Kidney Function & Control

Kidney Function & Control

1. Kidney Overview

   • NEPRHONS
     • Structure
       • Cortical and juxtamedullary nephrons
       • URINE
         • 5. COLLECTING DUCT = many nephrons join via collecting ducts. Collecting ducts under hormonal control > conc/dilute urine). Benefit from salty interstition set up by Loop of Henle.
           • 4. DISTAL CONV TUBULE = less absorption but fine tuning.
             • 3. Descends into MEDULLA > LOOP OF HENLE (thin desc (TDL) & thick asc limb (TAL) - membrane thickness). Sets up osmotic gradient - gets saltier along medulla - for further H2O to be absorbed later on.
               • 2. PROXIMAL CONV TUBULE = requires most energy for transport here (high blood supply & mitochon). Most modification of filtrate & secretion dealt with here.
                 • Hilum = Provided with O2, nutrients. VAN
                 • 1. INTERLOBAL ARTERY > afferent arteriole > GLOMERULUS* > efferent arteriole *Small ball of capillaries. Filtration of proteins > plasma-free filtrate into renal corpuscle.
                   • Flitration of plasma > Reabsorption of H2O and solutes > Secretion of solutes > Urine
       • Renal Corpuscle
         • X-section through glomerulus and Bowman’s capsule
           • Juxtaglomerular apparatus (structures near glomerulus) & RENIN (regulates BP in CVS)
             • Macula densa cells detect BP and ionic composition via blood flow. Juxtaglomerular cells secrete RENIN in response to vBP & ionic composition
               • Angiotensin I > Angiotensin II > BP restored
                 • *This helps us to determine GFR (Glomerular Filtration Rate)
     • Each human kidney consists of ~1 million nephrons, each ~5cm long. 50km to Swindon!
       • 180L of fluid filtered by kidneys each day (enough to fill bath!)
   • FUNCTIONS
     • Excretion of NITROGENOUS WASTE products eg. UREA & CREATININE
     • Body fluid regulation (ECF)
       • ION CONCS - see proportions above
         • Also glucose & amino acids
       • Body WATER VOLUME/OSMOLALITY (~285 mosmol/kg)
         • produces hypotonic, isotonic or hypertonic urine depending on condition of body
       • Arterial pH
     • HORMONES eg. RENIN, ERYTHROPOETIN, 1,25-DIHYDROXYVITAMIN D3
     • ie. HOMEOSTASIS!
   • HORMONES
     • Vit D
     • ERYTHROPOETIN
       • Kidney = ~80% of EPO production in the body. (Liver can also detect low O2 > erythropoesis)
       • Low O2 due to: CO poisoning, anaemia, haemorrhage, altitude, resp disease
         • Stimulates bone marrow progenitor cells > Erythrocytes
     • RENIN
       • Juxtaglomerular apparatus (structures near glomerulus) & RENIN (regulates BP in CVS)

2. Filtration - GLOMERULUS

   • 24 hours: 180L plasma filtered, 1.5L urine produced.
   • RATE ~90-125ml/min (BOTH kidneys) - MUCH higher than urine output ~1ml/min
     • High rate favoured by: High HYDROSTATIC PRESSURE in glomerular capillaries. FENESTRAE in glomerular capillaries.
     • No energy expenditure by kidney. All by beating of heart.
   • Some AUTOREGULATION in isolated kidneys but varies IN VIVO (eg. hypotension, exercise, renal nervous input, hormones)
     • Autoregulation meaning: relative independence from systemic blood pressure of renal blood flow and GFR (afferent & efferent arterioles protected)
   • FILTRATE = no cells, traces of protein, ions/small organic substances - ie. same as plasma but no proteins/RBCs
     • Depends on MOLECULAR WEIGHT (favours lighter), SHAPE (favours spherical over long, thin molecules), ELEC CHARGE ( +ve > neutral > -ve)
       • eg. Hb has bigger MR than Albumen but +ve charge, as opposed to -ve charge, so is allowed through
     • Reabsorption into PERITUBULAR CAPILLARY BED or VASA RECTA
       • Peritubular capillary bed (from efferent arteriole). Filtration fraction = 20:80 (20% through, 80% stays in blood)
         • Vasa Recta (from efferent arteriole) (drains into renal venules/vein)
     • RENAL CLEARANCE
       • = rate at which substance removed from blood plasma
         • affected by filtration at glomerulus AND reabsorption/secretion along nephron
         • Freely filtered and no reabsorption or secretion: clearance = GFR (good kidney health) If reabsorbed = LOW clearance. If secreted = HIGH clearance.
       • Glomerular Filtration Rate (GFR)
         • Starling's Forces
           • NB. KS = Filtration Coefficient. Where K = permeability of glomerular barrier S = surface area available for filtration
             • complete kidney failure/removal of kidney will affect this
             • Hydrostatic & Oncotic Pressure Changes during glomerular filtration
         • How to measure - Need to use a substance (X) that is freely filtered at glomerulus but not secreted/reabsorbed
           • eg. if 100% glucose is reabsorbed, clearance = 0 Some drugs clearance = up to 600ml/min

