Vanders Chapter 14.1-14.4 and Chapter 15.6 (liver and kidneys)

Renal Functions

• Kidneys regulate water concentration, inorganic ion composition, acid-base balance, and fluid volume of the internal environment.
• Kidneys excrete metabolic waste products like urea, uric acid, creatinine, and end products of hemoglobin breakdown into urine.
• Kidneys remove foreign chemicals and their metabolites.
• Kidneys synthesize glucose during prolonged fasting.
• Kidneys release hormones: erythropoietin, renin, and 1,25-dihydroxyvitamin D.

Kidney Structure and Urinary System

• Kidneys are retroperitoneal, located behind the peritoneum.
• Urine flows from kidneys through ureters to the bladder and then is eliminated via the urethra.
• Kidney consists of an outer renal cortex and an inner renal medulla.
• Kidney is divided into nephrons, each consisting of a renal corpuscle and a tubule.
• Renal corpuscle filters blood, producing a filtrate free of cells, larger polypeptides, and proteins.
• Tubule modifies the filtrate by adding or removing substances.
• Fluid at the end of each nephron combines in collecting ducts to form urine.

Renal Corpuscle

• Glomerulus, a tuft of interconnected capillary loops, is surrounded by Bowman's capsule.
• Afferent arteriole supplies blood to the glomerulus, and efferent arteriole carries blood away.
• About 20% of plasma filters into Bowman's capsule.
• Filtration barrier consists of three layers: (1) capillary endothelium, (2) basement membrane, and (3) podocyte foot processes.
• Mesangial cells surround glomerular capillary loops, their function is yet to be discussed.

Renal Tubule & Collecting Duct System

• Proximal tubule (consisting of the convoluted and straight tubule) drains Bowman's capsule.
• Loop of Henle is a hairpin-shaped loop with descending and ascending limbs.
• Distal convoluted tubule connects to the collecting-duct system (cortical and medullary collecting ducts).
• Collecting-duct system merges with other nephrons, ultimately draining urine into the renal pelvis through medullary collecting ducts.

Regional Differences in the Kidney

• Cortex contains all the renal corpuscles.
• Loops of Henle extend from the cortex into the medulla.
• Medullary collecting ducts pass through the medulla to the renal pelvis.
• Peritubular capillaries surround the tubule in the cortex.

Types of Nephrons

• Juxtamedullary nephrons have a renal corpuscle close to the cortical-medullary junction and long loops of Henle that penetrate deep into the medulla.
• Cortical nephrons have renal corpuscles in the outer cortex and short or absent loops of Henle.

Juxtaglomerular Apparatus (JGA)

• Ascending limb of each loop of Henle passes between the afferent and efferent arterioles.
• Macula densa is a patch of cells in the ascending limb.
• Juxtaglomerular (JG) cells are secretory cells in the afferent arteriole.
• JGA plays a role in regulating filtration rate. ### Basic Renal Processes
• Urine formation begins with the filtration of plasma from the glomerular capillaries into Bowman's space.
• The process is called glomerular filtration and the filtrate is called glomerular filtrate.
• The filtrate is cell-free and contains all substances except larger proteins in the same concentration as plasma.
• During its passage through the tubules, the filtrate's composition is altered by movements of substances from tubules to peritubular capillaries, and vice versa.
• Movements from tubular lumen to peritubular capillary plasma are called tubular reabsorption.
• Movements in the opposite direction are called tubular secretion.
• Tubular secretion can also denote the movement of a solute from the cell interior to the lumen in the cases when the kidney tubular cells themselves generate the substance.
•  A substance can gain entry to the tubule and be excreted in the urine by glomerular filtration or tubular secretion or both.
• The amount of any substance excreted in the urine is equal to the amount filtered plus the amount secreted minus the amount reabsorbed.
•  Not all processes—filtration, secretion, and reabsorption—apply to all substances. 
•  Important solutes like glucose are completely reabsorbed, whereas most toxins are secreted and not reabsorbed.
• About 20% of the plasma that enters the glomerular capillaries is filtered into Bowman's space.
•  This filtrate, which contains X, Y, and Z in the same concentrations as in the capillary plasma, enters the proximal tubule and begins to flow through the rest of the tubule.
• Assume that the tubule can secrete 100% of peritubular capillary substance X into the tubular lumen but cannot reabsorb X.
• The plasma that originally entered the renal artery is cleared of all of its substance X, which leaves the body via the urine.
• Assume that the tubule can reabsorb but not secrete Y and Z.
• The amount of Y reabsorption is moderate so that some of the filtered material is not reabsorbed and escapes from the body.
• For Z, however, the reabsorptive mechanism is so powerful that all the filtered Z is reabsorbed back into the plasma.
• Therefore, no Z is lost from the body.
• A specific combination of filtration, tubular reabsorption, and tubular secretion applies to each substance in the plasma.
• The rates at which these processes proceed are subject to physiological control.
• By triggering changes in the rates of filtration, reabsorption, or secretion whenever the amount of a substance in the body is higher or lower than the normal limits, homeostatic mechanisms can regulate the substance’s bodily balance.
•  It is important to stress that not all these processes—filtration, secretion, and reabsorption—apply to all substances. 
•  Important solutes like glucose are completely reabsorbed, whereas most toxins are secreted and not reabsorbed. 

