PHYL1010 014 Renal Physiology - Bowers.PDF

Renal Physiology (PHYL1010) Andre S. Bowers, PhD Physiology Section, Dept. of Basic Medical Sciences UWI, Mona, Kingston 7 Objectives oOverview of the properties & function of the kidneys. oPhysiological function and significance of renal components. oGlomerular filtration. oFactors affecting GFR. o...

Renal Physiology (PHYL1010) Andre S. Bowers, PhD Physiology Section, Dept. of Basic Medical Sciences UWI, Mona, Kingston 7 Objectives oOverview of the properties & function of the kidneys. oPhysiological function and significance of renal components. oGlomerular filtration. oFactors affecting GFR. oReview & control mechanisms. Overview – anatomical properties o Paired, pea-shaped extraperitoneal organs located against the posterior abdominal wall: ✓just above waistline ✓10 – 13 cm length ✓one on either side of vertebral column: ▪ 12th thoracic & 3rd lumbar column ✓L x W x T: 12cm x 5cm x 2.5cm. ✓range 113 – 170 g. Overview - anatomical properties oRenal hilum: ✓concaved side has a depression where renal artery enters: ▪ renal vein ▪ ureter exit the kidney here o Kidney is convex at each extremity: ✓upper end is more medially positioned. oRight slightly lower than left. Overview - anatomical properties Overview- anatomy Positioning - urogenital system P. 602, fig. 24-1 Overview - properties oKidneys have excellent blood supply: ✓extremely high metabolic rate ✓extracts >10% of O2 from renal arterial flow ✓delivery dramatically supersedes need ✓ultrafiltration oProcess approx. 1700L/day: ✓1.5L to urine. oGoal: filter physio- essentials – Na+, K+, Ca2+, Mg2+ ✓reabsorption – back to source. ✓secretion – selective elimination. Overview - properties oRenal veins – from kidney to posterior vena cava. oKidneys process plasma by removing, and sometimes, by adding substances to it: ✓separate urea, mineral salts, toxins, and other waste products from the blood ✓conserving water, salts, and electrolytes. Properties – other functions oPerforms endocrine functions: ✓renin-angiotensin-aldosterone system: ▪ involves several organ-systems. ▪ volume & electrolyte control – blood pressure. oErythropoietin – blood cell production. oProstaglandins – constriction + dilatation; G-proteincoupled. oRenin – vasoconstrictor: ✓restores perfusion pressure. oCalcitriol Macro- and microscopic structure oMulti-lobular (approx. 18) structure: ✓comprised of functional units – nephron. oFiltration/reabsorption units – bidirectional flow of H2O, electrolytes & solutes. oNet movement determines: ✓electrolyte balance - osmolarity ✓vascular turgor pressure: ▪ rise or fall of the GFR. ▪ hormonally-mediated. Macro- and microscopic structure oTwo main components when cut longitudinally: ✓cortex ✓medulla o Cortex – the more superficial of the layers: ✓reddish-brown layer between renal capsule and renal pyramid (cortical arch) ✓extends between pyramids - renal column. ✓majority of the nephron is located here: ▪ glomeruli ▪ proximal tubules ▪ vascular network Macro- and microscopic structure oMedulla – radially-striated layer: ✓pelvis, blood vessels, nerves, adipose tissue, minor and major calyces, renal papillae, renal column. oMedulla – lightly-stained conical cell – pyramids. ✓pyramids are interspersed by renal columns (Bertini). ▪ pyramids terminate into - papillae. oPyramids correspond to cortical region – lobe. oHence, the no. of lobes present // no. papillae: ✓apex end in small openings: ▪ empty into collecting ducts. Macro- and microscopic structure oFunnel-shaped channeling segment – pelvis. ✓contains minor and major calyces (sing. calyx). ✓cup-like – drain cortical + medullary segments ✓exit to the - ureter. oElectrolyte & acid-base balance: ✓loop of Henle & collecting ducts ✓site of salt, H2O & urea absorption Macroscopic Renal covering oDense, elastic connective tissue sheath. oProtects against mechanical stress & infection: ✓susceptible to stress – pelvic, groin oSince extraperitoneal