3. Tubular Reabsorption

   • Blood leaving via Peritubular capillary bed/Vasa recta favours the reabsorption of SALTS & H2O:
     • Low HYDROSTATIC PRESSURE in capillary. High ONCOTIC PRESSURE. High HAEMATOCRIT > slow blood flow.
     • Can be PARAcellular transport (passive, through tight junctions) OR TRANScellular transport (through cells, requires right transporters)
   • PROXIMAL TUBULE
     • Tubular lumen has BRUSH BORDER MICROVILLI and is ONE CELL THICK. Capillary bed is wrapped around.
     • Longest segment of nephron (15mm). Split into PARS CONVOLUTA and PARS RECTA
     • Many mitochondria for Active Transport
     • Reabsorbs 60-70% of glomerular filtrate
     • Reabsorption is ISOSMOTiC (~300mosm/kg in tubular fluid)
     • Virtually no hormonal control - largely unregulated. Major driving force for reabsorption is low intracellular Na+ AND carrier molecules on apical membrane
     • Glomerular capillaries filter INTO the proximal tubule:
     • Na+
       • Na+ mostly via 2o AT. Mostly in exchange for H+. Driven by IONIC GRADIENTS across apical membrane and ATPase in basolateral membrane.
     • K+
       • K+ mostly via PARAcellular route passively DOWN IONIC GRADIENT.
       • Ca2+ via TRANScellular and PARAcellular routes passively DOWN IONIC GRADIENT.
       • & Ca2+
     • Glucose
       • Against conc grad via 2o AT. Dependent on Na+ gradient on apical membrane. Facilitated diffusion on basolateral membrane. When transport maximum (Tm) is reached excess is excreted in urine (diabetes).
       • & AA's
     • H2O
       • Down OSMOTIC GRADIENT (follows mvmt of solutes). TRANScellular on apical and basolateral membranes via AQUAPORINS. PARAcellular via gap junctions. *Also in LoH, distal tubule, collecting duct.
     • HCO3-
       • & H+
       • HCO3- combines with H+ for INDIRECT reabsorption in presence of CARBONIC ANHYDRASE.
         • In distal tubule, new HCO3- is formed and H+ secreted via buffers (PO3- & NH3) > urine usually acidic. Hormones and drugs also secreted.
   • LOOP OF HENLE (Salty Interstition)
     • Tubular fluid entering LoH is same conc/ISOtonic (300mosmol/kg) to plasma. leaving LoH is more dilute/HYPOtonic (100mosmol/kg). urine is more conc/HYPERtonic (1200mosmol/kg)
     • Osmotic gradient in renal medulla. Set up by LoH (countercurrent multiplier). Longer LoH creates larger osmotic grad > more conc urine (eg. dry habitat animals)
       • Urine Concentrating Mechanism
       • NaCL in interstition increases as move up TAL. More dilute inside tubule.
         • *Urea also moves out of collecting duct, and back into TAL (makes collecting duct even more dilute inside)
           • < urea* <
         • TAL walls = APICAL Na+/K+/2Cl- co-transporter & BASOLATERAL Na-pump
           • About 20% of the filtered Na+, K+ and Cl- is reabsorbed.
       • Thick Ascending Limb (TAL) > salty intersition
     • Countercurrent Exchange in Vasa Recta
       • osmolarity of blood does not change so medulla can be supplied to nutrients but doesn’t impact on salty interstition
   • DISTAL NEPHRON
     • = Distal conv tubule + Cortical AND Medullary portions of collecting duct
       • . Receives less than 20% of glomerular filtrate. Fine tuning - volume, composition (acc. to dietary intake). K+ reabsorption in deficiency / K+ secretion in hyperkalaemia. Aldosterone acts here for H+ and K+ secretion (H+K+ATPase).

