Use of function diagrams in physiology education: Nessie the Nephron and Navigating the Lochs.

Function diagrams focus on physiological concepts rather than associated structures and can serve as elaboration tools and mnemonic aids. A function diagram prototype of the gastrointestinal system was recently described (Wilson & Barrett, Adv Physiol Educ, 45:264–268, 2021). Currently, a functional diagram of the glomerulus, nephron, urinary system, and bladder is proposed. Colloquially named “Nessie the Nephron” to loosely capture the looping structure and illusive understanding of renal blood flow, glomerular filtration, and epithelial transport for the student, not to mention the nearly mythical countercurrent multiplier. “Navigating the Lochs” references Nessie’s possible habitat and more importantly the movement and storage of the modified ultrafiltrate from the nephron. The primary analogies that form the structure of this function diagram are: Rain Barrel, Soaker Hose, & Hose Nozzle (afferent and efferent blood flow and filtration pressure); Water Purification System (glomerular filtration barrier forming multiple step filtration process involving the capillary, basement membrane, and podocytes); Mixed Recycling Machine (proximal tubule individual, co-, and bulk transport); Desiccator & Briner (thin descending limb removal of water and thin/thick ascending limb movement of salt); Conveyor Belt Picker (distal nephron selective ion transport); and Concentrator (collecting duct water and urea transport). The primary analogies that elaborate “Navigating the Lochs” are Aqueduct & Cistern System (fluid movement and collection); and Pressure Gauge, Syringe Bulb, and Two-valve Plumbing (bladder storage and micturition). Complimenting these analogies is the rich potential for inclusion of clinical and comparative applications and examples to link previous knowledge and strengthen memories for future retrieval. University of Kentucky College of Medicine. This is the full abstract presented at the American Physiology Summit 2024 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.

Function diagrams put the focus on physiology and physiological concepts rather than the associated anatomy. Function diagrams could potentially serve as an elaboration tool and memory aid (mnemonic) to improve learning and recall. The function diagram prototype of the gastrointestinal system can aid in the instruction of difficult gastrointestinal physiology topics using a sequential focus on fundamental gastrointestinal functions.

Renal physiology underpins renal nuclear medicine, both academic and clinical. Clearance, an important concept in renal physiology, comprises tissue uptake rate of tracer (tissue clearance), disappearance rate from plasma (plasma clearance), appearance rate in urine (urinary clearance) and disappearance rate from tissue. In clinical research, steady-state plasma clearances of para-amino-hippurate and inulin have been widely used to measure renal blood flow (RBF) and glomerular filtration rate (GFR), respectively. Routinely, GFR is measured at non-steady state as plasma clearance of a filtration agent, such as technetium-99m diethylenetriaminepentaacetic acid. Scaled to three-dimensional whole body metrics rather than body surface area, GFR in women is higher than in men but declines faster with age. Age-related decline is predominantly from nephron loss. Tubular function determines parenchymal transit time, which is important in renography, and the route of uptake of technetium-99m dimercaptosuccinic acid, which is via filtration. Resistance to flow is defined according to the pressure-flow relationship but in renography, only transit time can be measured, which, being equal to urine flow divided by collecting system volume, introduces further uncertainty because the volume is also unmeasurable. Tubuloglomerular feedback governs RBF and GFR, is regulated by the macula densa, mediated by adenosine and renin, and can be manipulated with proximal tubular sodium-glucose cotransporter-2 inhibitors. Other determinants of renal haemodynamics include prostaglandins, nitric oxide and dopamine, while protein meal and amino acid infusion are used to measure renal functional reserve. In conclusion, for measuring renal responses to exogenous agents, steady-state para-amino-hippurate and inulin clearances should be replaced with rubidium-82 and gallium-68 EDTA for measuring RBF and GFR.

Diffusion of inulin and p-aminohippuric acid (PAH) in combined aqueous solution through artificial membranes was measured at room temperature and atmospheric pressure. The membranes had pore diameters of 26, 50, 100, 200, 250, 350, 510 or 990 A. The diffusion of PAH was only restricted with a pore size of 26 A, but inulin diffusion was restricted at 100 A. When diffusion of both solutes was unrestricted (pore diameter greater than or equal to 200 A), PAH diffused four times faster than inulin, and in restricted situations this ratio was even greater. The results of these diffusion studies allow the major and minor molecular dimensions of the solutes to be estimated. Filtration of the two solutes was studied in slowly flowing situations and also with increased temperature and pressure. Pore sizes required for unrestricted filtration were the same as for unrestricted diffusion but the passage ratio was reduced from 4 to 2. These results suggest strongly that two conditions are necessary if the glomerular filtration rate (GFR) of inulin is to equal the true GFR: membrane pore size must be at least 200 A and passage through the membranes must be by bulk transport.

