Kidney Function• 1. Maintain proper water balance in the body.• 2. Regulate the concentrations of most ECF ions such as Na+, H+, K+, Cl-, HCO3-, Mg++, PO4--etc.• 3. Maintain the proper plasma volume and therefore helping to regulating blood pressure.• 4. Help maintain the proper acid-base balance of the body.• 5. Maintain the proper osmolality of body fluids.• 6. Excrete waste products of metabolism.• 7. Excrete many foreign compounds such as drugs, food additives etc.• 8. Secrete erythropoietin, the hormone that controls red blood cell production.• 9. Secrete renin, an enzyme which participates in regulation of Na+ levels and blood pressure.• 10. Convert vitamin D into its active form which helps us absorb calcium from our food. 17-3
Kidney Structure• Paired kidneys are on either side of vertebral column below diaphragm – About size of fist• Urine made in the kidneys pools into the renal pelvis, then down the ureter to the urinary bladder.• It passes from the bladder through the urethra to exit the body.• Urine is transported using peristalsis.
Kidney Structure• The kidney has two distinct regions: – Renal cortex – Renal medulla, made up of renal pyramids and columns• Each pyramid drains into a minor calyx major calyx renal pelvis.
Nephron Tubules• Glomerular (Bowman’s) capsule surrounds the glomerulus. Together, they make up the renal corpuscle.• Filtrate produced in renal corpuscle passes into the proximal convoluted tubule.• Next, fluid passes into the descending and ascending loop of Henle.
Nephron Tubules• After the loop of Henle, fluid passes into the distal convoluted tubule.• Finally, fluid passes into the collecting duct. – The fluid is now urine and will drain into a minor calyx.
Glomerular Corpuscle• Capillaries of the glomerulus are fenestrated. – Large pores allow water and solutes to leave but not blood cells and plasma proteins.• Fluid entering the glomerular capsule is called Ultrafiltrate
Glomerular Filtration continued• Filtrates must pass through: 3. Visceral layer of the glomerular capsule composed of cells called podocytes with extensions called pedicles 17-20
Ultrafiltrate• Fluid in glomerular capsule gets there via hydrostatic pressure of the blood, colloid osmotic pressure, and very permeable capillaries. Contains everything except formed elements and plasma proteins
Filtration Rates• Glomerular filtration rate (GFR): volume of filtrate produced by both kidneys each minute = 115−125 ml. – 180 ml/ day – Total blood volume filtered every 40 minutes – Most must be reabsorbed immediately
Regulation of Filtration Rate• Vasoconstriction or dilation of afferent arterioles changes filtration rate. – Extrinsic regulation via sympathetic nervous system – Intrinsic regulation via signals from the kidneys; called renal autoregulation
Sympathetic Nerve Effects• In a fight/flight reaction, there is vasoconstriction of the afferent arterioles. – Helps divert blood to heart and muscles – Urine formation decreases
Renal Autoregulation• GFR is maintained at a constant level even when blood pressure (BP) fluctuates greatly. – Afferent arterioles dilate if BP < 70. – Afferent arterioles constrict if BP > normal. Achieved via effects of locally produced chemicals on afferent arterioles
Reabsorption• 180 ml of water is filtered per day, but only 1−2 ml is excreted as urine. – This will increase when well hydrated and decrease when dehydrated. – A minimum 400 ml must be excreted to rid the body of wastes = obligatory water loss. – 85% of reabsorption occurs in the proximal tubules and descending loop of Henle.This portion is unregulated.
Active Transport• Cells of the proximal tubules are joined by tight junctions on the apical side (facing inside the tubule). – The apical side also contains microvilli. – These cells have a lower Na+ concentration than the filtrate inside the tubule due to Na+/K+ pumps on the basal side of the cells. – Na+ from the filtrate diffuses into these cells and is then pumped out the other side.
Mechanism of H20 and Chloride Reabsorption• Na+ is actively transported out of the filtrate into the peritubular blood to set up a concentration gradient to drive osmosis of H2O. Chloride moves by passive transport.
