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RENAL PHYSIOLOGY (CHEAH SOOK PENG, CANDACE) (PART 2: SOLUTE REABSORPTION,…

- - - - receive 25% of cardiac output
      - filter blood, excrete metabolic waste
      - retrieve filtered substances needed by the body: water, glucose, electrolytes, & low–molecular-weight proteins
      - respond to changes by altering rate of re-absorption/ secretion of water, electrolytes, acid-base substances
      - produce hormone: regulate blood pressure & RBC production
    - - glomerulus: filters blood
      - Renal tubule Segments:
        
        absorb filtered substances
        
        secrete plasma components into tubule fluid
      - Renal Cortex:
        
        nephrons merge into collecting duct system (traverses kidney)
        
        empties into renal pelvis
  - - - example: avg. size beagle: 10kg with (w/) GFR of 3.7 mL/min/kg
        
        approx. 37mL of glomerulus filtrate/min
        
        53.3 L of glomerulus filtrate / day (~27x beagle's ECV)
  - - - network of capillaries
      - renal arterial blood flows to afferent arteriole
        
        divide to glomerular capillaries
        
        capillaries combine form efferent arteriole
        
        moves filtered blood away from glomerulus
      - encased by Bowman's capsule - parietal epithelium (single layer of cells)
      - Bowman's space: glomerular filtrate 1st appears
        
        filtrate enters lumen of 1st segment of proximal tubule
    - - Structure- determine rate & selectivity of glomerular filtration (GF)
        divided to 3 layers
        
        a) capillary endothelium
        
        single layer of thin cells- faces the blood in capillary lumen
        
        Endothelial fenestrae- transcellular pores that conduct water & noncellular components in the blood to GBM
        
        b) Glomerular basement membrane (GBM)
        
        acellular, various glycoproteins (laminins, type IV collagens, nidogens), agrin (mature), prelecan (dev. glomeruli)
        
        GBM- thicker & contains glycoprotein isoforms
        
        3 layers (fusion of basement membranes of endothelial and epithelial cell layers
        
        Lamina densa (dense layer)
        
        dark, resistant to passage of electrons, tightly packed glycoprotein fibrils
        
        Lamina rara interna (inside thin layer)
        
        endothelial side of GBM, loose network of glycoprotein fibrils
        
        Lamina rara externa (outside thin layer)
        
        epithelial side of GBM, loose network of glycoprotein fibrils
        
        c) visceral epithelium
        
        Podocytes- layer of intricate, interlocking cells
        
        Primary & secondary foot processes - long, narrow extensions
        
        interdigitate w/ foot processes of other podocytes
        
        wrap around individual capillaries
        
        Epithelial Slit Diaphragm
        
        spans btwn adjacent foot processes
        
        nephrin (transmembrane protein) - critical component, extending from adjacent foot processes interacts to form slit diaphragm
  - - - Favouring Filtration
        
        movement of H2O & solutes acress glomerular capillary wall
        
        hydrostatic pressure of blood in capillary & oncotic pressure of fluid in Bowman space (ultrafiltrate)
        
        Usually oncotic pressure of ultrafiltrate is insignificant cz medium- to high- mol. proteins NOT filtered
        
        main driving force for filtration: glomerular capillary hydrostatic pressure
      - Opposing Filtration
        
        plasma oncotic pressure within glomerular capillary & hydrostatic pressure in Bowman's space
    - - diff btwn capillary hydrostatic pressure (favoring filtration) & capillary oncotic pressure & hydrostatic pressure of ultrafiltrate (opposing filtration)
      - Relationship:
        Pf = Pgc − (πb + Pt )
      - Blood travels thru glomerular capillary
        
        fluid component of plasma forced across capillary wall
        
        Plasma protein retained in capillary lumen
        
        Plasma oncotic pressure ↑ along capillary bed
        
        ↓ plasma vol. along capillary bed cause ↓ in hydrostatic pressure in capillary
        -change is small: resistance of efferent arteriole
      - NFP ↓ along capillary bed
        
        BUT when blood flow ↑ through glomerular capillaries, ↑ in capillary oncotic pressure blunted
        
        ↑ filtration in distal portions of glomerular capillaries
    - - product of this + its surface area = ultrafiltration coefficient (Kf)
  - - - free filtered: Cationic form > neutral form > anionic form
        of the same molecule
      - Reason: charge-selective barrier in the glomerular capillary wall that is created by negatively charged residues of glycoproteins incorporated in the glomerular basement membrane
      - fixed negative charges repel negatively charged plasma proteins
        
        inhibit their passage across the filtration barrier.
  - - - RAAS imp. reg. of GFR & renal blood flow
        
        Renin (hormone)
        
        produced @ wall of afferent arteriole
        
        by granular extraglomerular mesangial cells (specialized juxtaglomerular cells)
        
        Release stimulated by ↓ in renal perfusion pressure
        
        catalyzes the transformation of angiotensinogen, which is produced by the liver, to angiotensin I.
        
