Alterations to peritubular capillary structure in a rat model of kidney interstitial fibrosis: Implications for oxygen diffusion.

Fibrosis and loss of functional capillary surface area may contribute to renal tissue hypoxia in a range of kidney diseases. However, there is limited quantitative information on the impact of kidney disease on the barriers to oxygen diffusion from cortical peritubular capillaries (PTCs) to kidney epithelial tubules. Here, we used stereological methods to quantify changes in total cortical PTC length and surface area, PTC length and surface densities, and diffusion distances between PTCs and kidney tubules in adenine-induced kidney injury. After 7 days of oral gavage of adenine (100 mg), plasma creatinine was 3.5-fold greater than in vehicle-treated rats, while total kidney weight was 83% greater. The total length of PTCs was similar in adenine-treated (1.47 ± 0.23 km (mean ± standard deviation)) to vehicle-treated (1.24 ± 0.24 km) rats, as was the surface density of PTCs (0.025 ± 0.002 vs. 0.024 ± 0.004 µm2/µm3). The total surface area of PTCs was 69% greater in adenine-treated than vehicle-treated rats. However, the length density of PTCs was 28% less in adenine-treated than vehicle-treated rats. Diffusion distances, from PTCs to the basal membrane of the nearest renal tubule (108%), and to the mid-point of the cytoplasmic height of the nearest tubular epithelial cell (57%), were markedly increased. These findings indicate that, in adenine-induced kidney injury, expansion of the renal cortical interstitium increases the distance required for diffusion of oxygen from PTCs to tubules, rendering the kidney cortex susceptible to hypoxia.

The Impact of Procedural Justice and Trust on Customers' Continuity Intention Toward Healthcare Providers.

As life has become noticeably more comfortable compared to the past, there is a mounting interest in various service sectors, such as healthcare, where growing demand has led to an increase in the number facilities that supply products essential to service provision. Enhancing the service quality is critical to gaining an advantage in the fiercely competitive healthcare environment and is especially important as the outcomes encompass not only the treatment of disease but also patients' emotional and experiential satisfaction. This study presents procedural justice and two dimensions of trust as factors related to physician and patient relationship, investigating their effects on patients' intention to continue the relationship with their healthcare providers. We found that procedural justice had a positive effect on the two dimensions of trust, and the latter had a significant positive effect on the continuity intention. As this study verifies the necessity of procedural justice and trust for patients to continuously experience medical services, it is imperative for the healthcare industry to understand and incorporate these factors into their practices.

Spatial composition and turnover of the main molecules in the adult glomerular basement membrane.

The glomerular basement membrane (GBM) is an important tissue structure in kidney function. It is the membrane through which filtrate and solutes must pass to reach the nephron tubules. This review focuses on the spatial location of the main extracellular matrix components of the GBM. It also attempts to explain this organization in terms of their synthesis, transport, and loss. The picture that emerges is that the collagen IV and laminin content of GBM are in a very slow dynamic disequilibrium, leading to GBM thickening with age, and in contrast, some heparan sulfate proteoglycans are in a dynamic equilibrium with a very rapid turnover (i.e. half-life measured in ~hours) and flow direction against the flow of filtrate. The highly rapid heparan sulfate turnover may serve several roles, including an unclogging mechanism for the GBM, compressive stiffness of the GBM fiber network, and/or enabling podocycte-endothelial crosstalk against the flow of filtrate.

Fast Saccadic Eye Movements Contribute to the Worsened Postural Sway in Older Adults Who Have Experienced Falls.

