Kidney

The facts In 24 hours the kidneys reclaim ~1,300 g of NaCl ~400 g NaHCO3 ~180 g glucose almost all of the180 liters of water that entered the tubules.

Homeostatic functions of the Kidney

Regulation of water and electrolyte balances Regulation of body fluid osmolarity and electrolyte concentrations Excretion of metabolic waste products and foreign chemicals Regulation of arterial pressure through excretion of varying amounts of sodium and water and secretion of substances, such as renin

Homeostatic functions of the Kidney

Regulation of acid-base balance through excretion of acids and regulation of body fluid buffer stores Regulation of erythrocyte production through secretion of erythropoietin Regulation of 1, 25-dihydroxy vitamin D3 production Synthesis of glucose from amino acids (gluconeogenesis) during prolonged fasting

Nephron Functional and structural unit Numbering to about 1 million in each kidney 2 types: 1) Cortical, 2) Juxtamedullary Composed of the following
1. 2.

Glomerulus tuft of glomerular capillaries Bowmans capsule capsule around the

3.

glomerulus Tubule site of filtered fluid converting into urine; subdivided into the following:

Nephron
1. 2.

3.

4. 5. 6.

7.

Proximal tubule lies in the outer portion of the kidney (cortex) Loop of Henle includes the descending and ascending limbs that dip into the inner part of the kidney (medulla) Loop of Henle includes the descending and ascending limbs that dip into the inner part of the kidney (medulla) Macula densa a plaque on the wall of the thick ascending limb Distal tubule lies in the renal cortex Connecting tubule, the cortical collecting tubule, and the cortical collecting ducts begin in the cortex and run downward into the medulla Medullary collecting ducts

Juxtamedullary nephrons

have glomeruli that lie deep in the renal cortex have long loops of Henle have long efferent arterioles extending from the glomeruli down into the outer medulla and divide into vasa recta

Renal Blood Flow

Constitutes 21% of cardiac output Renal aa interlobar aa arcuate aa interlobular aa (radial aa) afferent arterioles glomerular capillaries efferent arteriole peritubular capillaries intralobular v arcuate v interlobar v renal v Two capillary beds: 1) glomerular and, 2) peritubular The glomerular capillaries have high hydrostatic pressure (60mmHg) to allow rapid fluid filtration whereas the peritubular capillaries have lower hydrostatic pressure (13mmHg) for rapid fluid reabsorption Urine Formation a result of: 1) Glomerular filtration 2) Tubular absorption 3) Tubular secretion
Urinary excretion rate = Filtration rate Reabsorption rate + Secretion rate

TUBULAR PROCESSING OF THE GLOMERULAR FILTRATE

Basic Principles of Water and Solutes Transport Process of glomerular filtration and tubular reabsorption are quantitatively very large relative to urinary excretion for many substances Tubular reabsorption is highly selective by controlling the rate at which they reabsorb different substances, the kidneys regulate the excretion of solutes independently of one another, which is essential for precise control of the composition of body fluids There is a limit to the rate at which the solute can be transported (transport maximum) due to saturation of the specific transport systems involved when the amount of solute delivered to the tubule (tubular load) exceeds the capacity of the carrier proteins and specific enzymes involved in the transport process. The overall transport maximum for the kidneys is reached when all nephrons have reached their maximal capacity to reabsorb the solute.

TUBULAR PROCESSING OF THE GLOMERULAR FILTRATE

Routes

Transcellular route through the cell

membranes themselves. E.g. Na+ Paracellular route through the junctional spaces between the cells. E.g. Na+, H2O together with K+, Mg++ and Cl-

Mechanisms
1.

Active Transport 1. Primary

Solutes moving against and electrochemical gradient and requires energy transport coupled directly to an energy source as in hydrolysis of ATP bound to the membrane (Na+-K+ ATPase pump, Hydrogen ATPase, Hydrogen-K+ ATPase and Ca++ATPase). E.g. reabsorption of Na+ across the proximal tubular membrane

2.

Secondary

Transport uphill against a chemical gradient coupled indirectly to an energy source 2 or more substances interact with a specific membrane protein (a carrier molecule) and are co-transported together across the membrane and therefore does not required energy directly from ATP or from other high energy phosphate sources. E.g. reabsorption of glucose and amino acids in the proximal tubule

2.

Ultrafiltration

Mechanisms

through the peritubular capillary walls into the blood mediated by hydrostatic and colloid osmotic forces

3.

