RENALPHYSIOLOGY

HOMEOSTASIS AND THE INTERNAL ENVIRONMENT

• The cells of each organ of the body exist and function in an internal fluid environment - the extracellular fluid (ECF), which remains relatively constant despite wide fluctuations in our external environment.

• This concept was first set forth by the French physiologist Claude Bernard in 1857.

HOMEOSTASIS AND THE INTERNAL ENVIRONMENT

• The American physiologist Walter Cannon further developed these concepts and coined the term homeostasis to describe the constancy of composition and volume of the internal environment.

• Maintaining the homeostatic state of the organism, with regard to both its volume and composition, is the primary function of the kidney.

HOMEOSTASIS

To maintain homeostasis with regard to any constituent of the body,

its input, the amount of that substance ingested or generated metabolically

must be exactly balanced by its output, the amount of that substance excreted or metabolically destroyed. When input equals output the system is in balance.

TOPOGRAPHY • Each kidney has a concave

surface containing a slit called the hilus, allowing access to the renal sinus.

• Kidneys are normally supplied by a single renal artery branching from the abdominal aorta, and entering the kidney through the hilus.

• Also entering the kidney through the hilus are the renal sympathetic nerves which arise from the celiac ganglia.

• The ureter, the renal vein and renal lymphatics exit through the renal hilus.

INTERNAL STRUCTURE • If the kidney is bisected, a lighter

outer region, the cortex, and a darker inner region, the medulla, are seen.

• The medulla is divided into 8 to 16 conical structures called renal pyramids. The base of each pyramid is at the interface between the cortex and medulla, and the apex of each pyramid forms a papilla that extends into the renal pelvis.

• Each papilla contains approximately 25 small holes representing the distal ends of the collecting ducts which drain into the renal pelvis which empties into the ureter.

MAJOR ARTERIES• The renal arteries arise from the

abdominal aorta. Within the renal sinus they divide approximately eight times to become the segmental or lobar arteries.The segmental arteries give rise to the interlobar arteries which ascend between the pyramids toward the cortex.

• At the junction of the cortex and the medulla, they curve over the renal pyramids of the medulla to form the arcuate arteries from which arise the interlobular arteries.

• The interlobular arteries give rise to the afferent arteriolar supply to the glomeruli.

AFFERENT ARTERIOLES

• The afferent arterioles arise from interlobular arteries extending into the cortex from the arcuate arteries.

• The capillaries of the renal glomerulus are supplied with blood by the afferent arterioles.

• Approximately 20% of the plasma perfusing the afferent arteriole, including water, electrolytes, and other small molecules, but excluding protein, are filtered through the glomerulus.

GLOMERULAR CAPILLARIES

• Within the glomerular capillary blood pressure is about 55 mm Hg (approximately double the pressure in most other capillaries).

• The glomerular capillary bed is that it is situated between two arterioles (not between an arteriole and a venule as in other capillary beds).

• The high glomerular capillary pressure is due to the resistance afforded by the efferent arterioles. Because this pressure is always greater than the pressure in Bowman’s space, only filtration occurs.

• Fluid flow through the glomerular capillary membrane is unidirectional with no associated reabsorption by the capillaries.

EFFERENT ARTERIOLES & PERITUBULAR CAPILLARIES

• 80% of the plasma entering the glomerulus along with molecules too large to be filtered (proteins and protein bound substances) leave the glomerulus via the efferent arterioles.

• In the renal cortex the efferent arterioles of the glomeruli of cortical nephrons give rise to a peritubular capillary bed supplying the renal tubules of the cortical nephrons.

• A major function of the peritubular capillaries is to carry away in the renal veins water and solutes reabsorbed by the tubular epithelium.

• These peritubular capillaries also deliver blood to tubular secretory sites where certain substances are secreted from the plasma into the tubular fluid.

EFFERENT ARTERIOLES & PERITUBULAR CAPILLARIES

• The efferent arterioles of the juxtamedullary nephrons give rise to two different capillary beds. The glomeruli of these nephrons are located at the junction of the cortical and medullary regions of the kidney. They have long loops of Henle which extend deep into the renal medulla.

• One branch of their efferent arteriole gives rise to a peritubular capillary network which envelops the proximal and distal convoluted tubules.

• A second branch of the juxtamedullary efferent arteriole parallels the long loops of Henle extending deep into the medulla where they divide repeatedly into vascular bundles which form the vasa recta. The vasa recta are composed of the descending (arterial) limbs which gives rise to a capillary network that envelopes the loops of Henle and the collecting ducts. These medullary capillary beds drain into the ascending (venous) limb of the vasa recta.

THE NEPHRON• The nephron is the basic

functional unit of the kidney. Each kidney contains approximately 1 million nephrons, and each nephron has the ability to transport water and solutes and to produce urine.