The purpose of this study was to examine changes and between-group differences in postural sway during saccadic eye movement in older adults (n = 152). The participants were stratified into older adults who have experienced a fall (n = 58) (faller group) and those who have not (n = 94) (non-faller group). We measured postural sway during saccadic eye movement. Saccadic eye movement speed was such that the target was displayed at 0.5 Hz, 2 Hz, and 3 Hz. Postural sway was measured based on path length, velocity, and length between the maximal and minimal position of center of pressure in mediolateral and anteroposterior direction. In the faller group, path length, velocity, and mediolateral displacement of the center of pressure increased significantly during 3 Hz saccadic eye movement stimulation. However, in the non-faller group, there was no significant change in the center of pressure parameters during saccadic eye movement stimulation. Mediolateral displacement of the center of pressure increased significantly in both groups during saccadic eye movement, especially at 3 Hz. Therefore, rapid saccadic eye movement stimulation can contribute to the worsened postural sway in older adults who have experienced falls, and rapid external environmental stimuli may contribute to the deterioration of the upright standing stability in older adults.

Trifluoperazine and Its Analog Suppressed the Tumorigenicity of Non-Small Cell Lung Cancer Cell; Applicability of Antipsychotic Drugs to Lung Cancer Treatment.

Despite significant advances in diagnostic and therapeutic technologies, lung cancer remains the leading cause of cancer-related mortality worldwide. Non-small cell lung cancer (NSCLC) accounts for approximately 85% of lung cancer cases. Recently, some antipsychotics have been shown to possess anticancer activity. However, the effects of antipsychotics on NSCLC need to be further explored. We examined the effects of trifluoperazine (TFP), a commonly used antipsychotic drug, and its synthetic analogs on A549 human lung cancer cells. In addition, cell proliferation analysis, colony formation assay, flow cytometry, western blot analysis, and in vivo xenograft experiments were performed. Key genes and mechanisms possibly affected by TFP are significantly related to better survival outcomes in lung cancer patients. Treatment with TFP and a selected TFP analog 3dc significantly inhibited the proliferation, anchorage-dependent/independent colony formation, and migration of A549 cells. Treatment with 3dc affected the expression of genes related to the apoptosis and survival of A549 cells. Treatment with 3dc promoted apoptosis and DNA fragmentation. In all experiments, including in vivo studies of metastatic lung cancer development, 3dc had more substantial anticancer effects than TFP. According to our analysis of publicly available clinical data and in vitro and in vivo experiments, we suggest that some kinds of antipsychotics prevent the progression of NSCLC. Furthermore, this study indicates a synthetic TFP analog that could be a potential therapeutic for lung cancer.

Hyaluronan Synthase 1: A Novel Candidate Gene Associated With Late-Onset Non-syndromic Hereditary Hearing Loss.

OBJECTIVES: Hyaluronan synthase 1 (HAS1) is a membrane-bound protein that is abundant in the epidermis and dermis, and it is important for skin function. However, its association with hearing loss has not yet been studied. Herein, we sought to evaluate the potential contribution of HAS1: c.1082G>A to genetic hearing loss. METHODS: We used whole-exome sequencing to analyze blood DNA samples of six patients of a family with autosomal dominant familial late-onset progressive hearing loss, which was revealed to be related to a variant of the HAS1 gene. Confirmatory Sanger sequencing was performed with samples from 10 members. A missense variant was detected in HAS1 (c.1082 G>A, p.Cys361Tyr). In silico analyses predicted this variant to result in the functional loss of HAS1. Immunostaining was conducted using wild-type mouse samples to verify HAS1 expression. RESULTS: Has1 was detected in an otocyst at E10.5. In the pup, Has1 expression was localized in the stria vascularis (SV), hair cells, supporting cells of the organ of Corti, and some spiral ganglion neurons. SV marginal cells markedly expressed Has1 in the adult stage. The hearing threshold in the Has1-depleted condition was investigated by accessing the International Mouse Phenotyping Consortium's Auditory Brainstem Response (ABR) data. ABR of Has1 knock-out mice showed threshold elevations at 6, 12, and 18 kHz in young male adults. CONCLUSION: HAS1 may have a close relationship with auditory function and genetic hearing loss. Further investigation is needed to reveal the precise role of HAS1 in the auditory system. HAS1 is a candidate gene for future hereditary hearing loss genetic testing.