### Glomerular Filtration 

• Glomerular filtrate—that is, the fluid in Bowman’s space—normally contains no cells but contains all plasma substances except proteins in virtually the same concentrations as in plasma.
•  The filtration pathways in the corpuscular membranes are negatively charged, so they oppose the movement of these plasma proteins, most of which are also negatively charged.
•  The only exceptions to the generalization that all nonprotein plasma substances have the same concentrations in the glomerular filtrate as in the plasma are certain low-molecular-weight substances that would otherwise be filterable but are bound to plasma proteins and therefore not filtered. 

### Forces Involved in Filtration 

• Filtration across capillaries is determined by opposing Starling forces.
• The glomerular capillary hydrostatic pressure (PGC) is a force favoring filtration.
• The fluid in Bowman's space exerts a hydrostatic pressure (PBS) that opposes this filtration.
• Another opposing force is the osmotic force (πGC) that results from the presence of protein in the glomerular capillary plasma.
•  The osmotic force in Bowman’s space (πBS) is zero.

### Rate of Glomerular Filtration 

• The volume of fluid filtered from the glomeruli into Bowman’s space per unit time is known as the glomerular filtration rate (GFR).
• GFR is determined not only by the net filtration pressure but also by the permeability of the corpuscular membranes and  the surface area available for filtration.
•  The glomerular capillaries are much more permeable to fluid than most other capillaries. 
• The net glomerular filtration pressure causes massive filtration of fluid into Bowman's space.
• In a 70 kg person, the GFR averages 180 L/day (125 mL/min).
• The kidneys filter the entire plasma volume about 60 times a day.

### Tubular Reabsorption 

• There are at least three important conclusions we can draw from this table:
  • The filtered loads are enormous, generally larger than the total amounts of the substances in the body.
  • Reabsorption of waste products is relatively incomplete (as in the case of urea), so that large fractions of their filtered loads are excreted in the urine.
  • Reabsorption of most useful plasma components, such as water, inorganic ions, and organic nutrients, is relatively complete so that the amounts excreted in the urine are very small fractions of their filtered loads.
•  An important distinction should be made between reabsorptive processes that can be controlled physiologically and those that cannot.
•  The kidneys do not regulate the plasma concentrations of these organic nutrients. Rather, the kidneys merely maintain whatever plasma concentrations already exist.
•  The kidneys have powerful mechanisms to reclaim useful substances from tubular fluid while simultaneously allowing waste products to be excreted.
•  If water intake is decreased, the kidneys can increase water reabsorption to minimize water loss. 

Tubular Reabsorption

• Tubular reabsorption moves substances from the tubular lumen to interstitial fluid.
• This process does not occur by bulk flow due to insufficient pressure differences and limited permeability of tubular membranes.
• Two processes are involved: diffusion and mediated transport.
• Diffusion: reabsorption of substances across tight junctions connecting tubular epithelial cells.
• Mediated Transport: involves transport proteins in the plasma membranes of tubular cells.
• Final step in reabsorption is the movement of substances from the interstitial fluid into peritubular capillaries via diffusion and bulk flow.

Reabsorption by Diffusion

• Urea reabsorbed by the proximal tubule is an example of passive reabsorption by diffusion.
• Water reabsorption in the proximal tubule increases urea concentration in the tubular fluid, creating a concentration gradient.
• Urea diffuses down this gradient from the tubular lumen to the peritubular capillary.

Reabsorption by Mediated Transport

• Many solutes are reabsorbed by primary or secondary active transport.
• Transcellular epithelial transport: substances cross the apical membrane, diffuse through the cytosol, and cross the basolateral membrane.
• Sodium (Na+) moves passively into the cell across the apical membrane and is actively transported out of the cell across the basolateral membrane via Na+/K+-ATPases.
• Reabsorption of many substances is coupled to Na+ reabsorption.
• Cotransport: substances move uphill into the cell as Na+ moves downhill via the same cotransporter. This is how glucose, amino acids, and other organic substances are reabsorbed.
• Transport Maximum (Tm): mediated-transport-reabsorptive systems have a limit to the amount of material they can transport per unit time.
• Glucose: reabsorption is limited by Tm. When plasma glucose exceeds the threshold, glucose starts to appear in urine (glucosuria).
• Hyperglycemia: high filtered load of glucose can lead to glucosuria and diabetic nephropathy.

