interstitium. In PD, tracer albumin that has been injected into the peritoneal fluid is absorbed to the tissues surrounding the peritoneal cavity without much edema formation, due to the process of "volume recirculation". A small fraction of the dialysate albumin tracer (0.2-0.3 ml/minute) is directly reabsorbed to the plasma via the lymphatics. A significant portion of dialysis patients are affected by chronic inflammation, such as in the malnutrition inflammation and atherosclerosis syndrome, which is also associated with cardiovascular mortality and fluid overload. These patients usually have a reduced ability to compensate for external losses of albumin, which may result in hypoalbuminemia. Reduced plasma albumin levels in dialysis patients may thus be regarded as a sign of chronic inflammation rather than reflecting malnutrition.
Assuntos
Diálise Peritoneal , Diálise Renal , Albumina Sérica/análise , Soluções para Diálise , Humanos , Falência Renal Crônica/sangue , Falência Renal Crônica/terapiaRESUMO
In the present study, an extended two-pore theory is presented where the porous pathways are continuously distributed according to small- and large-pore mean radii and SDs. Experimental glomerular sieving data for Ficoll were analyzed using the model. In addition, several theoretical findings are presented along with analytic solutions to many of the equations used in distributed pore modeling. The results of the data analysis revealed a small-pore population in the glomerular capillary wall with a mean radius of 36.6 Å having a wide arithmetic SD of â¼5 Å and a large-pore radius of 98.6 Å with an even wider SD of â¼44 Å. The small-pore radius obtained in the analysis was close to that of human serum albumin (35.5 Å). By reanalyzing the data and setting the distribution spread of the model constant, we discovered that a narrow distribution is compensated by an increased mean pore radius and a decreased pore area-to-diffusion length ratio. The wide distribution of pore sizes obtained in the present analysis, even when considering electrostatic hindrance due to the negatively charged barrier, is inconsistent with the high selectivity to proteins typically characterizing the glomerular filtration barrier. We therefore hypothesize that a large portion of the variance in the distribution of pore sizes obtained is due to the molecular "flexibility" of Ficoll, implying that the true variance of the pore system is lower than that obtained using flexible probes. This would also, in part, explain the commonly noted discrepancy between the pore area-to-diffusion length ratio and the filtration coefficient.
Assuntos
Ficoll/metabolismo , Glomérulos Renais/fisiologia , Animais , Difusão , Barreira de Filtração Glomerular , Humanos , Modelos Biológicos , Modelos Teóricos , RatosRESUMO
BACKGROUND: Variation in residual volume between peritoneal dialysis dwells creates uncertainty in ultrafiltration determination, dialysis efficiency, and poses a risk of overfill if the residual volume is large. Measuring the dilution of a marker molecule during fluid fill offers a convenient approach, however, estimation accuracy depends on the choice of dilution marker. We here evaluate the feasibility of creatinine and urea as dilution markers compared to albumin-based residual volumes and three-pore model estimations. METHOD: This clinical, retrospective analysis comprises 56 residual volume estimations from 20 individuals, based on the dilution of pre-fill dialysate creatinine, urea and albumin concentrations during the dialysis fluid fill phase. Outcomes were compared individually. Bias induced by ultrafiltration, marker molecule mass-transfer and influence of fluid glucose contents was quantified using the three-pore model. Linear regression established conversion factors enabling conversion between the various marker molecules. RESULTS: Creatinine-based calculations overestimated residual volumes by 115â mL (IQR 89-149) in 1.5% dwells and 252â mL (IQR 179-313) in 4.25% glucose dwells. In hypertonic dwells, ultrafiltration was 52â mL (IQR 38-66), while intraperitoneal creatinine mass increased by 67% during fluid fill, being the leading cause of overestimation. Albumin-based volumes conformed strongly with three-pore model estimates. Correction factors effectively enabled marker molecule interchangeability. CONCLUSIONS: Mass-transfer of low molecular weight marker molecules is associated with residual volume overestimation. However, by applying correction factors, creatinine and urea dilution can still provide reasonable estimates, particularly when the purpose is to exclude the presence of a very large residual volume.