Predicting oxygen tension along the ureter.

Continuous measurement of bladder urine oxygen tension (Po2) is a method to potentially detect renal medullary hypoxia in patients at risk of acute kidney injury (AKI). To assess its practicality, we developed a computational model of the peristaltic movement of a urine bolus along the ureter and the oxygen exchange between the bolus and ureter wall. This model quantifies the changes in urine Po2 as urine transits from the renal pelvis to the bladder. The model parameters were calibrated using experimental data in rabbits, such that most of the model predictions are within ±1 SE of the reported mean in the experiment, with the average percent difference being 7.0%. Based on parametric experiments performed using a model scaled to the geometric dimensions of a human ureter, we found that bladder urine Po2 is strongly dependent on the bolus volume (i.e., bolus volume-to-surface area ratio), especially at a volume less than its physiological (baseline) volume (<0.2 mL). For the model assumptions, changes in peristaltic frequency resulted in a minimal change in bladder urine Po2 (<1 mmHg). The model also predicted that there exists a family of linear relationships between the bladder-urine Po2 and pelvic urine Po2 for different input conditions. We conclude that it may technically be possible to predict renal medullary Po2 based on the measurement of bladder urine Po2, provided that there are accurate real-time measurements of model input parameters.NEW & NOTEWORTHY Measurement of bladder urine oxygen tension has been proposed as a new method to potentially detect the risk of acute kidney injury in patients. A computational model of oxygen exchange between urine bolus and ureteral tissue shows that it may be technically possible to determine the risk of acute kidney injury based on the measurement of bladder urine oxygen tension, provided that the measurement data are properly interpreted via a computational model.

Estimating outflow facility parameters for the human eye using hypotensive pressure-time data.

We have previously developed a new theory for pressure dependent outflow from the human eye, and tested the model using experimental data at intraocular pressures above normal eye pressures. In this paper, we use our model to analyze a hypotensive pressure-time dataset obtained following application of a Honan balloon. Here we show that the hypotensive pressure-time data can be successfully analyzed using our proposed pressure dependent outflow model. When the most uncertain initial data point is removed from the dataset, then parameter estimates are close to our previous parameter estimates, but clearly parameter estimates are very sensitive to assumptions. We further show that (i) for a measured intraocular pressure-time curve, the estimated model parameter for whole eye surface hydraulic conductivity is primarily a function of the ocular rigidity, and (ii) the estimated model parameter that controls the rate of decrease of outflow with increasing pressure is primarily a function of the convexity of the monotonic pressure-time curve. Reducing parameter uncertainty could be accomplished using new technologies to obtain higher quality datasets, and by gathering additional data to better define model parameter ranges for the normal eye. With additional research, we expect the pressure dependent outflow analysis described herein may find applications in the differential diagnosis, prognosis and monitoring of the glaucomatous eye.

A cardiovascular model for renal perfusion during cardiopulmonary bypass surgery.

Acute kidney injury (AKI) is a major complication following cardiac surgery requiring cardiopulmonary bypass (CPB). It is likely that poor renal perfusion contributes to the occurrence of AKI, via renal hypoxia, so it is imperative to maintain optimal renal perfusion during CPB. We have developed a straightforward cardiovascular perfusion model with parameter values calibrated against experimental and/or clinical data from several independent studies of CPB in humans and animals. Following model development and calibration, we performed a one-at-a-time parametric study to investigate the response of renal perfusion to several variables during CPB, namely pump flow (denoted CO for 'cardiac output'), renal vascular resistance, and non-renal vascular resistance. From the parametric study, we have found that all three parameters had a similarly strong influence on renal perfusion. We simulated three potential strategies for maintaining optimum renal perfusion during CPB and tested their effectiveness. The strategies were: (1) increasing the pump flow; (2) administrating noradrenaline (vasopressor); and (3) administrating fenoldopam (renal vasodilator). Simulations have revealed that administration of fenoldopam is likely to be the most effective of the three strategies. Other findings from our simulations are that increasing pump flow is less effective when central venous pressure is elevated. Further, renal autoregulation is likely inoperative during CPB, as evidenced by an unchanging renal vascular resistance with increasing CO and blood pressure. The cardiac-renal perfusion model developed in this study can be linked with other kidney models to simulate the changes in renal oxygenation during CPB.