        Angiotensin I → active angiotensin II by angiotensin converting enzyme (ACE) @ vascular endothelium of lung / kidney- interstitial cap. endothelium & proximal tubule
        
        angiotensin I → angiotensin II @ kidney
        
        regulate renal blood flow & transport processes independent of systemic effects.
        
        *Angiotensin II
        
        vasoconstrictor- ↑ systemic BP & renal perfusion pressure
        
        activates Na uptake in:-
        
        proximal tubule
        
        distal convoluted tubule
        
        collecting duct
        
        stimulates the release of aldosterone from the adrenal gland
        
        Release sopressin from pituitary
        
        enhance water reabsorption
        
        ↑ Na and H2O retention, intravascular vol. & vascular resistance
        
        ↑ angiotensin II, suppression of renin released
        
        negative feedback: renal perfusion & GFR
    - - Intrinsic control- mediated by 2 auto-regulatory sys.
        
        control resistance to flow in afferent & efferent arterioles
        
        tubuloglomerular feedback (TGF)
        
        auto-reg. mechanism: changes in tubule fluid delivery
        
        associated with juxtaglomerular apparatus
        
        ↑ glomerular filtration, ↑ tubule fluid flow & NaCl conc. in tubule fluid @ macula densa
        
        ↑ NaCl in NKCC2 @ macula densa → depolarisation of cells & basolateral release of ATP
        
        ATP release suppress renin release @ juxtaglomerular xells, ↑ resistance @ afferent arteriole, ↓ glomerular capillary perfusion pressure, triggers mesangial cell contraction, & ↓ Kf
        
        lead to ↓ GFR @ single-nephron GFR → prevents excessive loss of fluid & solute
        
        ↑ NaCl delivery to distal nephron stimulates production of vasodilatory agents by macula densa cells
        
        blunts TGF response (brake to prevent excessive ↓ in single-nephron GFR)
        
        myogenic reflex
        
        afferent arteriolar constriction, ↑ arteriolar wall tension
        
        ↑ resistance to blood flow when ↑ perfusion pressure
        
        Vasoconstrictive arm = depolarisation of vascular SM cells in pre-glomerular arteries & arterioles
        
        rapid entry of calcium thru VG calcium channels= stimulate SM cell contraction
        
        response is independent of renal innervation, influenced by chemical mediators (Nitric Oxide)
        
        auto-regulated mechanism
        changes in glomerular perfusion
    - - Endothelium-derived constricting factors
        
        thromboxane A2 (mediates PGE2 (a metabolite of arachidonic acid)
        
        endothelin
        
        angiotensin II
      - Endothelium-derived relaxing factors
        
        Nitric oxide (NO)
        
        produced in the kidney by oxidation of l-arginine
        
        prevents renal damage by quenching reactive oxygen species,
        
        prostacyclin (prostaglandin I2)
        
        PGE2
    - - many hormones reg. blood vol. (BV)
        
        Enhance water & solute reabsorption by kidney & ↑ BV
        
        Atrial natriuretic peptides,
        produced in the cardiac atria, cause both natriuresis (sodium wasting) & diuresis (water wasting) & ↓ BV
      - also affect systemic blood pressure, renal perfusion, and ultrafiltration
      - vasoconstrictors can affect the other determinant of GFR, the ultrafiltration coefficient Kf. (cause mesangial cells to contract, ↓ filtration area)
      - Factors ↑ GFR: insulin-like growth factor & high dietary protein
        
        ↑ GFR from high-protein diets: cause more rapid progression of glomerular injury & renal failure
  - - - freely filtered by the glomerulus but is neither reabsorbed nor secreted by the renal tubule cells.
      - rate of its disappearance from the blood after intravascular injection is strictly related to the rate of glomerular filtration.
    - - most widely used measure of glomerular filtration
      - byproduct of muscle metabolism that is handled similar to inulin by the kidney
      - freely filtered, is not reabsorbed by the tubule,
      - serum creatinine level
        
        freq. used to assess renal function.
        
        very small increase in serum creatinine correlates with a large reduction in glomerular filtration rate
- - - - 100% of filtered glucose reabsorbed by the proximal tubule; approx. 99% of the filtered water & sodium are retrieved.
  - - - transcellular pathway
        
        subs. cross apical plasma membrane, cytoplasm & basolateral plasma membrane (into interstitial fluid)
        
        occurs by carrier-mediated transport
        
        factor: vast plasma membrane surface area of prox. tubule
        
        basolateral surface area = apical surface area in portions of the proximal tubule
        
        Benefit: ↑ capacity for solute transporters & ↑ exposure to luminal & interstitial fluids.
      - paracellular pathway
        
        subs. pass thru across zonula occludens (cell junction)
        
        subs. enter lateral intercellular space
        
        reabsorbed subs. can be taken up by the peritubular capillary.
        