4. CONTROL

   • Plasma Osmolality
     • NB. ‘OsmolaRity refers to the number of solute particles per 1L of solvent, whereas osmolaLity is the number of solute particles in 1kg of solvent’. Units: osm.kg-1 solvent
     • THIRST and URINE conc/vol are the only things we can control physiologically
     • Understand terms iso/hypo/hypertonic > cells shrink/burst.
     • NORMAL plasma osmolality (Posm): 290 mosmol.kg-1. Variation by only 1% (±3 mosmol.kg-1) > compensatory mechanisms
     • Negative Feedback Mechanism Summary (THIRST & URINE)
       • THIRST
       • URINE
       • If we had to wait for change in osmolality to be detected, we would keep drinking to excess. Therefore, we have a short-term feedback mech to SFO (subfornical organ), MnPO (median preoptic nucleus), OVLT (organum vasculosum laminae terminalis)
     • COLLECTING DUCT
       • If wall of COLLECTING DUCT was impermeable to H2O > LARGE vol of DILUTE urine If wall of COLLECTING DUCT made permeable to H2O > SMALL vol of CONC urine
         • LOOP DIURETICS > LARGE vol of DILUTE urine. eg. frusemide, bumetamide - block Na+/K+/2Cl- co-transporter in TAL
           • TAL walls = APICAL Na+/K+/2Cl- co-transporter & BASOLATERAL Na-pump
         • ADH > SMALL vol of CONC urine
           • ^ H2O permeability of CD
             • ^ urea permeability in medullary part of CD
               • ^ NaCl reabsorption in TAL
                 • As ADH increases, urine osmolality increases (more concentrated), and urine flow decreases
             • ADH binds to receptor on BL membrane > stimulates adenylyl cyclase > cAMP > protein kinases > INSERTION OF AQUAPORINS in CD WALL
           • ADH aka 'vasopressin/AVP' produced by POSTERIOR PITUITARY
             • (also has vasoconstriction and cerebral function - suppress fear)
             • "8-arginine vasopressin" to distinguish it from ADH produced by non-humans
             • Produced in SUPRAOPTIC and PARAVENTRICULAR nuclei neurones > Axon terminals in post pituitary > Blood
               • VERY sensitive - released by only tiny increase in plasma osmolality. Reduced when osmolality falls (less sucking of H2O). Half-life 10/15mins - removed by liver & kidneys.
               • PROBLEM WITH ADH = DIABETES INSIPIDUS. Lack action of ADH on the CD > large vol dilute urine (24L/day!) > polyuria & excessive thirst
                 • Do water deprivation test to distinguish these.
                 • Urine urine osmolality is LOW, but plasma osmolality is NORMAL - this could be because urine output is being matched with drinking.
   • Blood Volume
     • Starling's Law - HYPOvolaemia > vCardiac filling (preload) > vSV vCO vBP HYPERvolaemia (too much Na+ in Western diet) > ^Cardiac filling (preload) ^SV ^CO ^BP
       • Kidneys control this as regulate Na+ (and therefore H2O excretion)
     • HYPOvolaemia
       • KIDNEYS and BARORECEPTORS working on their own in first 2 stages. Stage 3 baroreceptors working overtime! Needing external support in Stage 3 & 4.
         • NB. OLIGuria = reduced urine Anuria = no urine
       • Responses - Kidneys & Baroreceptors
         • Renin-angiotensin-aldosterone RAAS System for HYPOVOLAEMIA
           • JUXTAGLOMERULAR CELLS synthesise, store, release RENIN after signals from MACULA DENSA cells
           • Substrate = Angiotensinogen (produced by liver)
             • Product = ANGIOTENSIN I
               • ANGIOTENSIN II
                 • Angiotensin converting enzyme (ACE) in lung
                   • (Why ACE inhibitor drugs restore BP)
                 • Vasoconstriction
                 • ADH release (H2O retention)