Passive Transport

aka Osmosis diffusion of H2O from a region of lower solute concentration (high [H2O] to one of high solute concentration (low [H2O]) reabsorption of water, most specially in the proximal tubules, is usually secondary to reabsorption of solute (Na+) from the tubules and the water will carry along with it Na+, K+, Cl-, Ca2+ and Mg2+ solvent drag
energy liberated from the downhill movement of one of the substances enables uphill movement of a second substance in the opposite direction e.g. active secretion of hydrogen ions coupled to Na+ reabsorption in the luminal membrane of the proximal tubule mediated by a specific protein in the brush border of the luminal surface

4.

Counter-Transport

5.

Pinocytosis

Mechanisms

reabsorption of large molecules (proteins) which first attach to the brush border of the luminal membrane that will invaginate to the interior of the cell until it is completely pinched off and a vesicle is formed the protein is digested into its constituent amino acids which are reabsorbed into the interstitial fluid it requires energy, therefore an active transport

6.

Gradient-time Transport

Substances that are passively reabsorbed do not demonstrate a transport maximum because their rate of transport is determined by other factors: the electrochemical gradient for diffusion of the substance across the membrane the permeability of the membrane for the substance the time that the fluid containing the substance remains within the tubule

Mechanisms

reabsorption of sodium in the proximal tubule is an actively transported substance that has characteristics of gradient-time transport

reabsorption of Cl- is coupled with the active reabsorption of Na+ by way of an electrical potential and a [Cl-] gradient it can also be reabsorbed by secondary active transport by the cotransport of Cl- with Na+ across the luminal membrane urea is passively reabsorbed from the tubule but only about 50% is reabsorbed due its lesser permeability creatinine is essentially impermeable to the tubular membrane Na+ is transported across the basolateral membrane against an electrochemical gradient by the Na+-K+ ATPase pump Na+ diffuses across the luminal membrane into the cell down an electrochemical gradient established by the Na+-K+ ATPase pump on the basolateral membrane Na+, H20 and other substances are reabsorbed from the interstitial fluid into the peritubular capillaries by ultrafiltration

REABSORPTION AND SECRETION ALONG THE NEPHRON

I. Proximal Tubules

1. Reabsorption

About 65% of the filtered load of Na+ and H2O and a slightly lowered percentage of Cl- are reabsorbed epithelial cells contain large mitochondria that can support active transport processes extensive brush borders and extensive labyrinth of intercellular and basal channels epithelial brush border contains protein carrier molecules in the first portion of the proximal tubules, Na+ is reabsorbed by cotransport along with glucose, amino acids and other solutes in the second portion, higher [Cl-] favors the diffusion of this ion from the tubule lumen through the intercellular junctions into the renal interstitial fluid

2. Secretion

important site for secretion of organic acids and bases such as bile salts, oxalate, urate and catecholamines drug metabolites secreted also are penicillin and salicylates about 90% of para-aminohippuric acid (PAH) from the plasma is secreted rapidly and therefore used as an index of renal plasma flow

II. Loop of Henle 3 functionally distinct segments

1.

REABSORPTION AND SECRETION ALONG THE NEPHRON

Descending Thin Segment

2.

Thick Ascending Segment

highly permeable to H2O and moderately permeable to most solutes including urea and Na+ main function is mainly to allow simple diffusion of substances through its walls thick epithelial cells with high metabolic activity and capable of active reabsorption of Na+, Cl-, and K+ made possible because of the Na+K+ ATPase pump considerable amounts of Ca2+, HCO3- and Mg2+ are also reabsorbed movement of Na+ across the luminal membrane is mediated 1oly by a 1-Na+, 2 Cl-, 1 K+ co-transporter it also has a Na+-H+ counter-transport mechanism in its luminal cell membrane

3.

Thin Ascending Segment

has a much lower reabsorptive capacity than the thick segment and the descending limb does not reabsorb significant amounts of any of these solutes

III. Early Distal Tubule the very first portion of the distal tubule forms part of the juxtaglomerular complex that provides feedback control of GFR and blood flow in this same nephron the next part is highly convoluted and has many of the same reabsorptive characteristics of the thick ascending segment of the loop of Henle reabsorbs most of the ions and virtually impermeable to H2O and urea, therefore also known as the diluting segment IV. Late Distal Tubule and Cortical Collecting Tubule both have similar functional characteristics 2 distinct cell types:
1.

Principal cells

2.

Intercalated cells

sodium reabsorption and potassium secretion depend on the activity of a Na+-K+ ATPase pump

H+ is secreted by mediation of the H+-ATPase transport mechanism H+ is generated by action of carbonic anhydrase on H20 and CO2 to form H2CO3 which then dissociates for each H+ secreted, a HCO3- will be available for reabsorption

V. Medullary Collecting Duct reabsorb <10% of the filtered H20 and Na+ final site for processing the urine and important in determining the final urine output of H20 and solutes made up of cuboidal cells with smooth surfaces and few mitochondria permeability to H20 is controlled by the level of ADH permeable to urea and some of the tubular urea is reabsorbed raising the osmolality in this region capable of secreting H+ against a large concentration gradient key role in regulating acid-base balance

REGULATION OF TUBULAR REABSORPTION

1.

