|MEDICAL EDUCATION TEACHING NOTE
|Year : 2019 | Volume
| Issue : 1 | Page : 22-27
To pee and to poo: Cross-organ principles and mechanisms in renal and gastrointestinal physiology
Hwee-Ming Cheng, See-Ziau Hoe
Department of Physiology, Faculty of Medicine, University of Malaya, Kuala Lumpur, Malaysia
|Date of Submission||26-Apr-2019|
|Date of Acceptance||28-May-2019|
|Date of Web Publication||20-Jun-2019|
Prof. Hwee-Ming Cheng
Department of Physiology, Faculty of Medicine, University of Malaya, Kuala Lumpur 50603
Source of Support: None, Conflict of Interest: None
Cross-organ principles can be recognized and taught as an expression of the shared functional symmetry and common design in physiology. This integrated concept will help students to appreciate the unifying mechanisms that maintain the homeostatic balance in the body. In this article, the cross-organ similarities in gastrointestinal and renal physiology are extracted to aid learning and teaching. Some fun conversations between the Kiddo Urinary (U) and the Gastro Intestinal (I) are included to promote enjoyment in physiology.
Keywords: Cross-organ principles, gastrointestinal physiology, integration, renal physiology
|How to cite this article:|
Cheng HM, Hoe SZ. To pee and to poo: Cross-organ principles and mechanisms in renal and gastrointestinal physiology. BLDE Univ J Health Sci 2019;4:22-7
When you can tell your students that there are many examples of shared symmetry and design in physiological events across different organ systems, they will be interested and curious to find out.
It will certainly get student's attention that in these mechanisms, they only “need to understand it once!” and can apply their common knowledge and understanding to the physiology of several organ systems. Physiology is a moving subject, and the physical factors that determine blood flow in the circulation and airflow in the respiratory tree are the same, for example, the vascular resistance and the airway resistance (R) are both altered significantly with changes in the structural radius, in which R is reciprocally related to the 4th power of radius.
The gastrointestinal (GI) and renal systems have excretory functions, expelling the final undigested feces and the metabolic products in urine. Both the gastric chyme and the glomerular filtrate travel a considerable distance along the digestive tract and the nephron/collecting ducts, respectively. Several features of chyme and filtrate processing have common characteristics and physiological importance. Here are some examples of major cross-organ gastro-renal physiology.
| The Control of Gastric Emptying and the Control of Renal Blood Flow/glomerular Filtration|| |
The regulated entry of gastric chyme into the duodenum, or gastric emptying (GE), involves the pylorus [Figure 1]. The pyloric smooth muscle functions to allow controlled exit of the acidic gastric chyme from the stomach where there is a unique mucosal barrier to gastric acid into the duodenum. Luminal acidity in the duodenum is then a major factor that regulates GE. The other factors that also affect the pyloric muscular control are osmolarity and the lipid content of the chyme. These are involved, respectively, to ensure optimal intestinal water reabsorption, as well as digestion and absorption of fats.
|Figure 1: Motor events during normal gastric emptying. Adapted by permission from Springer Nature: Nature Reviews Gastroenterology and Hepatology “New management approaches for gastroparesis” by Rayner and Horowitz 2005.|
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At the nephron, the autoregulation of renal blood flow (RBF)/glomerular filtration rate (GFR) is centered on the smooth muscle of the preglomerular afferent arteriole. The GFR is maintained fairly constant at the beginning of the nephronic fluid journey just as the gastric chyme begins its journey from the duodenum. The renal tubular fluid is modified along the convoluted nephron similar to the way the chyme is processed along the small and large intestines. In renal autoregulation of RBF/GFR, the vascular arteriolar response is altered compensatory by paracrines from the distal macula densa that monitors fluid electrolytes as an indicator of any GFR changes upstream [Figure 2]. The student should obviously have noted that the kidneys and the gut have physiology that goes beyond excreting urine and producing undigested feces.
|Figure 2: Tubuloglomerular feedback mechanism of renal autoregulation. Adapted from Berne RM, Levy MN, Koeppen BM, Stanton BA. Physiology. 5th ed. St. Louis: Mosby, Elsevier Science; 2004. Figures 34 and 17. GFR = Glomerular filtration rate, JGA = juxtaglomerular apparatus|
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| Water Balance: Intestinal and Renal Reabsorption of Water|| |
The daily rate of total water reabsorbed from the gut is around 8 l, depending on the water intake. The daily water consumed is about 2 l in drinks and foods. This indicates that a large portion of the fluid absorbed by the intestines is the fluids that were secreted as saliva and gastric and pancreatic juices. Recycling of digestive secretions is then a very important contributor to the water balance. Any cause of watery stools as in either secretory, osmotic, or hypermotility diarrhea will lead to a volume contraction of the extracellular fluid (ECF) and hypovolemia. The water reabsorption in the gut is not under any major hormonal regulation unlike in the kidneys.