Proximal Tubular Fluid• The pumping of sodium into the interstitial space attracts negative Cl− out of the filtrate.• Water then follows Na+ and Cl− into the tubular cells and the interstitial space.• The increased concentration of salts and water diffuses into the peritubular capillaries.
Proximal Tubular Fluid• Reduced by 1/3 but still isosmotic – Plasma membrane is freely permeable to water and salts – Because both H2O and electrolytes are reabasorbed here in the same ratio, the tubular fluid stays isotonoic to blood
Significance of PCT Reabsorption• ≈65% Na+, Cl-, & H20 is reabsorbed in PCT & returned to bloodstream• An additional 20% is reabsorbed in descending loop of Henle• Thus 85% of filtered H20 & salt are reabsorbed early in tubule – This is constant & independent of hydration levels – Energy cost is 6% of calories consumed at rest – The remaining 15% is reabsorbed variably, depending on level of hydration 17-35
Secondary active transport in the Proximal Tubule• Glucose, amino acids, Ca++, etc. are reabsorbed in the proximal tubule by secondary active transport.
Glucose & Amino Acid Reabsorption• Filtered glucose & amino acids are normally 100% reabsorbed from filtrate – Occurs in PCT by carrier- mediated cotransport with Na+ • Transporter displays saturation if glucose & amino acids concentration in filtrate is too high – Level needed to saturate carriers & achieve maximum transport rate is transport maximum (Tm) – Glucose & amino acid transporters dont saturate under normal conditions 17-58
Glycosuria• Is presence of glucose in urine• Occurs when glucose > 180-200mg/100ml plasma (= renal plasma threshold) – Glucose is normally absent because plasma levels stay below this value – Hyperglycemia has to exceed renal plasma threshold – Diabetes mellitus occurs when hyperglycemia results in glycosuria 17-59
Renal Acid-Base Regulation• Kidneys help regulate blood pH by excreting H + &/or reabsorbing HC03-• Most H+ secretion occurs across walls of PCT in exchange for Na+ (Na+/H+ antiporter)• Normal urine is slightly acidic (pH = 5-7) because kidneys reabsorb almost all HC0 3- & excrete H+ 17-73
Reabsorption of HCO3- in PCT• Is indirect because apical membranes of PCT cells are impermeable to HCO3- 17-74
Reabsorption of HCO3- in PCT continued• When urine is acidic, HCO3- combines with H+ to form H2C03 (catalyzed by CA on apical membrane of PCT cells)• H2C03 dissociates into C02 + H2O• C02 diffuses into PCT cell & forms H2C03 (catalyzed by CA)• H2C03 splits into HCO3- & H+ ; HCO3- diffuses into blood 17-75
Concentration Gradient in Kidney• In order for H20 to be reabsorbed, interstitial fluid must be hypertonic• Osmolality of medulla interstitial fluid (1200- 1400 m O sm) is 4X that of cortex & plasma (300 m O sm) – This concentration gradient results largely from loop of Henle which allows interaction between descending & ascending limbs 17-36
Descending Limb LH• Is permeable to H20• Is impermeable to, & does not AT, salt• Because deep regions of medulla are 1400 mOsm, H20 diffuses out of filtrate until it equilibrates with interstitial fluid – This H20 is reabsorbed by capillaries 17-37
Ascending Limb LH• Has a thin segment in depths of medulla & thick part toward cortex• Impermeable to H20; permeable to salt; thick part ATs salt out of filtrate – AT of salt causes filtrate to become dilute (100 mOsm) by end of LH 17-38
Countercurrent Multiplier System• Countercurrent flow & proximity allow descending & ascending limbs of LH to interact in way that causes osmolality to build in medulla• Salt pumping in thick ascending part raises osmolality around descending limb, causing more H20 to diffuse out of filtrate – This raises osmolality of filtrate in descending limb which causes more concentrated filtrate to be delivered to ascending limb – As this concentrated filtrate is subjected to AT of salts, it causes even higher osmolality around descending limb (positive feedback) – Process repeats until equilibrium is reached when osmolality of medulla is 1400 17-41