                 • ALDOSTERONE release from adrenal cortex (^Na+ reabsorption by nephron)
                   • Steroid hormone secreted by zona glomerulosa of adrenal glands.
                     • Steroid hormones alter output of genome > sustained & slow response (told to drink slowly after giving blood)
                     • Aldosterone binds to basolateral receptor in distal tubule/CD > transcription of APICAL Epithelial Na+ Channels (ENaC) AND ^mitochondria. Increases Na+ reabsorption - Cl- and H2O follow.
                       • Aldosterone also facilitates K+ secretion into distal tubular fluid > regulates plasma K+
                         • ie. adrenocortical dysfunction (inc. increased or decreased aldosterone secretion) has important consequences on Na+ and K+ regulation and hence on CVS/renal function.
             • Proteolytic enzyme = RENIN (breaks off last 10 aa's).
     • HYPERvolaemia = too high Na+. So Na+ removed in urine "natriuresis"
       • Hypervolaemia ^ECV
         • Atrial stretch (sensors in cardiac atria and pulmonary vasculature)
           • Atrial Natriuretic Peptide (ANP) released (opposite action to aldosterone)
             • Inhibits Aldosterone secretion
             • Vasodilation ^GFR
             • Inhibits Renin secretion
             • Inhibits ADH release
   • Arterial pH
     • • HENDERSON HASSELBALCH EQUATION (simplified from pH=pK + log [A-]/[HA])
       • CO2
         • If rate of CO2 production by tissues is constant, HYPERventilation must lead to hypocapnia, HYPOventilation must lead to hypercapnia [Ref range = 4.67 – 6.0 kPa]
       • HCO3-
         • Why bicarbonate (HCO3-) buffer important? High conc of its pair in plasma. Resp system can 'blow off' additional CO2 to help buffer system. New [HCO3-] that is lost in buffering is REGENERATED by DistConvTub of kidney.
           • REABSORPTION of filtered HCO3-
             • 99.9% is reabsorbed in the ProxConvTub. Little change in pH of tubular fluid (no net secretion of H+). ^HCO3- (due to pathology) above reabsorption limit = lost in urine.
               • Increased by:
                 • vECF volume (sometimes due to RAAH system)
                 • Increased PaCO2 (provides more CO2 for conversion to HCO3-)
           • REGENERATION of NEW HCO3-
             • Collecting Duct - NH3 (lipid soluble so diffuses into distal tubule) + H+ > NH4+ (not-lipid soluble so trapped and excreted. Causes one new HCO3-.
               • Proximal Tubule - Glutamine metabolised > new HCO3- (associated with Ammonium (NH4+) excretion). In chronic acidosis the enzymes involved (in NH3 synthesis) are increased to ^H+ ions
                 • NB. HYPERkalaemia inhibits synthesis of NH3 and reduces excretion of H+ > METABOLIC ACIDOSIS HYPOkalaemia stimulates synthesis of NH3 and increases excretion of H+
             • Distal Nephron - by α Intercalated Cells
               • H+ ATPase H+-K+ ATPase on luminal membrane
                 • H+ secreted into the lumen is buffered by HPO42- For each H+ secreted into lumen (titratable acid) one NEW HCO3- is added to blood to help replace that lost to buffering
                 • (Explains why pH is linked to K+)
     • Acids & Bases
       • Where does acid in body come from?
         • Carbonic Acid = volatile acid. End product of AEROBIC METABOLISM (when CO2 from Kreb's dissolved in H2O). Most CO2 (13-20mmol/day) removed by ventilation, some remains in plasma.
         • Sulphuric & Phosphoric acid = fixed acids. Generated by CATABOLISM of aa's, phospholipids, nucleic acids. Can only be excreted by kidneys (0.1mmol/day).