In the nephrons, urine production is a mere 1%–2% of the GFR at 125 ml/min. The filtration fraction is a significant 20% in the renal process of “purifying” or thein vivo physiologic dialyzing of the ECF/blood volume. The GFR at 180 l/day highlights the multiple blood volumes (5 l, 3 l being plasma) of plasma that is filtered for this purpose.
In the gut, the osmolarity of the chyme along the GI tract remains iso-osmotic as water is reabsorbed down an osmotic gradient following solute transport from lumen by the enterocytes. In juxtamedullary nephrons, the osmolarity of the tubular fluid changes along the nephron, increasing as the fluid flows down and decreasing as the fluid flows up the loop of Henle (LoH), respectively. Further down the collecting ducts, the fluid osmolarity increases again when the hormone vasopressin is secreted during negative water balance. The urine that exits is hyperosmotic and concentrated a homeostatic result of restoring the water balance by water conservation.
An interestingly shared histology is seen between the ducts of the salivary glands and the ascending portion of the LoH [Figure 3]., Salivary ducts such as the ascending LoH are uniquely impermeable to water. In the mouth, this property accounts for the observation that the saliva becomes more hypotonic as the oral fluid flow is increased. In the nephron, the ascending LoH is termed as the “diluting segment” as solute but not water is reabsorbed. The tubular fluid that exits the ascending LoH is always hypotonic.
|Figure 3: (a) Loop of Henle. Adapted and modified from Human Physiology 12th by Fox SI. New York: The McGraw-Hill Companies; 2011. Figure 17.14. (b) Salivary gland. Adapted and modified with permission from Elsevier: Autoimmunity Reviews “The imprint of salivary secretion in autoimmune disorders and related pathological conditions” by Bhattarai et al. 2018.|
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In the pancreatic ductal cells, any net solute secretion will be accompanied by fluid secretion, and the bicarbonate secreted under the action of the hormone secretin would lead to added iso-osmotic fluid to the digestive juice as the pancreatic ductal cells are permeable to water.
| Epithelial Transport: Glucose, Amino Acids, and Electrolytes|| |
The gut and the kidneys share common epithelial transport mechanisms for the common solutes carried transepithelially either by absorption or secretion. Glucose is transported in identical ways by secondary active transport by a combination of primary active sodium ATPase activity at the basolateral membrane and a luminal membrane sodium/glucose symporter [Figure 4]. For amino acids, the family of sodium-coupled cotransporters for the basic/acidic/neutral groups of amino acids are similar, energized by the sodium ATPase pump that maintains the electrochemical sodium gradient for the secondary active transport.
|Figure 4: Transepithelial transport of glucose. Adapted from Human Physiology. An Integrated Approach. 6thed by Silverthorn DU. Boston: Pearson Education; 2014. Figure 5.21.|
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In the nephron, the hormone aldosterone has a primary role in sodium balance by increasing sodium reabsorption at the collecting ducts during negative sodium balance. Aldosterone also has some action in the intestine. The same mineralocorticoid hormone also has the dual function in potassium balance by enhancing potassium secretion, also at the principal cells of the renal collecting ducts and enterocytes.
| Erythropoiesis|| |
Normal renal function maintains the hematocrit. The hormone erythropoietin is secreted from the kidneys in response to hypoxia. Renal failure is often associated with anemia. The stomach is not an essential organ for digestion as the pancreas secretes the enzymes that can digest all classes of food energy substrates. However, the gastric parietal cells that secrete hydrochloric acid also release an essential erythropoietic, intrinsic factor that complexes with dietary Vitamin B12 before the vitamin can be absorbed in the intestinal ileum.
| Acid Secretion and Bicarbonate Production|| |
The secretion of protons by the stomach is part of the event for secreting hydrochloric acid for the action of pepsin. The parietal cells have the enzyme carbonic anhydrase that generates the hydrogen ions from carbonic acid for secretion. The protons are actively extruded into the lumen by a potassium/hydrogen ATPase. The bicarbonate ions from the carbonic acid are released across the basolateral membrane, and this alkalinizes the postprandial portal blood.