This article reviews the current understanding of memory system anatomy and physiology, as well as relevant evaluation methods and pathologic processes. Our understanding of memory formation advances each year. Successful episodic memory formation depends not only on intact medial temporal lobe structures but also on well-orchestrated interactions with other large-scale brain networks that support executive and semantic processing functions. Recent discoveries of cognitive control networks have helped in understanding the interaction between memory systems and executive systems. These interactions allow access to past experiences and enable comparisons between past experiences and external and internal information. The semantic memory system is less clearly defined anatomically. Anterior, lateral, and inferior temporal lobe regions appear to play a crucial role in the function of the semantic processing system. Different but tightly interconnected cortical regions, such as the prefrontal region, may play a controlling role in this system. The presentation of clinical disease affecting memory is the result of the selective vulnerability of the memory system. An understanding of current concepts of memory anatomy, physiology, and evaluation plays a central role in establishing an accurate diagnosis. Different memory systems rely on separate but overlapping distributed brain networks. Certain pathologic processes preferentially affect memory systems. An understanding of memory formation stages will enable more accurate diagnosis.

A subset of patients with acute exacerbation of chronic pulmonary disease present with concomitant acute renal failure (ARF). Acute hypercapnia remains an underappreciated and often overlooked cause of ARF in these patients with acute hypercapnic respiratory failure (AHRF). A nephrology consultation is requested for oliguric ARF in a woman with obesity-hypoventilation syndrome who has been admitted for AHRF and was treated with non-invasive ventilation. Despite stable hemodynamic status, the patient receives a large volume of intravenous fluids in an attempt to improve the renal function and urine output, and develops pulmonary edema and worsening respiratory status.The decision is made to hemodialyze the patient for pulmonary edema and resistant hyperkalemia. However, prior to initiation of hemodialysis, the patient is intubated and started on mechanical ventilation because of progressively worsening respiratory status. This is followed by rapid improvement in hypercapnia and acidosis, and then by a significant increase in urine output. The patient’s renal function and hyperkalemia improves over the next few hours, obviating the need for renal replacement therapy.The potential causes of ARF in patients with AHRF are numerous, and include hemodynamic instability and hypotension, intravascular volume depletion (due to increased insensible loss), concomitant use of medications that affect renal hemodynamics (eg, angiotensin-converting enzyme-I and diuretics), presence of comorbidities with potential impact on renal function (eg, chronic kidney disease, diabetes, heart failure), and interventions performed at the time of admission (eg, intravenous contrast studies and nephrotoxic medications).Management of AHRF frequently parallels the conservative treatment of ARF in these patients, which very often includes administration of large volumes of intravenous fluids with the assumption that the patient is intravascularly volume-depleted. This approach is certainly indicated in patients with hemodynamic instability as well as in those with evidence of intravascular volume depletion and organ hypoperfusion. However, unnecessary and injudicious administration of a large volume of intravenous fluids can result in severe volume overload and worsening respiratory status in other patients.In this regard, it is important to emphasize the role of acute hypercapnia as a potential cause of ARF in patients presenting with AHRF. Although chronically hypercapnic subjects (eg, those with stable chronic obstructive pulmonary disease) have a baseline renovascular resistance similar to normocapnic patients, acute increase in serum CO2 levels is shown to be associated with renal vasoconstriction.1,2 This impact on renal vascular tone is believed to be both direct and indirect (ie, via the sympathetic nervous system).3,4 Vasoconstriction leads to a decrease in renal blood flow and intra-glomerular pressure, with subsequent reduction in glomerular filtration rate. Therefore, it is not unexpected to observe ARF, with pre-renal characteristics without intracascular volume depletion, in patients presenting with AHRF. This physiological concept is further supported by clinical observations such as the one mentioned earlier, in which renal function is improved after successful management of hypercapnia with no additional kidney-oriented intervention.It therefore seems prudent to focus on management of AHRF in patients who present simultaneously with AHRF and ARF. Unnecessary administration of large volumes of intravenous fluids should be avoided in patients without evidence of intravascular volume depletion, and renal replacement therapy can be deferred, if possible, because resolution of AHRF and hypercapnia is typically followed by improvement in renal function.