Renal oxygenation: From data to insight.

Computational models have made a major contribution to the field of physiology. As the complexity of our understanding of biological systems expands, the need for computational methods only increases. But collaboration between experimental physiologists and computational modellers (ie theoretical physiologists) is not easy. One of the major challenges is to break down the barriers created by differences in vocabulary and approach between the two disciplines. In this review, we have two major aims. Firstly, we wish to contribute to the effort to break down these barriers and so encourage more interdisciplinary collaboration. So, we begin with a "primer" on the ways in which computational models can help us understand physiology and pathophysiology. Second, we aim to provide an update of recent efforts in one specific area of physiology, renal oxygenation. This work is shedding new light on the causes and consequences of renal hypoxia. But as importantly, computational modelling is providing direction for experimental physiologists working in the field of renal oxygenation by: (a) generating new hypotheses that can be tested in experimental studies, (b) allowing experiments that are technically unfeasible to be simulated in silico, or variables that cannot be measured experimentally to be estimated, and (c) providing a means by which the quality of experimental data can be assessed. Critically, based on our experience, we strongly believe that experimental and theoretical physiology should not be seen as separate exercises. Rather, they should be integrated to permit an iterative process between modelling and experimentation.

No flow through the vitreous humor: How strong is the evidence?

When analyzing vitreal drug delivery, or the pharmacological effects of drugs on intraocular pressure, or when interpreting outflow facility measurements, it is generally accepted that the fluid in the vitreous humor is stagnant. It is accepted that for all practical purposes, the aqueous fluid exits the eye via anterior pathways only, and so there is negligible if any posteriorly directed flow of aqueous through the vitreous humor. This assumption is largely based on the interpretation of experimental data from key sources including Maurice (1957), Moseley (1984), Gaul and Brubaker (1986), Maurice (1987) and Araie et al. (1991). However, there is strong independent evidence suggesting there is a substantial fluid flow across the retinal pigment epithelium from key sources including Cantrill and Pederson (1984), Chihara and Nao-i, Tsuboi (1985), Dahrouj et al. (2014), Smith and Gardiner (2017) and Smith et al. (2019). The conflicting evidence creates a conundrum-how can both interpretations be true? This leads us to re-evaluate the evidence. We demonstrate that the data believed to be supporting no aqueous flow through the vitreous are in fact compatible with a significant normal aqueous flow. We identify strong and independent lines of evidence supporting fluid flow across the RPE, including our new outflow model for the eye. On balance it appears the current evidence favors the view that there is normally a significant aqueous flow across the RPE in vivo. This finding suggests that past and future analyses of outflow facility, interpretations of some drug distributions and the interpretation of some drug effects on eye tissues, may need to be revised.

What Makes the Kidney Susceptible to Hypoxia?

Per gram of tissue, the kidneys are among our most highly perfused organs. Yet the renal cortex and, in particular, the renal medulla are susceptible to hypoxia. In turn, hypoxia is a major pathophysiological feature of both acute kidney injury and chronic kidney disease. We identify seven factors that render the kidney susceptible to hypoxia: (1) the large metabolic demand imposed by active reabsorption of sodium; (2) limitations on oxygen delivery to cortical tissue imposed by the density of peritubular capillaries; (3) the poor capacity for angiogenesis in the adult kidney; (4) the limited ability of the renal vasculature to dilate in response to hypoxia; (5) diffusive oxygen shunting between arteries and veins in the cortex and descending and ascending vasa recta in the medulla; (6) the physiological requirement for low medullary blood flow to facilitate urinary concentration; and (7) the topography of vascular-tubular arrangements in the outer medulla that limit oxygen delivery to the thick ascending limb of Henle's loop. Recent collaborative efforts between anatomists, physiologists, and mathematicians have improved our understanding of the roles of these factors in both physiological regulation of intrarenal oxygenation and development of renal hypoxia under pathophysiological conditions. We are also better able to understand these apparent maladaptations in the context of evolution. That is, they can be explained by the combined effects of historical contingency (our ancestral life in the sea) and selection pressures imposed by the multiple functions of the kidney to regulate extracellular fluid volume, retain water, and control erythrocyte production.