injury generally exclusive of peritoneal involvement. Renal covering o Tough fibrous capsule and a fat bi-layer which dampens mechanical stresses: ✓paranephric fat: ▪ superficial to fascia ✓renal fascia - fascia of Gerota: ▪ connective tissue ▪ encapsulates kidney + adrenal glands ✓perinephric (perirenal) fat: ▪ between capsule & fascia ✓renal capsule Renal covering Macroscopic structure o Renal Pyramid: ✓triangular shaped unit in the medulla. ✓houses the loop of Henle and collecting duct of the nephron. oRenal Column: ✓area between the pyramids, located in the medulla ✓used as recess for blood vessels Macroscopic structure oRenal Papillae: ✓tips of the renal pyramids ✓release urine into the calyces oRenal Calyces: ✓collecting sacs that surround the renal papillae ✓transport urine from renal papillae to renal pelvis oRenal Pelvis: ✓cavity which lies in the centre of the kidney and which extends into the ureter ✓collects urine from all of the calyces in the kidney Vascular supply oSolitary renal artery supplies kidneys. oBranches into 5 segmental smaller arteries: ✓enter via hilus. ✓these, in turn, branch into lobular arteries: ▪ supply upper, mid & lower regions. ✓which, then divides into interlobular: ▪ Junction of cortico-medullary junction. oAnd yet, more branching into the arcuate arteries: ✓semi-circular arch at upper ends of the pyramids. Vascular supply oThe kidneys receive roughly 1.2 L urine/min. oMost of this blood reaches cortex: ✓>10% reaches medulla. ✓approx. 1% to papillae. oAbnormally low perfusion and/or sympathetic innervation: ✓shunts to medullary regions. ✓lowers glomerular filtration. ✓maintains urine-concentrating functions. Arterial blood supply oFig 24-3; pg. 603. Frontal cross section Microscopic structure o Nephron: Functional unit responsible for actual blood purification and filtration: ✓total of about 2.5 million in the 2 kidneys. ✓each nephron consists of 2 functional components: ▪ tubular component (contains what will eventually become urine) ▪ vascular component (blood supply) o The mechanisms by which kidneys perform their functions include: ✓filtration ✓reabsorption ✓secretion The nephron o Urineferous tubules – refers to microstructures of the kidneys: ✓nephrons and collecting tubules. oTwo types of nephrons depending on locale: ✓cortical ✓medullary oCortical – 85%- responsible for Na+ absorption ✓loop of Henle transitions cortex The nephron ✓short, thick loops of Henle. ▪penetrates medulla superficially. oJuxtramedullary – 15% - for H2O absorption: ✓originates deep in cortex. ✓long, thin loops of Henle - extends depth of medulla. ✓deep LoH adept at H2O handling: ▪urine concentrating segment The Nephron The nephron oSupplied by 2 capillary systems – 1) glomerular 2) peritubular. oGlomerulus - high-pressure capillary network: ✓positioned between afferent & efferent arterioles. ✓renal arterioles are resistance vessels: ▪ Afferent – short wider-bored. ▪ Efferent – long w/ smaller lumen. ✓Clinical relevance: intra-glomerular pressures very high for capillary network: ▪ required for ultrafiltration – ‘primary filtrate’. ▪ selective impermeability restricts protein & haematological components. // Nephron - structures oAfferent Arteriole: ✓transport arterial blood to glomerulus for filtration oEfferent Arteriole: ✓transports filtered blood from glomerulus through the peritubular capillaries and to the kidney venous system The nephron oPrincipal components are: ✓renal corpuscle = Bowman capsule + Glomerulus ✓proximal convoluted tubule ✓DCT ✓Henle’s loop oThe main differences between the two types of nephrons are: ✓the length to which the loop of Henle extends into the kidney. ✓position of renal corpuscle ✓functions Nephron - structures oGlomerulus: ✓nonspecific filtration site for blood contents ✓product of the glomerulus – filtrate oBowman’s Capsule: ✓glomerulus enclosing sac ✓First repository for fluid to become urine ✓parietal & visceral layers Renal corpuscle