RESUMO
In the current study we explore the electrostatic interactions on the transport of anionic Ficoll (aFicoll) vs. neutral Ficoll (nFicoll) over the glomerular filtration barrier (GFB) modeled as a charged fiber matrix. We first analyze experimental sieving data for the rat glomerulus, and second, we explore some of the basic implications of a theoretical model for the electrostatic interactions between a charged solute and a charged fiber-matrix barrier. To explain the measured difference in glomerular transport between nFicoll and aFicoll (Axelsson J, Sverrisson K, Rippe A, Fissell W, Rippe B. Am J Physiol 301: F708-F712, 2011), the present simulations demonstrate that the surface charge density needed on a charged fiber matrix must lie between -0.005 C/m(2) and -0.019 C/m(2), depending on the surface charge density of the solute. This is in good agreement with known surface charge densities for many proteins in the body. In conclusion, the current results suggest that electrical charge makes a moderate contribution to glomerular permeability, while molecular size and conformation seem to be more important. Yet, the weak electrical charge obtained in this study can be predicted to nearly totally exclude albumin from permeating through "high-selectivity" pathways in a charged-fiber matrix of the GFB.
Assuntos
Barreira de Filtração Glomerular/fisiologia , Modelos Biológicos , Animais , Ficoll , Humanos , Potenciais da Membrana , Ratos , Eletricidade EstáticaRESUMO
INTRODUCTION: Intradialytic hypotension is a common complication of haemodialysis, but uncommon in peritoneal dialysis (PD). This may be due to lower ultrafiltration rates in PD compared to haemodialysis, allowing for sufficient refilling of the blood plasma compartment from the interstitial volume, but the underlying mechanisms are unknown. Here we assessed plasma volume and hemodynamic alterations during experimental PD with high versus low ultrafiltration rates. METHODS: Experiments were conducted in two groups of healthy Sprague-Dawley rats: one group with a high ultrafiltration rate (N = 7) induced by 8.5% glucose and a low UF group (N = 6; 1.5% glucose), with an initial assessment of the extracellular fluid volume, followed by 30 min PD with plasma volume measurements at baseline, 5, 10, 15 and 30 min. Mean arterial pressure, central venous pressure and heart rate were continuously monitored during the experiment. RESULTS: No significant changes over time in plasma volume, mean arterial pressure or central venous pressure were detected during the course of the experiments, despite an ultrafiltration (UF) rate of 56 mL/h/kg in the high UF group. In the high UF group, a decrease in extracellular fluid volume of -7 mL (-10.7% (95% confidence interval: -13.8% to -7.6%)) was observed, in line with the average UF volume of 8.0 mL (standard deviation: 0.5 mL). CONCLUSION: Despite high UF rates, we found that plasma volumes were remarkably preserved in the present experiments, indicating effective refilling of the plasma compartment from interstitial tissues. Further studies should clarify which mechanisms preserve the plasma volume during high UF rates in PD.
Assuntos
Diálise Peritoneal , Ultrafiltração , Ratos , Animais , Diálise Peritoneal/efeitos adversos , Volume Plasmático/fisiologia , Ratos Sprague-Dawley , Hemodinâmica , GlucoseRESUMO
A healthy and functional peritoneal membrane is key to achieve sufficient ultrafiltration and to restore fluid balance, a major component of high-quality prescription in patients treated with peritoneal dialysis (PD). Variability in membrane function at the start of PD or changes over time on treatment influence dialysis prescription and outcomes, and dysfunction of the peritoneal membrane contributes to fluid overload and associated complications. In this review, we summarize the current knowledge about the structure, function and pathophysiology of the peritoneal membrane with a focus on clinical implications for patient-centered care. We also discuss the molecular and genetic mechanisms of solute and water transport across the peritoneal membrane, including the role of aquaporin water channels in crystalloid vs. colloid osmosis; why and how to assess membrane function using peritoneal equilibration tests; the etiologies of membrane dysfunction and their specific management; and the impact of genetic variation on membrane function and outcomes in patients treated with PD. This review also identifies the gaps in current knowledge and perspectives for future research to improve our understanding of the peritoneal membrane and, ultimately, to improve the care of patients treated with PD.
RESUMO
INTRODUCTION: Glucose absorption during peritoneal dialysis (PD) is commonly assumed to occur via paracellular pathways. We recently showed that SGLT2 inhibition did not reduce glucose absorption in experimental PD, but the potential role of glucose transport into cells is still unclear. Here we sought to elucidate the effects of phlorizin, a non-selective competitive inhibitor of sodium glucose co-transporters 1 and 2 (SGLT1 and SGLT2), in an experimental rat model of PD. METHODS: A 120-min PD dwell was performed in 12 anesthetised Sprague-Dawley rats using 1.5% glucose fluid with a fill volume of 20 mL with (n = 6) or without (n = 6) intraperitoneal phlorizin (50 mg/L). Several parameters for peritoneal water and solute transport were monitored during the treatment. RESULTS: Phlorizin markedly increased the urinary excretion of glucose, lowered plasma glucose and increased plasma creatinine after PD. Median glucose diffusion capacity at 60 min was significantly lower (p < 0.05) being 196 µL/min (IQR 178-213) for phlorizin-treated animals compared to 238 µL/min (IQR 233-268) in controls. Median fractional dialysate glucose concentration at 60 min (D/D 0) was significantly higher (p < 0.05) in phlorizin-treated animals being 0.65 (IQR 0.63-0.67) compared to 0.61 (IQR 0.60-0.62) in controls. At 120 min, there was no difference in solute or water transport across the peritoneal membrane. CONCLUSION: Our findings indicate that a part of glucose absorption during the initial part of the dwell occurs via transport into peritoneal cells.