• The nephron consists of a glomerulus and the renal tubule to which it is attached.

• The renal tubule may be divided by functional and histological criteria into the proximal convoluted tubule, the proximal straight tubule (pars recta), the loop of Henle, the juxtaglomerular apparatus (JGA), the distal convoluted tubule, the connecting tubule, and the collecting duct.

GLOMERULUS, BOWMAN’S CAPSULE & MESANGIUM

• The glomerulus is a ball of capillary loops that are surrounded by the blind end of the renal tubule called Bowman’s capsule.

• Between the loops are mesangial cells which together with the surrounding matrix form the mesangium. The mesangium contains myofilaments that resemble smooth muscle.

• The contractile nature of the mesangium permits it to function as a regulator of glomerular filtration by altering the capillary surface area available for filtration.

GLOMERULAR CAPILLARIES

• The basal lamina of the glomerular capillaries are lined by endothelial cells that contain pores or fenestrations of ~0.1 mm in diameter

• On the outer surface of the glomerular capillaries, in the space between the capillary loops and Bowman’s capsule, there are epithelial cells called podocytes.

• The interdigitation of the projections creates 25 nm wide slit pores. The slit pores play a role in restricting filtration of large molecules.

GLOMERULAR CAPILLARIES

• The combined barrier of the endothelial cells, basal lamina, and epithelial cells create a filtration apparatus.

• Water and neutral substances of less than 3.0 nm in diameter pass freely. The filtration rate for larger molecules decreases progressively with increasing size.

• Due to the negative charge in the slit pores anions are less permeant than cations of equal weight and size.

PROXIMAL TUBULE, PARS CONVOLUTA & PARS RECTA

• The outer basement membrane of Bowman’s capsule is continuous with the basement membrane of the remainder of the renal tubule.

• The portion of the tubule directly adjacent to Bowman’s capsule is the proximal convoluted tubule, (pars convoluta).

• The proximal convoluted tubule winds randomly within the cortex, and then straightens to become the proximal straight tubule, (pars recta), as it turns and descends into the medulla.

LOOP OF HENLE • Henle’s loop consists of a thin

descending limb (a thin ascending limb characterized by a thin flat squamus epithelial cell) and a thick ascending limb with somewhat taller squamous epithelial cells.

• The thin limb begins at the end of the pars recta, descends into the medulla, makes a hairpin turn becoming the thin ascending limb which parallels the course of the descending limb back towards the cortex.

LOOP OF HENLE It is necessary to distinguish between three types of nephrons:

• Superficial cortical nephrons have glomeruli located in the outermost cortex, have short loops of Henle extending only a short way into the medulla, and lack thin ascending limbs.

• Mid cortical nephrons have glomeruli located between the superficial and the juxtamedullary nephrons, and may have short or long loops of Henle.

• Juxtamedullary nephrons have glomeruli located in the cortex just above the junction of cortex and medulla and all have long loops of Henle which descend deep into the medulla.

LOOP OF HENLE

• The thin descending limb is water permeable and relatively impermeant to solutes.

• Both thin and thick ascending limbs are impermeable to water.

• The thin ascending limb is permeable to solutes and the thick ascending limb has a high capability for active salt reabsorption.

• The loop of Henle and the closely associated vasa recta play a critical role in the mechanism for urinary concentration or dilution.

JUXTAGLOMERULAR APPARATUS

• The juxtaglomerular apparatus (JGA), located in the renal cortex, is a unique segment of the nephron where the thick ascending limb of the loop of Henle passes between the afferent and efferent arterioles of its own glomerulus.

• The macula densa is the specialized area of the thick ascending limb which makes contact with the vascular elements of the JGA.

• The vascular elements of the JGA contain modified smooth muscle cells of the arterioles which contain secretory granules that synthesize and secrete the enzyme renin.

• A second group of JGA cells or extraglomerular mesangial cells, are not granular but also secrete renin.

JUXTAGLOMERULAR APPARATUS

The JGA plays a major role in the renin-angiotensin-aldosterone system.

• One theory holds that the macula densa senses changes in the Na+ or Cl- concentration and changes the rate of renin secretion.

• A second theory states that renin secretion is controlled by changes in volume and stretch of the afferent arteriole.

• The JGA has also been implicated in the autoregulation of GFR.

DISTAL CONVOLUTED TUBULE & CONNECTING TUBULE

• The distal convoluted tubule begins at the end of the macula densa. It has short epithelial cells with highly invaginated basal membranes. It empties into the connecting tubule which in turn drains to the cortical collecting duct.

• Both the distal convoluted tubule and the connecting tubule contain a few apical microvilli on each cell, but no distinct brush border as in the proximal tubule.