Analysis of the critical determinants of renal medullary oxygenation.

We have previously developed a three-dimensional computational model of oxygen transport in the renal medulla. In the present study, we used this model to quantify the sensitivity of renal medullary oxygenation to four of its major known determinants: medullary blood flow (MBF), medullary oxygen consumption rate (V̇o2,M), hemoglobin (Hb) concentration in the blood, and renal perfusion pressure. We also examined medullary oxygenation under special conditions of hydropenia, extracellular fluid volume expansion by infusion of isotonic saline, and hemodilution during cardiopulmonary bypass. Under baseline (normal) conditions, the average medullary tissue Po2 predicted for the whole renal medulla was ~30 mmHg. The periphery of the interbundle region in the outer medulla was identified as the most hypoxic region in the renal medulla, which demonstrates that the model prediction is qualitatively accurate. Medullary oxygenation was most sensitive to changes in renal perfusion pressure followed by Hb, MBF, and V̇o2,M, in that order. The medullary oxygenation also became sensitized by prohypoxic changes in other parameters, leading to a greater fall in medullary tissue Po2 when multiple parameters changed simultaneously. Hydropenia did not induce a significant change in medullary oxygenation compared with the baseline state, while volume expansion resulted in a large increase in inner medulla tissue Po2 (by ~15 mmHg). Under conditions of cardiopulmonary bypass, the renal medulla became severely hypoxic, due to hemodilution, with one-third of the outer stripe of outer medulla tissue having a Po2 of <5 mmHg.

Estimating three-dimensional outflow and pressure gradients within the human eye.

In this paper we set the previously reported pressure-dependent, ordinary differential equation outflow model by Smith and Gardiner for the human eye, into a new three-dimensional (3D) porous media outflow model of the eye, and calibrate model parameters using data reported in the literature. Assuming normal outflow through anterior pathways, we test the ability of 3D flow model to predict the pressure elevation with a silicone oil tamponade. Then assuming outflow across the retinal pigment epithelium is normal, we test the ability of the 3D model to predict the pressure elevation in Schwartz-Matsuo syndrome. For the first time we find the flow model can successfully model both conditions, which helps to build confidence in the validity and accuracy of the 3D pressure-dependent outflow model proposed here. We employ this flow model to estimate the translaminar pressure gradient within the optic nerve head of a normal eye in both the upright and supine postures, and during the day and at night. Based on a ratio of estimated and measured pressure gradients, we define a factor of safety against acute interruption of axonal transport at the laminar cribrosa. Using a completely independent method, based on the behaviour of dynein molecular motors, we compute the factor of safety against stalling the dynein molecule motors, and so compromising retrograde axonal transport. We show these two independent methods for estimating factors of safety agree reasonably well and appear to be consistent. Taken together, the new 3D pressure-dependent outflow model proves itself to capable of providing a useful modeling platform for analyzing eye behaviour in a variety of physiological and clinically useful contexts, including IOP elevation in Schwartz-Matsuo syndrome and with silicone oil tamponade, and potentially for risk assessment for optic glaucomatous neuropathy.

Stimulation of erythropoietin release by hypoxia and hypoxemia: similar but different.