In the pancreas, the same cellular carbonic anhydrase is involved in the production of bicarbonate ions that are then secreted as a major component of the alkaline pancreatic juice. The hormone secretin stimulates the pancreatic bicarbonate secretion.
The kidneys secrete protons and reabsorb and synthesize bicarbonate anions. The daily production of noncarbonic acids has to be excreted by the kidneys after the immediate neutralization by chemical buffers in the ECF. The renal tubular cells also contain the carbonic anhydrase that produces the protons and bicarbonate ions. The luminal membrane proton transporters at the renal tubular cells include besides the H/K ATPase, the sodium/hydrogen antiporter, and hydrogen ATPase. The reabsorption of filtered bicarbonate and the generation of bicarbonate to replenish the used anion during ECF buffering are linked to the secretion of protons at both the proximal and distal portions of the nephron. Secreted protons that are excreted in urine are bound to urinary buffers, the two major ones being phosphate and ammonium.
| pH Sensors and Feedback in Gastro-Renal Physiology|| |
In gastric physiology, the secretion of acid is itself homeostatically regulated by the hydrogen ion concentration in the gastric lumen. The major gastric hormone gastrin is released during feeding, and gastrin stimulates gastric parietal cells to secrete hydrochloric acid. The gastric enzyme pepsin requires an acidic medium for optimal digestion of proteins. In the empty stomach, gastrin secretion into gastric capillary is inhibited. The increased acidity in the gastric lumen stimulates the paracrine somatostatin which then suppresses gastrin release. When food enters the stomach, the physical buffering by food increases the luminal pH (still acidic) enough to release the acid suppression of gastrin. Gastrin secretion is further stimulated by parasympathetic and enteric activities and by the products of protein digestion.
pH sensors are also operative in the duodenal wall. The duodenum, unlike the stomach, has no unique gastric mucosal barrier that prevents autodigestion of the stomach wall. The occurrence of ulceration by acid is more or just as common in the duodenum. The acidic gastric chyme is emptied slowly into the duodenum. The pancreatic enzymes need a higher pH than pepsin for optimal action. In addition, rapid neutralization of the gastric chyme also protects the duodenal wall from acid corrosion. Duodenal sensors for hydrogen ions are activated, and this leads to stimulation of the hormone secretion from the endocrine cells in the duodenum. The polypeptide secretin increases the bicarbonate secretion and alkalinizes the pancreatic juice secretion. Secretin also has an inhibitory action on GE.
Kidneys are essential organs in the regulation of extracellular pH. The noncarbonic acid production each day can only be handled by renal excretion. The kidneys excrete excess hydrogen ions mainly in the form of urinary ammonium and phosphate. These solutes also called urinary buffers do not maintain urine pH (meaning of buffer as used in the ECF). The hydrogen ions complexed in ammonium and phosphate allow more secretion and excretion of acid as the maximum concentration of free protons (pH) in urine is limited to around 4.0.
The sensors for pH are located at both the epithelial cells of the convoluted proximal and distal collecting ducts. pH sensing can involve actual components located on the basolateral membranes of the nephron segments. Decreased pH is monitored and leads to increased carbonic anhydrase activity in the epithelial cells. Cytosolic carbonic acid is produced and dissociated into bicarbonate and protons. The protons are secreted into the lumen while the bicarbonate basic anion is released into the capillary. The proximal and collecting ductal cells also respond to increased partial pressure of CO2 in the ECF, and similar carbonic anhydrase reactions are activated. Respiratory and nonrenal causes of acid-base disturbances are corrected by renal mechanisms that reabsorb filtered bicarbonate, synthesize bicarbonate, and secrete protons.
| Capillary Dynamics in Gastro-Renal Physiology|| |
Most of the textbooks will describe the standard capillary exchange by looking at the Starling's forces at the upstream arteriolar and then the downstream venular end of the capillary. At the capillary microcirculation in skeletal muscle tissues, there is, in general, fluid filtration at the arteriolar end as the net Starling's force is positive. Along the capillary, as the hydrostatic pressure decreases, the net Starling's force at the venular end becomes negative, indicating a net reabsorption of the filtered fluid from the interstitial space. Most of the filtered fluids are reabsorbed, and the lymphatic vessels drain any excess fluid and prevent fluid accumulation in the interstitial space (edema).