Tubular Secretion

• Tubular secretion moves substances from peritubular capillaries into the tubular lumen.
• Important secreted substances: H+, K+, organic anions, and foreign chemicals.
• Active secretion: requires active transport from the blood side into the tubule cell or from the cell into the lumen.
• Secretion increases the ability of the kidneys to dispose of substances.

Metabolism by the Tubules

• Renal tubules synthesize glucose during fasting and can catabolize certain organic substances.

Regulation of Membrane Channels and Transporters

• Activity or concentrations of the membrane channel and transporter proteins involved in reabsorption or secretion are physiologically controlled.
• This regulation is achieved by hormones and paracrine or autocrine factors.

Small Intestine Anatomy

• The small intestine has a complex structure that maximizes surface area for digestion and absorption.
• Circular folds: surface area specializations of the mucosa and submucosa.
• Villi: fingerlike projections covering the circular folds.
• Microvilli (brush border): small projections on the surface membranes of epithelial cells covering each villus.
• Goblet cells: secrete mucus to lubricate and protect the intestinal wall.
• Lacteal: a single, blind-ended lymphatic vessel in the center of each villus.
• Capillary network: also present in the center of each villus.

Small Intestine Segments

• Duodenum: initial, short segment.
• Jejunum: intermediate segment.
• Ileum: longest segment.

Small Intestine Secretion

• Secretions: approximately 1500 mL of fluid secreted daily from the blood into the lumen.
• Mineral ions: Na+, Cl−, and HCO 3 − are secreted into the lumen, followed by water by osmosis.
• Osmotic gradient: enhanced by the hypertonic chyme entering from the stomach.
• Secretions lubricate the intestinal surface and protect epithelial cells.

Pancreatic Secretions

• Exocrine pancreas: secretes HCO 3 − and digestive enzymes into the duodenum.
• Acinar cells: secrete enzymes.
• Pancreatic duct cells: secrete HCO 3 − to neutralize the acidity of chyme.
• CFTR: cystic fibrosis transmembrane conductance regulator, involved in chloride recycling and water movement into the duct lumen.
• Zymogens: inactive forms of proteolytic enzymes secreted by the pancreas.

Liver Secretion

• Liver: secretes bile into the duodenum.
• Gallbladder: stores bile between meals.
• Sphincter of Oddi: controls bile flow into the duodenum.

Pancreas

• The pancreas has both endocrine and exocrine functions
• The exocrine pancreas secretes digestive enzymes and bicarbonate, while the endocrine pancreas secretes hormones like insulin and glucagon
• Acinar cells in the pancreas secrete digestive enzymes
• Duct cells in the pancreas secrete bicarbonate
• The pancreatic duct system connects the pancreas to the duodenum, allowing for the delivery of digestive secretions

Pancreatic Enzyme Secretion

• Pancreatic enzymes are secreted in inactive forms, such as trypsinogen, chymotrypsinogen, and procarboxypeptidase
• Trypsinogen is activated by enteropeptidase, a brush border enzyme found in the small intestine
• Once activated, trypsin activates other pancreatic enzymes
• Pancreatic enzyme secretion is stimulated by hormones like cholecystokinin (CCK) and secretin

Bile

• Bile is produced by the liver
• Bile contains bile salts, cholesterol, phospholipids, bicarbonate, and bile pigments
• Bile salts are crucial for fat digestion and absorption
• The liver synthesizes and secretes bile salts
• Bile is concentrated and stored in the gallbladder

Bile Secretion

• Bile secretion is stimulated by secretin
• Bile salts are absorbed in the ileum and recycled via the enterohepatic circulation
• The liver also secretes cholesterol into bile

Gallbladder

• The gallbladder stores and concentrates bile
• Contraction of the gallbladder is stimulated by CCK
• The sphincter of Oddi controls the flow of bile into the duodenum

Carbohydrate Digestion

• Salivary amylase begins carbohydrate digestion in the mouth, but pancreatic amylase is the primary enzyme in the small intestine
• Pancreatic amylase breaks down starch into maltose and short glucose chains
• Brush border enzymes, such as lactase, sucrase, and maltase, further break down disaccharides into monosaccharides (glucose, fructose, galactose)
• Monosaccharides are then absorbed into the bloodstream through the small intestine

Protein Digestion

• Pepsin begins protein digestion in the stomach
• Pancreatic proteases, including trypsin and chymotrypsin, continue protein breakdown in the small intestine
• Brush border enzymes like aminopeptidases and carboxypeptidases help break down peptides into amino acids
• Most amino acids are absorbed by secondary active transport

Fat Digestion

• Fat digestion mainly occurs in the small intestine

• Pancreatic lipase breaks down triglycerides into monoglycerides and free fatty acids

• Bile salts solubilize fats, forming micelles for easier absorption

• Micelles facilitate the absorption of fatty acids and monoglycerides

• Lipid absorption involves the formation of chylomicrons, which enter the lymphatic system and eventually the bloodstream### Protein Digestion and Absorption

• Protein digestion begins in the stomach with the help of pepsin, a protease enzyme.