Erythropoietin is released from the kidney in response to tissue hypoxia. Montero and Lundby found that increases in plasma erythropoietin induced by reducing arterial oxygen content in healthy humans were independent of arterial oxygen tension. Their observations accord with the established physiology of kidney oxygenation and can be predicted by a computational model of renal oxygen transport. However, model simulations indicate that the interpretation implicit in the title of their paper may be an oversimplification.

A model of oxygen transport in the rat renal medulla.

The renal medulla is prone to hypoxia. Medullary hypoxia is postulated to be a leading cause of acute kidney injury, so there is considerable interest in predicting the oxygen tension in the medulla. Therefore we have developed a computational model for blood and oxygen transport within a physiologically normal rat renal medulla, using a multilevel modeling approach. For the top-level model we use the theory of porous media and advection-dispersion transport through a realistic three-dimensional representation of the medulla's gross anatomy to describe blood flow and oxygen transport throughout the renal medulla. For the lower-level models, we employ two-dimensional reaction-diffusion models describing the distribution of oxygen through tissue surrounding the vasculature. Steady-state model predictions at the two levels are satisfied simultaneously, through iteration between the levels. The computational model was validated by simulating eight sets of experimental data regarding renal oxygenation in rats (using 4 sets of control groups and 4 sets of treatment groups, described in 4 independent publications). Predicted medullary tissue oxygen tension or microvascular oxygen tension for control groups and for treatment groups that underwent moderate perturbation in hemodynamic and renal functions is within ±2 SE values observed experimentally. Diffusive shunting between descending and ascending vasa recta is predicted to be only 3% of the oxygen delivered. The validation tests confirm that the computational model is robust and capable of capturing the behavior of renal medullary oxygenation in both normal and early-stage pathological states in the rat.

Revisiting the Effect of Slag in Reducing Heat of Hydration in Concrete in Comparison to Other Supplementary Cementitious Materials.

Blast furnace slag (SL) is an amorphous calcium aluminosilicate material that exhibits both pozzolanic and latent hydraulic activities. It has been successfully used to reduce the heat of hydration in mass concrete. However, SL currently available in the market generally experiences pre-treatment to increase its reactivity to be closer to that of portland cement. Therefore, using such pre-treated SL may not be applicable for reducing the heat of hydration in mass concrete. In this work, the adiabatic and semi-adiabatic temperature rise of concretes with 20% and 40% SL (mass replacement of cement) containing calcium sulfate were investigated. Isothermal calorimetry and thermal analysis (TGA) were used to study the hydration kinetics of cement paste at 23 and 50 °C. Results were compared with those with control cement and 20% replacements of silica fume, fly ash, and metakaolin. Results obtained from adiabatic calorimetry and isothermal calorimetry testing showed that the concrete with SL had somewhat higher maximum temperature rise and heat release compared to other materials, regardless of SL replacement levels. However, there was a delay in time to reach maximum temperature with increasing SL replacement level. At 50 °C, a significant acceleration was observed for SL, which is more likely related to the pozzolanic reaction than the hydraulic reaction. Semi-adiabatic calorimetry did not show a greater temperature rise for the SL compared to other materials; the differences in results between semi-adiabatic and adiabatic calorimetry are important and should be noted. Based on these results, it is concluded that the use of blast furnace slag should be carefully considered if used for mass concrete applications.

Iatrogenic Development of Cerebrospinal Fluid Leakage in Diagnosing Spontaneous Intracranial Hypotension.