o Dense capillary array, encased by a cup-like structure, the Bowman’s capsule: ✓glomerular filtrate/ultrafiltrate deposited here. ✓within Bowman’s space. oFed by afferent and exit through the efferent: ✓branch out as the peritubular capillaries. ✓throughout cortex + deep medullary regions. ✓all essential filtrate reabsorbed. Renal corpuscle oCapillary network + capsule – renal corpuscle: ✓Fluid passes from glomerulus to the Bowman’s space ❖Area between layers ✓glomerular filtrate – Ultrafiltrate. oFiltration layers + parietal Bowman’s : ✓parietal layer is not involved in filtration ✓mechanical support ✓Indeterminate – differentiate into podocytes (Bussolati B. et al, AM J Pathol, 2005) Filtration layers oTri-layered apparatus: 1. capillary endothelium 2. basement membrane 3. visceral layer of B.C. oThe endothelium is fenestrated: ✓larger pores than other endothelial layers ✓enables processing of most blood components ❖not macromolecules or blood cells oG.C. also have aquaporin transmembrane proteins: ✓facilitates rapid water transfer Basement membrane oBasement membrane: acellular macromolecular meshwork: ✓mucopolysaccharides (glycosaminoglycan) ✓collagen – principal structural connective tissue. ✓glycoprotein oPrincipal structural determinant of glomerular flow rate: ✓endothelium - variable porosity. ✓B.M. more tightly organized. ✓main barrier to blood cells. oA size-determined barrier to macro- transport. Glomerulus + visceral layer o Podocytes – visceral epithelial cells: ✓encircle glomerular capillaries, except at slits – filtration pore ✓along with the basement membrane prevent proteins getting into the tubular fluid: ▪ water, solutes and sugars pass oGlomerular disease – structural and functional: ✓blood in ultrafiltrate. ✓Transmembrane protein defect Renal Corpuscle (Malpighian body) Podocytes oModified epithelial cells – regulate filtration rate: ✓Pedicels - Pseudopod-like cytoplasmic projections ✓contractility/relaxation ✓hydrostatic pressure-related oEncapsulate the glomerular capillaries. oPseudopodia-like projections: ✓ interdigitate – open/close ✓nephrin – transmembrane ❖slit-diaphragm or pore ✓Actin-cytoskeleton destabilization - pathologic Slit-diaphragm oSites of filtration – filtration slits: ✓elongated empty spaces ✓about 25 nm wide ✓filtrate deposited in the Bowman’s space Visceral layer Filtration layers Mesangium oAnother type of glomerular cells. oMainly provide structural support to capillary network: ✓areas where endothelium & BM only partially encircle capillaries. ✓lie between tufts of capillary. ▪ prod. intercellular substance – covers BM-free areas of endothelium. ✓continuous with arteriolar smooth muscle cells. oAlso exhibit some degree of contractility: ✓glomerular blood flow regulation. Mesangium oBelieved to have phagocytic properties: ✓intercellular macromolecular elimination. oThe mesangium is a very isolated area in normally functioning kidneys. oAlso occur in the juxtaglomerular cells and in the vicinity of the efferent arteriole. oMesangial hyperplasia is seen in several glomerular pathologies. Tubular segments - Proximal tubule o Single-layer of epithelial cells + BM ✓variable structure – linked to function. o Proximal convoluted tubule (PCT): ✓highly coiled – leads to descending loop of Henle. ✓returns to renal corpuscle – distal tubule. ✓microvilli – resorption. ✓thick, constantly active segment of the nephron. ✓abundant mitochondria. o Reabsorbs most of the useful substances of the filtrate: sodium (65%), water (65%), bicarbonate (90%), chloride (50%), glucose (nearly 100%). o Proximal tubular exhibits isotonic reabsorption. Proximal tubule oThe primary site for elimination of drugs, waste and hydrogen ions. oHighly permeable to water. oWater balance linked to relative osmolarity on either side of the tubular segment. oRapid osmotic transport – the kinetics of H2O transport means the concentration gradient difference is always within a few miliosmoles. Proximal