When we consider the secretory glands of the GI tract, for example, the salivary and the pancreatic secretions, the capillaries that supply the acinar cells of both salivary/pancreatic glands should only filter fluid that will become the aqueous medium of the digestive juices. At the ductal cells of the digestive glands (pancreas), the capillaries that supply them secrete more fluid and add volume to the primary secretory fluids that flow from the acinar cells.
When we consider the convoluted proximal tubule, the only peritubular capillary fluid movement is reabsorption. The water is reabsorbed iso-osmotically following solute absorption, most of which are sodium coupled. The Starling's net force along the peritubular capillary that supplies the proximal epithelial cells is always negative. The peritubular oncotic pressure is higher than the peritubular hydrostatic pressure along the capillary that is anatomically in series with the glomerular capillary. The high filtration fraction at the glomerulus accounts for this profile of Starling's forces at the peritubular capillary, contributing to its function in renal physiology.
Intestinal absorption of solutes and fluid are key events at the enterocytes. All reabsorption of fluid is iso-osmotic and follows solute reabsorption. Osmotic diarrhea is a consequence when indigestible lactose exerts osmotic pressure and interferes with the water transport from the lumen into the capillaries. The students can hopefully infer physiologically that at the intestinal capillaries, the balance of Starling's forces should also be pro-absorption.
Similarly, in uncontrolled diabetes mellitus with glucosuria, the nonreabsorbed glucose results in an osmotic diuresis and polyuria.
| Conversations between the Kidneys (Kiddo U) and the Digestive Tract (Gastro I)|| |
To add humor and enjoyment in understanding these cross-organ mechanisms in gastro-renal physiology, here are a few happy homeostatic conversations between them [Figure 5].
Kiddo: We have many things in common
Gastro: No Kidding!
Gastro: I control the amount of chyme leaving to begin the long-enteric journey
Kiddo: Well I do something similar called autoregulation of GFR before the filtrate starts a long-nephronic journey.
Gastro: Everyday I do a lot of water recycling for my digestive juices
Kiddo: Without your effort and my countercurrent responsibility, the body will be water deprived.
Kiddo: I can't get more acidic than 4
Gastro: I can and that's only because I have a special protective barrier
Gastro: We both have the same catalysts in our homes
Kiddo: Yes, Carbo Nick and Hydrase
Kiddo: Lack of oxygen always stimulates me
Gastro: That's a bloody response by your erythropoietin. I also have a crucial intrinsic factor for my red-faced colleagues.
Kiddo: You have the same epithelial set up to sweeten your blood
Gastro: Yes, we share the same SOP, and you don't want to sweeten your urine!
Gastro: Your peritubular capillary don't obey classical Starling's forces
Kiddo: Speak for yourself. We both have the same needs to absorb so we have to modify Starling's general protocol.
Kiddo: My bladder and your tummy bag are very accommodative.
Gastro: Better be. Or “all you can eat” buffer will not be popular and it will be inconvenient for you to be incontinent.
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Conflicts of interest
There are no conflicts of interest.
| References|| |
Rayner CK, Horowitz M. New management approaches for gastroparesis. Nat Clin Pract Gastroenterol Hepatol 2005;2:454-62.
Berne RM, Levy MN, Koeppen BM, Stanton BA. Physiology. 5th
ed. St. Louis: Mosby, Elsevier Science; 2004.
Fox SI. Human Physiology. 12th
ed. New York: The McGrawHill Companies; 2011.
Bhattarai KR, Junjappa R, Handigund M, Kim HR, Chae HJ. The imprint of salivary secretion in autoimmune disorders and related pathological conditions. Autoimmun Rev 2018;17:376-90.
Silverthorn DU. Human Physiology. An Integrated Approach. 6th
ed. Boston: Pearson Education; 2014.
Cheng HM, Jusof F. Defining Physiology: Principles, Themes, Concepts: Cardiovascular, Respiratory and Renal Physiology. Singapore: Springer Nature; 2018.
Cheng HM, Hoe SZ. Students' convoluted trouble with renal autoregulation: A teaching note for students and physiology educators. BLDE Univ J Health Sci 2016;1:25-7. [Full text]
Cheng HM. Intestinal absorption In: Cheng HM, editor. Physiology Question-Based Learning: Neurophysiology, Gastrointestinal and Endocrine Systems. Singapore: Springer 2016. p. 159-69.
[Figure 1], [Figure 2], [Figure 3], [Figure 4], [Figure 5]