A 34-year-old woman came to the emergency room complaining of a severe orthostatic headache. Results of a cerebrospinal fluid tap and brain computed tomography were normal. Based on her history and symptoms, she was found to have spontaneous intracranial hypotension. She was hospitalized and her symptoms improved with conservative treatment. On the next day, her headache suddenly worsened. Cisternography was performed to confirm the diagnosis and determine the spinal level of her cerebrospinal fluid leak. It revealed multiple cerebrospinal fluid leaks in the lumbar and upper thoracic regions. It was strongly believed that she had an iatrogenic cerebrospinal fluid leak in the lumbar region. An epidural blood patch was performed level by level on the lumbar and upper thoracic regions. Her symptoms resolved after the epidural blood patch and she was later discharged without any complications. In this case, an iatrogenic cerebrospinal fluid leak was caused by a dural puncture made while diagnosing spontaneous intracranial hypotension, which is always a risk and hampers the patient's progress. Therefore, in cases of spontaneous intracranial hypotension, an effort to minimize dural punctures is needed and a non-invasive test such as magnetic resonance imaging should be considered first.

Accounting for oxygen in the renal cortex: a computational study of factors that predispose the cortex to hypoxia.

We develop a pseudo-three-dimensional model of oxygen transport for the renal cortex of the rat, incorporating both the axial and radial geometry of the preglomerular circulation and quantitative information regarding the surface areas and transport from the vasculature and renal corpuscles. The computational model was validated by simulating four sets of published experimental studies of renal oxygenation in rats. Under the control conditions, the predicted cortical tissue oxygen tension ([Formula: see text]) or microvascular oxygen tension (µPo2) were within ±1 SE of the mean value observed experimentally. The predicted [Formula: see text] or µPo2 in response to ischemia-reperfusion injury, acute hemodilution, blockade of nitric oxide synthase, or uncoupling mitochondrial respiration, were within ±2 SE observed experimentally. We performed a sensitivity analysis of the key model parameters to assess their individual or combined impact on the predicted [Formula: see text] and µPo2 The model parameters analyzed were as follows: 1) the major determinants of renal oxygen delivery ([Formula: see text]) (arterial blood Po2, hemoglobin concentration, and renal blood flow); 2) the major determinants of renal oxygen consumption (V̇o2) [glomerular filtration rate (GFR) and the efficiency of oxygen utilization for sodium reabsorption (ß)]; and 3) peritubular capillary surface area (PCSA). Reductions in PCSA by 50% were found to profoundly increase the sensitivity of [Formula: see text] and µPo2 to the major the determinants of [Formula: see text] and V̇o2 The increasing likelihood of hypoxia with decreasing PCSA provides a potential explanation for the increased risk of acute kidney injury in some experimental animals and for patients with chronic kidney disease.

A pseudo-three-dimensional model for quantification of oxygen diffusion from preglomerular arteries to renal tissue and renal venous blood.

To assess the physiological significance of arterial-to-venous (AV) oxygen shunting, we generated a new pseudo-three-dimensional computational model of oxygen diffusion from intrarenal arteries to cortical tissue and veins. The model combines the 11 branching levels (known as "Strahler" orders) of the preglomerular renal vasculature in the rat, with an analysis of an extensive data set obtained using light microscopy to estimate oxygen mass transfer coefficients for each Strahler order. Furthermore, the AV shunting model is now set within a global oxygen transport model that includes transport from arteries, glomeruli, peritubular capillaries, and veins to tissue. While a number of lines of evidence suggest AV shunting is significant, most importantly, our AV oxygen shunting model predicts AV shunting is small under normal physiological conditions (~0.9% of total renal oxygen delivery; range 0.4-1.4%), but increases during renal ischemia, glomerular hyperfiltration (~2.1% of total renal oxygen delivery; range 0.84-3.36%), and some cardiovascular disease states (~3.0% of total renal oxygen delivery; range 1.2-4.8%). Under normal physiological conditions, blood Po2 is predicted to fall by ~16 mmHg from the root of the renal artery to glomerular entry, with AV oxygen shunting contributing ~40% and oxygen diffusion from arteries to tissue contributing ~60% of this decline. Arterial Po2 is predicted to fall most rapidly from Strahler order 4, under normal physiological conditions. We conclude that AV oxygen shunting normally has only a small impact on renal oxygenation, but may exacerbate renal hypoxia during renal ischemia, hyperfiltration, and some cardiovascular disease states.