• In the small intestine, pancreatic proteases, like trypsin and chymotrypsin, further break down proteins into smaller peptides and amino acids.

• Amino acids are absorbed into the intestinal epithelial cells through cotransport with Na+ across the apical membrane.

• Amino acids then cross the basolateral membrane by facilitated diffusion using specific transporters.

• Once in the interstitial fluid, amino acids diffuse into the blood through capillary pores.

• Na+/K+-ATPase pumps on the basolateral membrane provide energy for the whole process.

Fat Digestion and Absorption

• Fats are insoluble in water and form large droplets in the stomach.
• Pancreatic lipase, a water-soluble enzyme, digests fats only at the surface of droplets, making digestion slow due to a low surface-area-to-volume ratio.
• Emulsification process breaks down large fat droplets into smaller ones, greatly increasing the surface area for lipase action. This is achieved by mechanical mixing and the presence of emulsifying agents such as phospholipids from food and bile salts from the liver.
• Phospholipids and bile salts are amphipathic, meaning they have both polar and nonpolar parts. Their nonpolar parts interact with the lipid droplets, while the polar parts face the watery environment, preventing reaggregation of droplets.
• Colipase, a protein secreted by the pancreas, binds lipase to the surface of lipid droplets, further enhancing digestion.
• Bile salts also form micelles, tiny aggregates of bile salts, fatty acids, monoglycerides, and phospholipids. Micelles keep fat digestion products in solution, allowing continued digestion and absorption.
• Fatty acids and monoglycerides diffuse across the apical plasma membrane into intestinal epithelial cells.
• Inside the cells, fatty acids and monoglycerides are resynthesized into triglycerides in the smooth endoplasmic reticulum, which maintains a gradient favoring absorption from the lumen.
• Newly formed triglycerides aggregate into droplets covered by amphipathic proteins and are packaged into chylomicrons, which exit the cell by exocytosis into the interstitial fluid.
• Chylomicrons, being too large to enter blood capillaries, enter the lacteals, lymphatic vessels in the intestinal villi.
• Chylomicrons travel through the lymphatic system and eventually reach the bloodstream, delivering lipids and fat-soluble vitamins to body cells.

Vitamin Absorption

• Fat-soluble vitamins (A, D, E, and K) are solubilized in micelles and follow the pathway for fat absorption.
• Water-soluble vitamins are absorbed by diffusion or mediated transport, except vitamin B12.
• Vitamin B12, a large charged molecule, requires intrinsic factor, secreted by parietal cells in the stomach, for absorption.
• Intrinsic factor-bound vitamin B12 binds to specific sites in the lower ileum, where it is absorbed by endocytosis.

Water and Mineral Absorption

• Approximately 80% of the ingested and secreted water (around 8000 mL) is absorbed in the small intestine.
• The small intestine is highly permeable to water, and net water diffusion occurs due to the active absorption of solutes.
• Na+ is the primary actively transported solute, driven by Na+/K+-ATPase pumps.
• Cl- and HCO3- are absorbed with Na+, further contributing to the osmotic gradient for water absorption.
• Other minerals, such as K+, Mg2+, PO43-, and Ca2+, are also absorbed along with trace elements like Fe, Zn, and I.

Iron Absorption

• Iron is essential for hemoglobin and many enzymes.
• About 10% of ingested iron is absorbed each day.
• Iron ions are actively transported into intestinal epithelial cells, where most bind to ferritin, an intracellular iron storage protein.
• Unbound iron is released into the blood, binding to transferrin, a plasma protein.
• Iron absorption is regulated by body iron stores. High iron levels lead to increased ferritin synthesis, reducing iron release into the blood. Conversely, low iron stores reduce ferritin production, increasing iron release.
• Excess iron intake can overwhelm homeostatic mechanisms, leading to hemochromatosis, a condition with toxic effects.
• Iron absorption is influenced by food types. For example, iron in liver is more readily absorbed than iron in egg yolk, due to phosphate binding in egg yolk.

Nutrient Transport Pathways

• Fats and fat-soluble nutrients enter the lymphatic system through lacteals.
• All other absorbed nutrients enter the bloodstream through capillaries.
• Venous drainage from the intestines, pancreas, and parts of the stomach passes through the hepatic portal vein into the liver before entering the general circulation. This allows the liver to process nutrients before they reach other body organs.
• This portal system also carries pancreatic hormones insulin and glucagon to the liver for regulating nutrient metabolism.

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