        Transport occurs by passive diffusion / solvent drag
    - - origin: glomerular efferent arteriole, subdivides, and wraps closely around the basal aspect of the proximal tubule
      - has low resistance
      - high peritubular plasma oncotic pressure/low peritubular capillary hydrostatic pressure: favor fluid & solute uptake from the interstitium into the bloodstream.
    - - by active transport of Na ions by sodium-potassium-adenosinetriphosphatase (Na+,K+-ATPase) pump @ basolateral plasma membrane
        
        ↓ intracellular Na ions conc., ↑ intracellular K ions conc.
      - Bicarbonate (HCO3-) reabsorption
        
        Secreted H ions + filtered HCO3- in tubule fluid = Water and CO2 (catalyst: carbonic anhydrase)
        
        Carbonic anhydrase catalyses hydroxylation of CO2 w/ OH- from water, form H+ & HCO3-
        
        Prox. tubule reabsorbs 60% - 85% of filtered HCO3-
      - Chloride ion (Cl-) reabsorption
        
        occurs through paracellular &transcellular routes.
        
        As solutes (ions of sodium, bicarbonate, glucose, etc) are selectively reabsorbed & water is taken up along with these solutes, ↑ conc. of Cl− in the tubule fluid, forming chemical gradient for Cl− movement toward the blood side
        
        Early prox. tubule: uptake of Na+ > anions (net +ve charge): favor anion re-absorption
        
        zonula occludens highly permeable to Cl−
        
        passive, paracellular transfer of Cl− from the tubule lumen to the interstitial fluid
        
        Trancellular Cl- reabsorption also @ prox. tubule
        
        Distal portion of prox. tubule: Na+ uptake occur by electrically neutral NaCl uptake facilitated by coordinated Na+ and Cl−-coupled transporters & by passive reabsorption of Na+ through the paracellular pathway.
        
        As Cl- move down chemical gradient, carries Na+ thru electrostatic attraction
      - Calcium ions reabsorption
        
        65% filtered Ca ions reabsorbed by prox. tubule
        
        90% of Ca ion uptake is paracellular
      - Potassium ion reabsorption
        
        passive mechanisms: paracellular
      - Filtered Peptides
        
        degraded to amino acids by peptidases in the proximal tubule brush border
        
        reabsorbed by co-transport w/ Na+ across apical plasma membrane
        
        short chain peptides: transported thru co-trans. w/ H+ by PEPT1 & PEPT2
        
        dipeptides & tripeptides- degraded by intracellular peptidases (some exit intact to blood side)
      - Low-molecular-weight proteins
        
        insulin, glucagon, parathyroid hormone, & etc. - taken up by receptor-mediated endocytosis
        
        delivered by endocytic vesicles to lysosomes, receptors recycled to apical plasma membrane
        
        Proteolytic enzymes degrade the reabsorbed proteins
        Amino acids (end products), transported into interstitial fluid & returned to blood
  - - - Transporters involved:
        
        organic anion transporters
        
        organic cation transporters
        
        apical P-glycoprotein (Pgp)
        
        basolateral Na+ -dicarboxylate co-transporter
        
        several multi drug resistance transporters (MRP)
    - - bile salts, oxalate, urate, creatinine, prostaglandins, epinephrine, and hippurates
    - - antibiotics (e.g., penicillin G, trimethoprim), diuretics (e.g., chlorothiazide, furosemide), antiviral agents (e.g., acyclovir, ganciclovir), the analgesic morphine and many of its derivatives, the potent herbicide paraquat, & etc
    - - End product of protein metabolism is uric acid.
  - - - downstream from the straight portion of prox. tubule: thin limb of Henle’s loop
        
        active transport of solutes in this segment is virtually nonexistent
        
        Fx: determined by the segmental distribution of specific solute & water transporters & passive permeability properties & its spatial orientation in the medulla
        