In order to quantify the renal handling of iodopyracet (IOD) and sulfamethizole (SMZ), single-drug clearance studies in rabbits were performed under quasi-steady state conditions with stepwise increasing the infusion rate of IOD or SMZ. Although concentration dependence of plasma protein binding was observed for both drugs, the urinary excretion rate of IOD was proportional to its total plasma concentration at low total plasma concentrations of 0.05-0.8 mM. On the other hand, the relationship between urinary excretion rate and total plasma concentration of SMZ was a concave-ascending curve at low plasma concentrations and the renal clearance of SMZ was sensitive to changes in plasma protein binding. However, renal clearances referenced to unbound plasma concentration at total plasma concentrations of 0.05 mM for IOD and SMZ were 9.5 and 38 l/h, respectively. Those values were much greater than the effective plasma flow in rabbits. These facts indicated that the intrinsic clearances at the sites of tubular secretion were high and that the rates of secretion were fully or partially limited by the renal plasma flow. Furthermore it was suggested that unbound drug was liberated from plasma protein at the sites of tubular secretion. The data obtained at high plasma concentrations indicated that the tubular secretion of IOD had capacity limited characteristics and that the urinary excretion of SMZ involved tubular reabsorption as well as saturable tubular secretion. From the data obtained, a perfusion-limited pharmacokinetic model was constructed characterizing the excretory processes, namely, glomerular filtration, passive tubular reabsorption, saturable tubular secretion and reequilibrium between bound and unbound drugs in plasma. For both drugs, the estimates for bulk flow rate were reasonable values of effective renal plasma flow and the dissociation constants for tubular secretion agreed well with those for in vitro renal cortex accumulation, suggesting that the kinetic model based on physiological concepts was useful for the understanding of the drug elimination processes.

The cAMP-mediator Epac1 (RapGef3) has high renal expression. Preliminary observations revealed increased diuresis in Epac1-/- mice. We hypothesized that Epac1 could restrict diuresis by promoting transcellular collecting duct (CD) water and urea transport or by stabilizing CD paracellular junctions to reduce osmolyte loss from the renal papillary interstitium. In Epac1-/- and Wt C57BL/6J mice, renal papillae, dissected from snap-frozen kidneys, were assayed for the content of key osmolytes. Cell junctions were analysed by transmission electron microscopy. Urea transport integrity was evaluated by urea loading with 40% protein diet, endogenous vasopressin production was manipulated by intragastric water loading and moderate dehydration and vasopressin type 2 receptors were stimulated selectively by i.p.-injected desmopressin (dDAVP). Glomerular filtration rate (GFR) was estimated as [14 C]inulin clearance. The glomerular filtration barrier was evaluated by urinary albumin excretion and microvascular leakage by the renal content of time-spaced intravenously injected 125 I- and 131 I-labelled albumin. Epac1-/- mice had increased diuresis and increased free water clearance under antidiuretic conditions. They had shorter and less dense CD tight junction (TJs) and attenuated corticomedullary osmotic gradient. Epac1-/- mice had no increased protein diet-induced urea-dependent osmotic diuresis, and expressed Wt levels of aquaporin-2 (AQP-2) and urea transporter A1/3 (UT-A1/3). Epac1-/- mice had no urinary albumin leakage and unaltered renal microvascular albumin extravasation. Their GFR was moderately increased, unless when treated with furosemide. Our results conform to the hypothesis that Epac1-dependent mechanisms protect against diabetes insipidus by maintaining renal papillary osmolarity and the integrity of CD TJs.

A review of systems and networks of the limbic forebrain/limbic midbrain

Klein and colleagues1 have retrospectively analyzed results derived from the prospective, randomized Outcomes of a Prospective Trial of Intravenous Milrinone for Exacerbations of Chronic Heart Failure (OPTIME-CHF) study and contribute an interesting article to this inaugural issue of Circulation: Heart Failure . Their analysis provides further evidence that the level of renal function in patients with worsening heart failure and impaired systolic function is an important predictor of rehospitalization for cardiovascular events and death within 60 days of discharge. Renal function was assessed at admission. Change during hospitalization was recorded for blood urea nitrogen (BUN) and estimated glomerular filtration rate (GFR). Estimated GFR was calculated with the 4-variable equation of the Modification of Diet in Renal Disease study, which depends on serum creatinine, age, and sex.2 Of interest, the BUN on admission and change in BUN during the hospital stay (independent of the admission value) was a statistically better predictor of the 60-day death rate and days of rehospitalization than was estimated GFR. Because BUN is affected by protein intake, catabolism, and tubular reabsorption of urea, it is not as reliable an index of renal function as GFR. Thus, this observation by Klein et al1 is of particular interest and deserves explanation. Article p 25 Serum creatinine is freely filtered at the glomerulus, not reabsorbed, but undergoes tubular secretion. Thus, creatinine clearance exceeds inulin clearance, the gold standard for GFR. In contrast, urea is freely filtered, not secreted, but is reabsorbed by the renal tubules. This reabsorption of urea is flow dependent so that more urea is reabsorbed at lower urine flow rates (Figure 1).3 Most importantly, the reabsorption of urea in the collecting duct is mediated by the effect of arginine vasopressin (AVP) on the urea transporter in the collecting …