Vasa Recta• Is important component of countercurrent multiplier• Permeable to salt, H20 (via aquaporins), & urea• Recirculates salt, trapping some in medulla interstitial fluid• Reabsorbs H20 coming out of descending limb• Descending section has urea transporters• Ascending section has fenestrated capillaries 17-42
Effects of Urea• Urea contributes to high osmolality in medulla – Deep region of collecting duct is permeable to urea & transports it 17-43
Collecting Duct (CD)• Plays important role in water conservation• Is impermeable to salt in medulla• Permeability to H20 depends on levels of ADH 17-45
Nephron sites of aquaporin (AQP) water channels (blue), ion transporters (black), and urea transporters (green) Schrier R W JASN 2006;17:1820-1832
ADH Fig 17.21• Is secreted by post pituitary in response to dehydration• Stimulates insertion of aquaporins (water channels) into plasma membrane of CD• When ADH is high, H20 is drawn out of CD by high osmolality of interstitial fluid – & reabsorbed by vasa recta 17-46
Electrolyte Balance• Kidneys regulate levels of Na+, K+, H+, HC03-, Cl-, & PO4-3 by matching excretion to ingestion• Control of plasma Na+ is important in regulation of blood volume & pressure• Control of plasma of K+ important in proper function of cardiac & skeletal muscles 17-61
Role of Aldosterone in Na+/K+ Balance• 90% filtered Na+ & K+ reabsorbed before DCT – Remaining is variably reabsorbed in DCT & cortical CD according to bodily needs • Regulated by aldosterone (controls K+ secretion & Na+ reabsorption) • In the absence of aldosterone, 80% of remaining Na+ is reabsorbed in DCT & cortical CD • When aldosterone is high all remaining Na+ is reabsorbed 17-62
K+ Secretion• Is only way K+ ends up in urine• Is directed by aldosterone & occurs in DCT & cortical CD – High K+ or Na+ will increase aldosterone & K+ secretion 17-63
Juxtaglomerular Apparatus (JGA)• Is specialized region in each nephron where afferent arteriole comes in contact with thick ascending limb LH 17-64
Renin-Angiotensin-Aldosterone System• Is activated by release of renin from granular cells within afferent arteriole – Renin converts angiotensinogen to angiotensin I • Which is converted to Angio II by angiotensin-converting enzyme (ACE) in lungs • Angio II stimulates release of aldosterone 17-65
Regulation of Renin Secretion• Inadequate intake of NaCl always causes decreased blood volume – Because lower osmolality inhibits ADH, causing less H2O reabsorption – Low blood volume & renal blood flow stimulate renin release • Via direct effects of BP on granular cells & by Symp activity initiated by arterial baroreceptor reflex (see Fig 14.26) 17-66
Macula Densa• Is region of ascending limb in contact with afferent arteriole• Cells respond to levels of Na+ in filtrate – Inhibit renin secretion when Na+ levels are high – Causing less aldosterone secretion, more Na+ excretion 17-68
Hormonal Control of Kidney by Negative Feedback Circuits
Atrial Natriuretic Peptide (ANP)• Is produced by atria due to stretching of walls• Acts opposite to aldosterone• Stimulates salt & H20 excretion• Acts as an endogenous diuretic 17-70
Na , K , H , & HC03 + + + - Relationships 17-71
Na+, K+, & H+ Relationship• Na+ reabsorption in DCT & CD creates electrical gradient for H+ & K+ secretion Insert fig. 17.27• When extracellular H+ increases, H+ moves into cells causing K+ to diffuse out & vice versa – Hyperkalemia can cause acidosis• In severe acidosis, H+ is secreted at expense of K+ 17-72
Urinary Buffers• Nephron cannot produce urine with pH < 4.5• Excretes more H+ by buffering H+s with HPO4-2 or NH3 before excretion• Phosphate enters tubule during filtration• Ammonia produced in tubule by deaminating amino acids• Buffering reactions – HPO4-2 + H+ → H2PO4- – NH3 + H+ → NH4+ (ammonium ion) 17-76