Glomerulotubular Balance intrinsic ability of the tubules to increase their reabsorption rate in response to increased tubular load occurs in the glomeruli and the tubular segments especially the loop of Henle can occur independently of hormones helps prevent overloading of the distal tubular segments when GFR increases 2nd line of defense to buffer the effects of spontaneous changes in GFR on urine output

2.

Peritubular Capillary and Renal Interstitial Fluid Physical Forces hydrostatic and colloid osmotic forces govern the rate of reabsorption across the peritubular capillaries peritubular colloid osmotic pressure is determined by: 1. systemic plasma colloid osmotic pressure: increase the plasma protein concentration raise peritubular capillary colloid osmotic pressure increase reabsorption 2. filtration faction: the higher filtration fraction, the greater the fraction of plasma filtered through the glomerulus the more concentrated the protein becomes in the plasma that remains behind increase peritubular capillary reabsorption rate

2.

Peritubular Capillary and Renal Interstitial Fluid Physical Forces (contd) peritubular hydrostatic pressure is influenced by: 1. arterial pressure: increases in arterial pressure increase peritubular capillary hydrostatic pressure decrease reabsorption rate 2. resistances of the afferent and efferent arterioles: increase resistance of either reduces peritubular capillary hydrostatic pressures ultimately, changes in peritubular capillary physical forces influence tubular reabsorption by changing the physical forces in the renal interstitium surrounding the tubules a decrease in the reabsorptive forces across the peritubular capillary membranes reduces the uptake of fluid and solutes from the interstitium into the peritubular capillaries raises renal interstitial fluid hydrostatic pressure and decreases interstitial fluid colloid osmotic pressure because of dilution of the proteins in the renal interstitium

3.

Pressure-Naturiuresis and Pressure Diuresis Mechanisms small increases in arterial pressure often cause marked increases in urinary excretion of Na+ and H20 GFR autoregulation allows only a small increase of urine output under increased arterial pressure increased renal arterial pressure also decreases the percentage of filtered load of Na+ and H20 that is reabsorbed by the tubules resulting in part from increase in peritubular capillary hydrostatic pressure and subsequent increase in the renal interstitial fluid hydrostatic pressure when arterial pressure is increased, the secretion of Angiotensin II is decreased therefore sodium reabsorption is reduced and also secretion of ADH is reduced

4.

Sympathetic Nervous System Activation SNS activation decreases Na+ and H20 excretion by constricting both the afferent and efferent arterioles thereby reducing GFR increases also Na+ reabsorption in the proximal tubule and the thick ascending limb increases renin release and Angiotensin II formation

5.

Hormonal Control
1.

Aldosterone
Secreted by the zone glomerulosa (adrenal cortex) Important regulator of Na+ reabsorption and K+ secretion Primary site of action: principal cells of the cortical collecting tubules Stimulates the Na+-K+ ATPase pump on the basolateral side of the cortical collecting tubules Increases the Na+ permeability of the luminal side of the membrane

2.

Angiotensin II
Most powerful Na+ retaining hormone Increases in cases of low BP and/or low extracellular fluid volume

2.

Angiotensin II
3 main effects:
1. 2.

3.

Stimulates aldosterone secretion Na+ reabsorption Constricts the efferent arterioles which will reduce peritubular capillary hydrostatic pressure increases net tubular reabsorption. At the same time, it reduces renal blood flow raises filtration fraction in the glomerulus increases concentration of CHONs and the colloid osmotic pressure in the peritubular capillaries increases the reabsorptive force raises tubular reabsorption of Na+ and H2O Directly stimulates Na+ reabsorption, especially in the proximal tubules by stimulating the Na+-K+ ATPase pump on the basolateral membrane and the Na+-H2O exchange in the luminal membrane of the proximal tubules

3.

Antidiuretic hormone
Increases H2O permeability of the distal tubule, collecting tubule and collecting duct epithelia Plays a key role in controlling the dilution or concentration of the urine

4.

Atrial Natriuretic Peptide

Secreted when the cardiac atria is distended due to plasma volume expansion Inhibit the reabsorption of Na+ and H2O by the renal tubules especially in the collecting ducts

5.

Parathyroid hormone
Most important Ca+ regulator In the kidneys it increases tubular reabsorption of Ca+, especially in the thick ascending limb of the loop of Henle and in the distal tubule It also inhibits phosphate reabsorption by the proximal tubule Stimulates Mg++ reabsorption by the loop of Henle