Electrolytes in the Aging

A new type of urea transporter was identified by a database search and shown to be highly expressed in the renal proximal tubule cells of teleosts; proximal tubule-type urea transporters have not been describe previously. We first identified urea transporter-like sequences in the fugu genome and in an EST database of rainbow trout. Based on these pieces of sequence information, we obtained a full-length cDNA for the eel ortholog, consisting of 378 amino acid residues, and named it eUT-C. Although its sequence similarity to the known urea transporters is low (approximately 35%), its heterologous expression in Xenopus laevis oocytes indicated that it is a facilitative urea transporter sensitive to phloretin. Its activity is not dependent on Na+. Northern blot analysis showed that expression of eUT-C is highly restricted to the kidney, with weak expression in the stomach. In both tissues, eUT-C mRNA was strongly induced when eels were transferred from freshwater to seawater. Immunohistochemistry and in situ hybridization histochemistry revealed proximal tubule cell localization of eUT-C. Taking into account that 1) urea is mainly secreted from the gill where another type of urea transporter (eUT) has been identified and 2) fish excrete a very small volume of urine in seawater, we propose that eUT-C cloned here is a key component working in combination with the gill transporter to achieve an efficient urea excretory system in fish, namely, eUT-C reabsorbs urea from glomerular filtrate and sends it to the gill, through the circulation, for excretion.

Atrial natriuretic factor (ANF) is a peptide hormone that increases renal NaCl and water excretion. Several renal sites of ANF action have been identified, but general agreement has not been reached concerning the quantitative contribution of each action to the natriuresis and diuresis. Using a five-nephron central core model of NaCl, urea, KCl, and water transport in the rat kidney, we have quantitatively evaluated the hypothetical effects on whole kidney function of three experimentally observed ANF actions: 1) inhibition of active NaCl absorption in the collecting duct, 2) inhibition of osmotic water permeability in the collecting duct, and 3) increased NaCl and water delivery out of the proximal convoluted tubule simulating an increase in glomerular filtration rate. The simulations show that inhibition of collecting duct active NaCl absorption by greater than or equal to 50% can increase NaCl and water excretion to levels that match experimental values. In addition, the model predicted that the urinary sodium concentration will increase to greater than plasma levels as observed experimentally. Simulated decreases in collecting duct water permeability predicted an increase in water excretion with little change in NaCl excretion. Simulated 2.5-5% increases in glomerular filtration rate also increased simulated NaCl and water excretion rates to experimentally observed levels in response to ANF. However, this action was less effective than inhibition of collecting duct active NaCl absorption in increasing the urinary NaCl concentration. We conclude that a combination of several actions are likely to account for the overall renal effect of ANF.

African Americans (AA) develop hypertension (HTN) at an earlier age, have a greater frequency and severity of HTN, and have poorer control of blood pressure (BP) as compared to the white population. The mechanisms responsible for these disparities are unknown. The multifactorial nature of HTN and the similar presentation of its etiologies complicate its treatment. Mathematical modeling provides the ability to analyze complicated interrelated effects across multiple systems. Our current model, HumMod, is a large physiological simulator that is comprised of 14 organ systems, and includes key systems that play an integral role in BP control such as neural, endocrine, circulatory, and renal systems. We have created tools that integrate HumMod to generate virtual populations that are calibrated from clinical data. Thiazide (THZ) diuretics generally reduce BP and improve cardiovascular outcomes in AA. Using de‐identified clinical data from the Genetic Epidemiology Network of Atherosclerosis (GENOA) study, we calibrated virtual populations to normotensive AA or hypertensive AA with or without THZ therapy. The clinical and virtual populations were statistically similar in multiple variables including mean arterial pressure (MAP), glomerular filtration rate (GFR), left ventricular mass index (LVMI), cardiac output, and total peripheral resistance (Figure 1). Interestingly, virtual patients that did not respond to 4 weeks of THZ therapy (ΔMAP = 0±5 mmHg) were associated with greater falls in renal hemodynamics, activation of the renin‐angiotensin system, and decreased plasma atrial natriuretic peptide (ANP) as compared to THZ responders (ΔMAP = −9±3 mmHg) (Figure 2). This suggests that differences in the hormonal response to diuretic therapy may be an important factor that prevents successful HTN treatment in AA. These data are both a proof of concept of established physiology and a tool to test existing and new hypotheses of the mechanisms of nonresponse to varying antihypertensive regimens. These techniques and the potential insights gleaned from these simulations may also have broad implications for improving BP control in other hypertensive populations.Support or Funding InformationSupported by AHA 17POST33661071 and NIH PO1 HL51971This abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.

The origins of hepatobiliary and gastrointestinal physiology.