• With regard to permeability and transport these segments are similar in most respects to the thick ascending limb of Henle’s loop.

COLLECTING DUCT

• The collecting duct is divided into the cortical collecting duct, the medullary collecting duct, and the papillary collecting duct, based on location.

• The epithelial cells of the cortical collecting duct are cuboidal shaped and become progressively more elongated toward the papillary collecting duct.

COLLECTING DUCT

• The collecting duct cells are of two types: 1. The intercalated cells are involved primarily in acidification of the urine and regulation of acid base balance. 2. The principal cells are involved mainly with sodium reabsorption and have a major role in sodium balance and regulation of ECF volume. The sodium transport activity of these cells is controlled by aldosterone.

• The water permeability of the collecting duct is variable depending on the level of ADH activity and so plays a role in regulation of body fluid osmolarity

FUNCTIONS OF THE KIDNEY

The primary function of the kidney to maintain homeostasis in the extracellular environment (ECF) includes:

A. the regulation of sodium balance and extracellular fluid

volume and its all important sub-compartment, the blood volume;

B. the regulation of water balance and body fluid osmolarity; C. the regulation of body fluid hydrogen ion concentration;D. the regulation of electrolytes such as potassium, calcium,

phosphate, magnesium, chloride, bicarbonate, etc.;E. the conservation of essential nutrients such as glucose and

amino acids;F. the excretion of metabolic end products and foreign matter; G. the secretion of the hormones, renin, 1,25-dihydroxy

vitamin D3 and erythropoietin.

MECHANISMS OF RENAL FUNCTION

• The kidney’s work involves transferring continuously from the blood to the renal tubule a portion of the plasma water and its solutes. About 180 L of fluid, about 32 times the blood volume, enter the renal tubules each day.

• The renal tubule modifies the tubular fluid and returns about 98 to 99 % of it to the body as a fluid whose composition and volume is ideal for sustaining normal body functions.

• Only that which is not useful, potentially harmful or present in excess of the body’s needs escapes into the urine.

FILTRATION PROCESS

• The process begins with glomerular filtration which is the ultrafiltration (formation of a protein free filtrate) of plasma across the glomerular membrane.

• Only a portion of the blood plasma delivered to the kidney via the renal artery is filtered.

• The plasma which escapes filtration, along with its protein and the cellular elements of the blood, perfuses the tubular capillary beds and is collected in the renal venous effluent.

• The filtration process is driven by the glomerular capillary blood pressure.

• In the average adult the entire ECF volume is filtered about 12 times per day.

REABSORPTION

• The filtrate flows from Bowman’s space into the tubule and reabsorption of solutes and water from the renal tubule returns to the renal veins an ideal fluid with regard to composition and volume.

• In addition to reabsorption some substances are also secreted, that is transported into the renal tubule from the blood which perfuses the nephron.

TRANSPORTED SUBSTANCES

• Some substances are transported across the tubular epithelium against their concentration gradients by active mechanisms which require energy derived, directly or indirectly, from cellular metabolism.

• Other substances are transported by passive mechanisms, moving down their concentration gradients.

• The tubular fluid which is not reabsorbed contains a variety of metabolic waste substances, foreign substances and physiological substances which are in excess of that required for homeostasis.

• This volume, normally only a very small fraction of the original filtrate, is delivered to the bladder and excreted as urine.

FILTRATION, REABSORPTION AND SECRETION

The quantitative relations among renal plasma flow (RPF), glomerular filtration rate (GFR), fluid reabsorption rate, and urine output are illustrated in the figure.

TRANSFER BETWEEN ICF AND ECF

• The distribution of Na+ and K+ between ICF and ECF is due to the presence in all cell membranes of a metabolically fueled (primary active transport) pump that transfers from the ICF to the ECF the small amount of Na+ that leaks into the cell.

• The same pump transfers from ECF to ICF the small amount of K+ that leaks out of the cell.

• In most cells this pump (the Na+,K+-ATPase) is distributed uniformly throughout the cell membrane.

PRIMARY ROLE OF SODIUM TRANSPORT

Of particular importance in renal function is the restriction of the primary active transport of sodium to the basolateral membrane of the renal tubular epithelial cell. This asymmetrical distribution of sodium pump activity results in the unidirectional, reabsorptive, transport of sodium across the renal tubular epithelium.

PRIMARY ROLE OF SODIUM TRANSPORT

• Under some circumstances a portion of the reabsorbed sodium may diffuse back into the tubule but the net transport is always from the tubular lumen to the renal ISF.

• In the renal tubule this process is responsible for sodium reabsorption from the filtrate which establishes an osmotic gradient for water reabsorption and also indirectly provides the energy for the secondary active transport of other substances.

CONTROL OF SALT AND WATER EXCRETION

Marked functional differences exist along the nephron.