tubule oAlso secrete organic ions – generally metabolic waste: ✓oxalate ✓urate oDrug detoxification: ✓penicillin ✓morphine ✓aspirin oGenerally, the latter are plasma protein-bound – not readily removed: ✓renal filtration only removes a small fraction. Reabsorption and secretion Tubular secondary active transport Loop of Henle oThin descending + thin & thick ascending limbs/segments: ✓thin segment – few mitochondria. o Begins in cortex, receiving filtrate from the PCT: ✓extends into the medulla, returns to the cortex to the DCT. ✓thin part makes a hair-pin bend in the deeper plane of medulla. o Close association of two limbs: ✓opposite flow of filtrate and variable H2O permeability ▪ responsible for the counter-current multiplier mechanism. Loop of Henle Loop of Henle oMajor role in regulating urine conc.: ✓receives from PT – passes “salty” filtrate to next segment ✓maintains high osmolarity in deep medullary interstitium. ✓reabsorption non-isotonic: ▪ Na+Cl- exceeds H2O. Loop of Henle oThin descending limb: ✓part of the counter current multiplier ✓highly permeable to H2O ✓impermeable to solutes ✓some suggest variably so to Na+, Cl-, urea? ▪ conc. increases with loop descent ▪ highest osmolarity at bottom of loop. Loop of Henle o Thin ascending limb – diluting segment: ✓impermeable to H2O. ✓Molecular motor: actively transports Na+, K+, Cl-: ▪ Na+/K+ - 2Cl- cotransporter {secondary transport} ▪ basolateral Na+/K+-ATPase lowers intracellular Na+ conc. ▪ Ca2+, Mg2+ and others Loop of Henle ✓filtrate diluted: ▪ approx. 100 mOsm/kg H2O. relative to plasma - 85 mOsm/kg H2O. ✓hyperosmotic interstitium oThick ascending limb – thickened epithelial cells: ✓similar H2O permeability + transporters. Loop of Henle oReabsorbs 20 – 25% filtered load – Na+, K+ + Cl-: ✓transport leads to transmembrane potential: ▪ passive reabsorption of divalent cation – Ca2+ + Mg2+. ▪ loop diuretics – pump inhibitor. oClose association of two limbs: ✓opposite flow of filtrate and variable permeability to H2O underpins the counter-current multiplier mechanism. Counter-current multiplier Counter-current multiplier oAlthough continuous, can be envisaged as 2 independent processes – (1) conc. grad. generation + (2) fluid flow 1. Single effect – driven by Na+Cl- in ascending limb: ✓generates conc. grad. in interstitium ✓reabsorption in thick ascending is active: ❖creates a hypoosmotic tubular, but hyperosmotic interstitium ❖propels H2O passively out of descending LoH ❖proceeds until equilibrium is reached Counter-current multiplier 2. Fluid flow – urine production is a process: dynamic ✓recall, fluid within the ascending limb renders the surrounding interstitium hyperosmotic ✓ meanwhile, less conc. filtrate moving down the descending PT and LoH is attracted to the more conc filtrate at the bottom of the LoH ❖H2O attracted to the hyperosmotic surrounding intersitium: ❖partly conc.-dependent ❖Regardless, only structurally permeable to H2O ❖surrounding interstitium becomes more hypotonic Distal convoluted tubule o Distal tubule cells possess Na+ transporter protein - amiloride-sensitive epithelial Na+ channel (ENaC): ✓aldosterone can increase the abundance of ENaC channels at the cell surface, thereby stimulating Na+ reabsorption. o Simple cuboidal epithelium. o Macula densa – transitions the DCT and contacts the afferent arteriole of glomerulus. Distal convoluted tubule o Distal convoluted tubule (DCT): ✓variably active portion of the nephron ✓receives dilute fluid from the ascending limb of the loop of Henle ✓Ca2+ & pH: luminal – Na+-Ca2+ cotransporter basolateral – Na+/k+ antiporter Early distal convoluted tubule oBegins at juxta-glomerular complex. oDivided into the early and late segments. oEarly tubule – diluting segment: ✓relatively impermeable to H2O. ✓reabsorbs approx. 