         • HCl = into stomach by GASTRIC PARIETAL CELLS. Also HCO3- into gastric venous blood "alkaline tide". Beyond pylorus, gut fluids have ^HCO3- and venous blood leaving has ^H+
       • pH
         • pH = -log [H+]
           • As H+ increases, pH decreases. Log means HUGE range of H+ concs shown on pH scale 1-14 ie. Small change in pH can be huge [H+] change!
             • Buffer reduces this shock by absorbing/releasing H+. In the body, buffer is HCO3-.
         • Why regulate arterial pH? ENZYME STRUCTURE & PUMPS impaired • ACIDOSIS can vCARDIAC CONTRACTILITY & cause ARRHYTHMIAS • Other cations (Ca2+ & K+) can cause NEUROLOGICAL & CARDIAC DAMAGE
       • Acid = proton donor, Base = proton acceptor > conjugate acid/base
         • Strong acids completely dissociate (HCl), Weak acids partially dissociate in equilibrium
           • eg. lactic acid --> lactate (conj base) + H+
             • eg. carbonic acid H2CO3 --> bicarbonate HCO3- (conj base) + H+
     • ABGs / Acid-Base Disturbances
       • CASE STUDY PRACTICE:&nbsp; https://www.ole.bris.ac.uk/bbcswebdav/pid-3792943-dt-content-rid-14165373_4/xid-14165373_4
       • 'Respiratory' = PaCO2 change 'Metabolic' = [HCO3-] change 'Simple' = 1 A-B disorder 'Complex' = >1 A-B disorder
       • Chronic vs Acute (chronic involves compensation so smaller disturbances in pH state)
         • Acute = mins/hrs eg. pneumonia, pulm oedema, PE Chronic = months/yrs eg. COPD
       • Anion Gap
         • Look at anion balance when there is a pathological fall in [HCO3-] (metabolic acidosis). Spaces CANNOT physically happen so must be a reason…
           • OR 'INCREASED anion gap metabolic acidosis'
             • Rise in Cl- ions? 'Hyperchloraemic metabolic acidosis w. NORMAL anion gap'
               • K+ REGULATION
                 • Most K+ is in ICF. Tomatoes/Bananas rich in K+. We should have 50-150mMol/day.
                   • Necc for excitable tissues - nerve & muscle. The K+ gradient across the cell membrane determines the resting membrane potential. Efflux of K+ drives the repolarisation phase of the act pot.
                 • Amount absorbed by gut should be balanced by amount excreted by kidney (aldosterone regulates this BUT affected by pH)
                   • HYPERkalaemia - K+ from ICF into ECF. Can be due to kidney failure (aldosterone)
                     • Insulin deficiency (eg. diabetic ketoacidosis)
                     • B2 adrenoceptor antagonist (B-blocker)
                     • Acidosis
                     • Hyperosmolarity of ECF (we don't know why)
                     • Exercise
                     • Cell lysis (eg. rhabdomyolysis, tumour lysis syndrome, chemo - breaks cells)
                     • CARDIAC ARHYTHMIAS / ARREST
                       • https://www.youtube.com/watch?v=PxoRJN3SVZQ
                   • HYPOkalaemia - K+ from ECF into ICF
                     • Insulin therapy (treatment for diabetes & hyperkalaemia)
                     • B2 adrenoceptor agonist (eg. salbutamol inhaler) stimulates Na-K ATPase (pumps Na+ out of cells and K+ into cells)
                     • Alkalosis
                     • Hyposmolarity of ECF
         • How to calculate AG: [Na+] - ([HCO -] + [Cl-]) Normal = 8-16mEq/l (same as mmol/l)
         • Body fluids must have equal balance of +ve & -ve charge
       • Causes
         • Causes of METABOLIC ACIDOSIS
           • Causes of METABOLIC ALKALOSIS
         • Causes of RESPIRATORY ACIDOSIS
           • Causes of RESPIRATORY ALKALOSIS
       • 7.35 - 7.45 (ref range)

Bilder und Dateien der Mindmap