        Urine conc. mechanism
    - - high capacity for active solute transport
      - electrochemical gradient for Na+ drives ion uptake thru NKCC2 co-transporter
      - Cl- absorption and K+ secretion cause lumen-positive voltage relative to the interstitium.
      - lumen-to blood electrical gradient drives diffusion of the cations, Ca2+ & Mg2+
        through cation-selective paracellular channels
        
        formed by tight junc. proteins- claudin
      - apical co-trans. in TAL inhibited by loop diuretics like bumetanide & furosemide
    - - contains apical NaCl co-trans. (NCC) that mediates Na+ movement from tubule fluid down the chemical gradient for Na+
      - Cl− exits through basolateral ClC-K/barttin Cl− channels, driven by the electrical gradient.
      - apical NaCl co-transporter is inhibited by thiazide diuretics.
    - - when fluid leaves DCT: 90% of filtered salts are reabsorbed (osmolality of fluid is reduced)
      - salt reabsorption in the TAL and DCT is driven by Na+,K+-ATPase in basolateral plasma membrane
      - TAL and DCT: impermeable to water
        
        avid reabsorption of salts w/out water cause hypotonic tubule fluid (diluting segments)
        
        Dilution of the tubule fluid takes place regardless of the volume status of the animal
        
        prevents water overload and plasma hypotonicity, & also generates a hypertonic medullary interstitium
  - - - connecting segment cells
      - intercalated cells
        
        has many intracytoplasmic vesicles and mitochondria
        
        account for the remainder of the cortical and outer medullary collecting duct cells
        
        subpopulation of intercalated cells contributes to Cl− reabsorption via an apical Cl−
        /HCO3- exchanger pendrin & basolateral Cl− channels.
        
        pendrin activity enhances ENaC activity in principal cells
      - DCT cells
      - principal cells
        
        has fewer intracytoplasmic vesicles and mitochondria but more extensive basolateral plasma membrane infoldings
        
        major cell type in the initial collecting duct, the cortical collecting duct, and the outer medullary CD (2/3 of cells in most regions)
        
        NaCl reabsorption in the CD is the primarily fx
    - - the apical K+ channel, ROMK, more permeable than basolateral K+ channel
      - lumen-negative electrical potential favors K+ secretion
    - - intracellular K is actively transported in exchange for hydrogen ions in the tubule fluid by apical H+,K+-ATPase
  - - - controlled by several hormones, including angiotensin II, aldosterone, antidiuretic hormone, endothelin-1, atrial natriuretic peptide, parathyroid hormone, 1α,25-(OH)2–vitamin D3, & calcitonin
  - - - released when an animal is volume depleted, dehydrated, or hypotensive (enhances salt reabsorption from the TAL & CD)
      - results from vasopressin-stimulated increases in the activity of the apical Na+,K+,2Cl− co-transporter (NKCC2) in TAL & ENaC in CD
      - allows maximal salt & water conservation: the ↑ salt uptake contributes to the interstitial osmolarity & enables enhanced water reabsorption in the CD
    - - type of gas produced by the catabolism of L-arginine, catalyzed by NO synthase (NOS) in renal endo/epithelial cells
      - Inhibit Na+ uptake mechanisms in
        several renal tubule segments
      - important role in reg. systemic extracellular fluid volume & BP
    - - a peptide hormone produced in the kidney in
        CD, endothelial cells, and the TAL of Henle’s loop.
      - ↑ renal NaCl & water excretion by effects on epithelial transport and renal microcirculation, mediated by NO & prostaglandins.
    - - produced in the cardiac
        atria.
      - Stimulated by atrial distention in healthy subjects
        plasma ANP levels are ↑ in patients with congestive heart failure & other conditions causing extracellular fluid retention.
      - inhibits aldosterone and renin release & increases renal Na+ excretion
  - - - small % of Ca2+ reabsorption in TAL occurs by transcellular transport
    - - vit. D3 located @ DCT and connecting segment: ↑ cellular content of Ca2+-binding protein (calbindin 28k) and enhance Ca2+ reabsorption
- - - - water-deprived dog with normal renal function can produce urine that is 7-8 times more concentrated than the osmolality of plasma
      - kidney also can produce hypotonic urine in response to a water overload
        
        same dog can excrete urine with an osmolality as low as 1/3 that of plasma
  - - - takes up solutes from the tubule fluid by both active and passive means.
    - - result in rapid movement of water from the tubule fluid to the interstitial fluid.
  - - - (B) dilution of the tubule fluid by the thick ascending limb and the distal convoluted tubule
        
        which allows excretion of dilute urine;
      - C) variability in the water permeability of CD in response to ADH
        
        determines the final urine concentration.
      - A) generation of a hypertonic medullary interstitium
        
        allows excretion of concentrated urine;
  - - - a) the reabsorption of osmotically active substances by tubules in the medulla
      - b) he removal of water from the medullary interstitium by the vasa recta
  - - - short loops of Henle that extend only into the inner stripe of the outer medulla
      - short-loop nephrons have a descending thin limb that parallels the TAL
      - do not have an ascending thin limb; the thin descending limb merges w/ thick ascending limb near the hairpin turn
    - - long loops of Henle that extend
        deep into the inner medulla.
      - long-loop nephrons have several segments of descending & ascending thin limbs with specific urea & water transporter expression
        