5% Na+/cl-. ✓luminal Na+/cl- symporter ✓ Gitelman Syndrome ✓basolateral Na+/K+-ATPase. oCa2+ reabsorption – 1ͦ segment for regulated uptake: ✓molecular motor - luminal Ca2+ channel + basolateral ATPase. ✓regulated by parathyroid hormone. EDCT LDCT oSimple cuboidal epithelium: ✓principal (light) cells ✓intercalated (dark) cells. oSmall fraction of solute reabsorption – regulated: ✓Na+, K+, H2O and Cl-. o Acid-base balance oCellular specialization (uniformity in others): ✓principal cells – reabsorbs H2O + Na+; excretes K+ ✓intercalated cells – reabsorbs K+; secretes H+ LDCT + Collecting tubules oLittle or no paracellular transport: ✓impermeable epithelium. oAldosterone – anti-diuresis promoting hormone: ✓increase basolateral Na+/K+-ATPase activity. ▪ Na+ reabsorbed into the interstitium. ✓increases luminal K+ secretion: ▪ maintain intracellular osmolarity. Principal cells oMolecular motor – Na+/K+-ATPase. ✓basolateral - low intracellular Na+ + high K+. ✓luminal – reabsorbs Na+ ; excretes K+ oPermeability shifts in response to ADH - increases osmotic potential. ✓Regulation – via transcellular channels - aquaporin: ❖Inactive state – sequestered to cytoplasm. ❖Active state – relocated to membrane (ADH-mediated) ❖Increased receptor recruitment Intercalated cells o Intercalated cells - adjust urinary pH by secreting either H+ or HCO3- ions. ✓also synthesizes atrial natriuretic peptide (ANP): ❖afferent arteriole relaxation ❖Reduces Na+ reabsorption oMolecular motor - luminal H+-ATPase & H+-K+ATPase. LDCT + Collecting tubules Glomerulus + Basement membrane (cs) oPeritubular capillaries: branch of the efferent arteriole: ✓extends throughout cortex and medulla: ❖all tubular segments lie in close proximity to an arm of the P.C. ❖allows rapid reabsorption from interstitium ✓low-pressure – adapted for interstitial reabsorption. ✓vasa recta – long, thin-walled, deep cortical P.C.: ❖looping – descending + ascending segments ❖serve juxtaglomerular complex ❖principal role is reabsorption of contents of the LoH Peritubular capillaries oAll H2O and solutes which passes nephronic membranes and back to renal interstitium. oCompletely passive – down electrochemical gradients. oNa+ and H2O reabsorption – Starling’s forces. Peritubular capillaries oVery high oncotic + low hydrostatic pressures: ✓solutes/ions moved to filtrate ✓pressure drop after passing (a)efferent arterioles oP. hydrostatic: pressure fall due to arteriolar resistance (R): ✓low systemic arterial press. + high arteriolar resistance = low hydrostatic. ✓pressure natriuresis – H2O + Na+ loss due to elevated arterial press oUnderlie conservation of H2O + Na+ transport into the capillaries: Other solutes transport generally linked secondarily to Na and H O. Peritubular capillaries oP. oncotic – pressure of blood from efferent: ✓filtration fraction – fraction sent to p. capillaries / fraction sent to efferent arteriole. ✓FF = GFR/ RBF o> efferent arteriole R = > hydrostatic press: ✓increases the vol. filtered to Bowman’s space. ✓> GFR Peritubular capillaries Transport maximum oUseful substances (c6H12O6) are readily transpored across the glomerulus. oThe maximum amount of solute/ion a transporter/transport system can reabsorb – transport maximum: ✓max. amt. reabsorbed by transport system per unit time. oA function of the no. of carrier proteins present: ✓enough to ensure total reabsorption of useful filtered substances. ✓prevents elimination in urine. Transport maximum oRenal or metabolic abnormality may cause loss of ‘useful’ substances - diabetes: ✓elevated blood glucose levels. ✓glomerular filtrate > than transport max. ✓urinary loss oFor glucose, transport max. is approx. 320 mg/min. Filtration Nephron - structures o Juxtaglomerular (JG) apparatus: ✓JG cells: secretes renin involved in blood pressure regulation – RAAS ✓Macula densa: specialized cell at transition to DCT assesses GFR by sensing Na+cl- Nephron - structures ✓Extraglomerular mesangial cell: wrap around blood vessels specialized smooth muscle cells near vascular pole of corpuscle blood pressure regulation The juxta-glomerular apparatus