Assuntos
Diálise Peritoneal , Inibidores do Transportador 2 de Sódio-Glicose , Animais , Ratos , Transporte Biológico , Soluções para Diálise/farmacologia , Glucose/metabolismo , Diálise Peritoneal/efeitos adversos , Florizina/farmacologia , Ratos Sprague-Dawley , Transportador 2 de Glucose-Sódio/metabolismo , Inibidores do Transportador 2 de Sódio-Glicose/farmacologia , Água/metabolismo , Transportador 1 de Glucose-Sódio/antagonistas & inibidoresRESUMO
Numerous in vivo studies on the ketogenic diet, a diet that can induce metabolic conditions resembling those following extended starvation, demonstrate strong outcomes on cancer survival, particularly when combined with chemo-, radio- or immunological treatments. However, the therapeutic application of ketogenic diets requires strict dietary adherence from well-informed and motivated patients, and it has recently been proposed that hemodialysis might be utilized to boost ketosis and further destabilize the environment for cancer cells. Yet, plasma ketones may be lost in the dialysate-lowering blood ketone levels. Here we performed a single 180-min experimental hemodialysis (HD) session in six anesthetized Sprague-Dawley rats given ketogenic diet for five days. Median blood ketone levels pre-dialysis were 3.5 mmol/L (IQR 2.2 to 5.6) and 3.8 mmol/L (IQR 2.2 to 5.1) after 180 min HD, p = 0.54 (95% CI - 0.6 to 1.2). Plasma glucose levels were reduced by 36% (- 4.5 mmol/L), p < 0.05 (95% CI - 6.7 to - 2.5). Standard base excess was increased from - 3.5 mmol/L (IQR - 4 to - 2) to 0.5 mmol/L (IQR - 1 to 3), p < 0.01 (95% CI 2.0 to 5.0). A theoretical model was applied confirming that intra-dialytic glucose levels decrease, and ketone levels slightly increase since hepatic ketone production far exceeds dialytic removal. Our experimental data and in-silico modeling indicate that elevated blood ketone levels during ketosis are maintained during hemodialysis despite dialytic removal.
Assuntos
Dieta Cetogênica , Cetose , Neoplasias , Humanos , Ratos , Animais , Diálise , Ratos Sprague-Dawley , Dieta , Cetonas/efeitos adversos , Diálise Renal , Adjuvantes Imunológicos/efeitos adversos , Neoplasias/terapiaRESUMO
Introduction: In kidney transplantation (KT), the role of the intravascular innate immune system (IIIS) in response to ischemia-reperfusion injury (IRI) is not well-understood. Here, we studied parallel changes in the generation of key activation products of the proteolytic cascade systems of the IIIS following living donor (LD) and deceased donor (DD) transplantation and evaluated potential associations with clinical outcomes. Methods: In a cohort study, 63 patients undergoing LD (n = 26) and DD (n = 37) transplantation were prospectively included. Fifteen DD kidneys were preserved with hypothermic machine perfusion (HMP), and the remaining were cold stored. Activation products of the kallikrein-kinin, coagulation, and complement systems were measured in blood samples obtained systemically at baseline and locally from the transplant renal vein at 1, 10, and 30 minutes after reperfusion. Results: DD kidneys exhibited a prompt and interlinked activation of all 3 cascade systems of IIIS postreperfusion, indicating a robust and local thrombo-inflammatory response to IRI. In this initial response, the complement activation product sC5b-9 exhibited a robust correlation with other IIIS activation markers and displayed a strong association with short-term and mid-term (24-month) graft dysfunction. In contrast, LD kidneys did not exhibit this thrombo-inflammatory response. The use of HMP was associated with reduced thromboinflammation and preserved mid-term kidney function. Conclusion: Kidneys from DD are vulnerable to a prompt thrombo-inflammatory response to IRI, which adversely affects both short-term and long-term allograft function. Strategies aimed at minimizing graft immunogenicity prior to reperfusion are crucial to mitigate the intricate inflammatory response to IRI.