        Role: maintaining the medullary hypertonicity & urine conc. ability
      - responsible for the kidney’s ability to concentrate urine at a much ↑ lvl than osmolality of plasma.
  - - - allows water to be abstracted from water-permeable descending thin limbs & returned to the circulation
  - - - Role of more important contribution is to the medullary hypertonicity is the reabsorption of urea
    - - urea remains in the tubule fluid until it reaches the terminal IMCD deep in the medulla.
    - - conditions demand water conservation & ADH is released, urea reabsorption is enhanced & the osmotic gradient for water uptake ↑.
    - - enhances the efficiency of the urine-concentrating mechanism.
    - - medullary hypertonicity in birds appears to depend on single-solute (NaCl) recycling.
  - - - a) anatomical arrangement of the thin limbs of Henle’s loop
      - b) differential water & salt permeabilities of the descending and ascending thin limbs
    - - descending & ascending thin limbs joined by a sharp, hairpin turn
        
        hairpin turns slow the rate of blood flow, which helps maintain the osmotic gradient required for water reabsorption.
        
        The limbs are parallel & juxtaposed, with the tubule fluid flow in opposite directions
    - - contains AQP1 water channels and is highly permeable to water.
      - Descending thin limb @ outer medulla- not permeable to salt
    - - tubule fluid osmolality ↑ until it reaches its max. conc. @ the hairpin turn.
      - descending thin limbs in the inner medulla are salt permeable
    - - ascending (↑) thin limb is impermeable to water & permeable to NaCl
      - equilibration occurs by diffusion of NaCl from the tubule fluid → interstitial fluid
        
        tubule fluid osmolality ↓ & solute is added to the interstitium,
    - - Passive means: thin limbs reabsorbed both water & salt
      - Water reabsorbed from the descending thin limb
      - salt was reabsorbed from the ascending thin limb
      - maintain medullary hypertonicity.
  - - - cause swelling of the inner medulla
        (if it were not for the ability of the vasa recta to remove the reabsorbed fluid)
      - vasa recta permeable to water, salts, and urea.
    - - luminal NaCl & urea conc. equilibrate with the interstitial concentration.
      - plasma osmolality & urea conc. ↑ at the vasa recta @ hairpin turn → fall as the vessels ascend out of the medulla
    - - a) plasma oncotic pressure falls
      - b) blood flow in ascending vasa recta is approx. double than in descending vasa recta
  - - - Absence of ADH: CD impermeable to water
      - tubule fluid delivered by the DCT remains hypotonic → the water is retained in the CD lumen
      - AQP2 contained in cytoplasmic vesicles in principal cells & IMCD cells
        
        ADH upregulates urea transporters & enhances urea reabsorption by IMCD
        
        enabling ↑ urea contribution to the medullary tonicity
    - - ADH released from pituitary (triggered by rise in plasma osmolarity)
      - rise in osmolarity due to dehydration/ salt overload / ↓ BP from systemic vasodilation, heart failure, isosmotic vol. depletion from vomiting, diarrhea, hemorrhage
      - animal needs to ↓ plasma osmolarity to normal / restore fluid vol. or BP
    - - water flows from dilute tubule fluid → cell
        
        and then the interstitium ↓ conc. gradient: prod. structural alterations (cell swelling & dilation of intercellular spaces)
      - the now water-permeable CD traverses (cross) the inner medulla thru regions of ↑ interstitial fluid osmolality
        
        tubule fluid equilibrates by diffusion of water into the interstitium (highly conc. urine is eliminated)
      - ADH secretion stimulates AQP2 to insert into the apical plasma membrane of these cells & water freely passes through these channels
  - - - myoinositol
      - amino acids
      - betaine
      - glycerophosphorylcholine (GPC)
      - Sorbitol
    - - ↑ duing periods of urine conc. when medullary interstitial osmolality is maximised
      - ↓ during diuresis, when medullary interstitial osmolality ↓
    - - the production (e.g., sorbitol, GPC) / transmembrane transport (e.g., betaine, myoinositol, amino acids) of the osmolytes
      - by counter-regulation of degradation of osmolytes (e.g., GPC)