• In the proximal tubule water and solute reabsorption are tightly coupled.

• In the distal portions of the nephron, however, there exist mechanisms which permit the separate control of salt and water reabsorption allowing the kidney to regulate independently the transport of these substances thus enabling the kidney to respond appropriately to a specific excess or deficit of one or the other.

CONTROL OF SALT AND WATER EXCRETION

Because sodium and its associated anions form by far the greatest proportion of osmotically active solute in the extracellular fluid, and because it is restricted to the extracellular fluid compartment, the degree to which it is reabsorbed from the tubule and carries water with it determines the extracellular fluid volume and therefore the blood volume.

CONSERVATION AND EXCRETION VS. REPLACEMENT

• The kidney functions to excrete substances which are present in excess of that required for homeostasis or to conserve those which are present in less than the required amount.

• The kidney itself does not replace material that has been lost from the body. Salt or water deficits, such as are incurred by perspiration, respiration, or via stool or urine must be replenished by ingestion from the external environment and absorption by the gastrointestinal tract.

• There is one important exception to this rule. The kidney plays a major role in regulation of acid base balance and does regenerate bicarbonate ion which is lost from the ECF in the process of buffering strong acid.

RENAL REGULATION OF OTHER SUBSTRATES

• A variety of substances in addition to sodium are also filtered through the glomerulus and transported across the renal epithelium.

• The plasma concentrations of these substances are determined by the balance between filtration, tubular transport and urinary excretion.

• The basic mechanisms for these processes are inherent in the kidney but their level of activity can be modified by a variety of neural and hormonal influences.

RENAL REGULATION OF OTHER SUBSTRATES

Examples are:• antidiuretic hormone (ADH)

which regulates distal nephron water transport

• atrial natriuretic peptide (ANP) which enhances sodium excretion

• aldosterone which stimulates sodium reabsorption and potassium secretion

• parathyroid hormone (PTH) and 1,25-dihydroxyvitamin D3 which play a role in calcium and phosphate transport.

WASTE EXCRETION

• The kidney is responsible for the removal from the blood of metabolic waste products such as urea, uric acid, creatinine and other end products of normal metabolism, and of foreign substances such as drugs, pesticides and other toxic agents.

• This function is accomplished by the complete or partial failure to reabsorb these substances from the filtrate or by their secretion from the blood into the tubules.

• Creatinine, an end product of muscle metabolism, is of particular interest because its urinary excretion rate and its blood plasma concentration can be used to quantify renal function and therefore to serve as a diagnostic indictor of renal disease.

RENAL GLUCONEOGENESIS

• Gluconeogenesis, the synthesis of glucose from amino acids and other precursors, occurs in the kidney.

• Under normal conditions this is a minor function but during prolonged fasting the kidney can become a major source of blood glucose producing about one fifth as much glucose as the liver.

• Organic nutrients such as glucose and amino acids are normally maximally conserved by the kidney. They are actively reabsorbed against steep concentration gradients and normally their urinary excretion is essentially zero.

RENAL HORMONE SECRETION: RENIN

Renin plays a primary role in initiating the cascade of events resulting in secretion of the hormone aldosterone. It is secreted mainly by the kidney. The primary stimulus for renin secretion is a decrease in arterial blood pressure which is usually associated with a decrease in ECF and blood volume.

RENAL HORMONE SECRETION: RENIN

Renin is a proteolytic enzyme which acts on angiotensinogen (a plasma protein of hepatic origin) to produce the angiotensin I. Angiotensin I is in turn acted upon by angiotensin-converting enzyme (ACE) found on the epithelial surface of blood vessels in most tissues (particularly of the pulmonary vessels). ACE acts on angiotensin I to produce the highly active peptide angiotensin II which: 1. stimulates the adrenal cortex to secrete aldosterone which causes sodium, and therefore water retention by the kidney thus playing a major role in maintenance of blood volume and blood pressure 2. is a potent vasoconstrictor and functions directly in the control of blood pressure

RENAL HORMONE SECRETION: ERYTHROPOIETIN

• Erythropoietin is a peptide hormone produced primarily in the kidney in response to a decrease in the partial pressure of oxygen in renal tissue.

• It acts on bone marrow to stimulate erythrocyte production.

• Decreased synthesis of erythropoietin is a cause of the anemia of chronic renal disease.

RENAL HORMONE SECRETION: 1,25-DIHYDROXYVITAMIN D3

1,25-dihydroxyvitamin D3 is the active form of vitamin D. It is synthesized in the kidney from its hepatic precursor 25-dihydroxyvitamin D3 and plays a major role in the regulation of calcium, affecting gastrointestinal absorption of calcium, bone resorption, and renal tubular reabsorption of both calcium and phosphate.

I thankall of youfor your patience!