RESUMO
The actions of systemic angiotensin II (ANG II) infusions on glomerular permeability were investigated in vivo. In anesthetized Wistar rats (250-280 g), the left ureter was cannulated for urine collection, while simultaneously blood access was achieved. Rats were continuously infused intravenously with either of four doses of ANG II ranging from 16 ng·kg(-1)·min(-1) (Lo-ANG II) to 1.82 µg·kg(-1)·min(-1) (Hi-ANG II), and in separate experiments with aldosterone (Aldo; 0.22 mg·kg(-1)·min(-1)), or with the calcium channel blocker nimodipine, or with the Aldo antagonist spironolactone together with a high ANG II dose (910 ng·kg(-1)·min(-1); Hi-Int-ANG II), respectively, and with polydisperse FITC-Ficoll-70/400 (molecular radius 10-80 Å) and (51)Cr-EDTA. Plasma and urine samples were taken at 5, 15, 30, 60, and 120 min and analyzed by high performance size-exclusion chromatography for determination of glomerular sieving coefficients (θ) to Ficoll. Mean arterial pressure (MAP) and glomerular filtration rate (GFR) were also assessed. For ANG II, there was a rapid, marked, partly reversible increase in glomerular permeability (θ) for Ficoll molecules >34 Å in radius, peaking at 5-15 min, which was completely abrogated by the ANG II blocker candesartan but not affected by spironolactone at 15 and 30 min. For Aldo, the response was similar to that found for the lowest dose of ANG II infused. For the two highest ANG II doses given (Hi-Int-ANG II and Hi-ANG II), GFR decreased transiently, concomitant with marked, sustained increases in MAP. Nimodipine completely blocked all hemodynamic ANG II actions, whereas the glomerular permeability response remained unchanged. Thus ANG II directly increased glomerular permeability independently of its hemodynamic actions and largely independently of the concomitant Aldo response. The ANG II-induced increases in glomerular permeability were, according to a two-pore and a log-normal distributed pore model, compatible with an increased number of "large pores" in the glomerular filter, and, to some extent, an increase in the dispersity of the small-pore radius.
Assuntos
Angiotensina II/administração & dosagem , Ficoll/urina , Glomérulos Renais/efeitos dos fármacos , Aldosterona/administração & dosagem , Bloqueadores do Receptor Tipo 1 de Angiotensina II/administração & dosagem , Animais , Benzimidazóis/administração & dosagem , Compostos de Bifenilo , Pressão Sanguínea/efeitos dos fármacos , Ficoll/sangue , Taxa de Filtração Glomerular/efeitos dos fármacos , Infusões Intravenosas , Glomérulos Renais/fisiologia , Masculino , Antagonistas de Receptores de Mineralocorticoides/administração & dosagem , Nimodipina/administração & dosagem , Permeabilidade/efeitos dos fármacos , Ratos , Ratos Wistar , Espironolactona/administração & dosagem , Tetrazóis/administração & dosagem , Vasodilatadores/administração & dosagemRESUMO
BACKGROUND: The continuous global rise of end-stage kidney disease creates a growing demand of economically beneficial home-based kidney replacement therapies such as peritoneal dialysis (PD). However, undesirable absorption and exposure of peritoneal tissues to glucose remain major limitations of PD. METHODS: We compared a reference (standard) automated PD regimen 6 × 2 L 1.36% glucose (76 mmol/L) over 9 h with a novel, theoretically glucose sparing (optimised) prescription consisting of 'ultrafiltration cycles' with high glucose strength (126 mmol/L) and 'clearance cycles' with ultra-low, physiological glucose (5 mmol/L) for approximately 40% of the treatment time. Twenty-one prevalent PD patients underwent the optimised regimen (7 × 2 L 2.27% glucose + 5 × 2 L 0.1% glucose over 8 h) and the standard regimen in a crossover fashion. Six patients were excluded from data analysis. RESULTS: Median glucose absorption was 43 g (IQR 41-54) and 44 g (40-55) for the standard and optimised intervention, respectively (p = 1). Ultrafiltration volume, weekly Kt/V creatinine and urea were significantly improved during optimised interventions, while no difference in sodium removal was detected. Post hoc analysis showed significantly improved ultrafiltration efficiency (ml ultrafiltration per gram absorbed glucose) during optimised regimens. No adverse events were observed except one incidence of drain pain. CONCLUSION: Optimised treatments were feasible and well tolerated in this small pilot study. Despite no difference in absorbed glucose, results indicate possible improvements of ultrafiltration efficiency and small solute clearances by optimised regimens. Use of optimised prescriptions as glucose sparing strategy should be evaluated in larger study populations.