Overview of the Human Body

• Structure is always related to function
• Homeostasis is the foundation of all physiology
• Daily secretion averages 6.5-8L, with 100 mL of water loss occurring in feces each day
• Blood filtration rate is 1.2L/min/70 kg
• Urine production is 1.5 L/day/70kg

Transporters, Pumps, and Channels: Electrolyte Distribution

Membrane Transport Pathways

• Channels: Facilitated diffusion of ions.
• Transporters: Solute carriers and secondary active transport, as well as facilitated diffusion
  • Example: Na⁺/Glucose Cotransporter, where high EC Na⁺ concentration pushes Na⁺ inside, pulling Glu along and creating a high Glu concentration IC
• Pumps: Primary active transport
  • Example: Na⁺/K⁺/ATPase uses 3 Na⁺ in and 2 K⁺ out and creates an ion gradient for secondary transport
• Hydrophobic molecules and small uncharged polar molecules move most easily across membranes
• Large polar molecules and ions do not pass easily

Ion Channel Types

• Ligand gated channels open in response to a specific molecule
• Voltage gated channels open in response to a voltage change
• Leak channels are always open
• Stretch activated channels open in response to mechanical change

Voltage and Concentration Gradients

• Electrochemical Equilibrium Potential is controlled by concentration gradient and degree of permeability of the membrane to that ion species
• Cell membrane potential is controlled by degree of ion permeability and ion concentration
  • K⁺ leak channels are major contributors to resting potential
  • Na/K/ATPase creates gradients

Body Fluids

• Total body water = 60% of body weight (~42 L)
• Extracellular Fluid (ECF) constitutes 20% of body weight (~14 L)
  • Interstitial Fluid (IF) is ¾ of ECF, or 15% of body weight (~10.5 L)
  • Plasma is ¼ of ECF, or 5% of body weight (~3.5 L)
• Intracellular Fluid (ICF) constitutes 40% of body weight (28 L)
• Capillary walls in the EC compartment control fluid movement via Starling pressures

Measurements

• Dilution principle: volume = x/c, where x = soluble substance, c = concentration
• In vivo: v = (x - quantity of x excreted)/c
  • Criteria for measurement of volume of a particular fluid compartment: fluid x must be freely distributed to entire compartment, must be non-toxic, not metabolized, and easily measured
• Measure unknown volume by adding 100g blue dye, mixing to equilibrium, and using the concentration to determine volume
  • Example: If c = 20g/L, then v = (100g)/(20g/L) → v = 5L
• Measure volume in specific compartments:
  • Plasma volume: use ¹³¹Iodine-labeled albumin or evans blue dye to bind to plasma proteins
  • ECFV: Use inulin, which must not enter the cell but equilibrate in plasma and IF
  • Total body H₂O: Use heavy water D₂O, must cross cell membrane freely
  • ICFV: calculate from total body water - ECFV

Osmolality

• Number of free particles in solution
• Determined by number of particles, not size
• Majority of ECF determined by electrolytes which associate to produce a molecule and dissociate in solution
  • Example: 1 mmol/L NaCl = 1Na⁺ + 1Cl⁻ = 2 mosml/KgH₂O
• Composition of ICF and ECF varies, but total osmolality is equal
• Reflection coefficient of 1.0 = sustained osmotic effect (no H₂O movement)

Expansion

• Hypotonic Expansion (drinking water): both ECF and ICF expand (cell swelling), decrease in osm
• Isotonic expansion (infusion of NaCl) - only ECF expands (edema), no change in osm
• Hypertonic expansion (ingest NaCl, no water) - decrease ICFV & increase in ECFV (cell shrinkage), increase in osm

Contraction

• Hypertonic contraction (heavy sweating) - both ECF and ICF volume decrease
• Isotonic contraction (diarrhea, vomiting) - decrease ECF only → CV collapse
• Hypotonic contraction (adrenal insufficiency) - decrease ECF, increase ICF (cell swelling)

Receptors and Signaling

• Water soluble hormones receptors on cell surface result in rapid signaling and slow signaling
  • Cell Surface Receptors: GPCR, ionotropic, catalytic (enzyme linked)
• Lipid soluble hormone receptors found intracellular, result in slow signaling

GPCR Activation

• Gas and Ga₁ - modulation of adenylyl cyclase (ex: stimulatory: V2-R, inhibitory: Epi) → cAMP → PKA
• Ga - activation of PLC (ex: AT1-R, a1ADR, V1-R) → IP3/DAG → Ca²⁺/PKC
• Ga - PLA2 → AA → PGs

Ionotropic Receptors (ligand gated)

• example: nACHR

Catalytic Receptors

• Have EC domains and activation of IC catalytic domain, 5 types
• Receptor guanylyl cyclases
  • example: ANP receptor that binds, which leads to R dimerize, then IC domains activated, then GTP conv to cGMP, which leads to downstream effects
• Receptor serine/threonine kinases
• Receptor tyrosine kinases
  • Example: NGF, insulin that binds, which leads to R dimerize, then IC domains activated, then autophosphorylation
• Tyrosine kinase-associated receptors
  • Example: GH receptor contains a single membrane molecule in different forms (a, B)
  • Binding leads to homodimers/heterodimers/heterotetramers → activation of receptor unit and no intrinsic kinase activity, but can activate closely associated tyrosine kinases JAK
• Receptor tyrosine phosphatases

Thyroid Hormone

• Absence of T₃, THR is bound to DNA and is a repressor.
• T₃ then enters nucleus and binds THR.

Glucocorticoid Receptor

• GR is in cytosol in inactive state bound to hsp90, cortisol binds Gr and hsp90 dissociates
• GR-cortisol complex enters nucleus and dimerizes with another GR, initiates transcription

Autonomic Nervous System

• 7 main parts:
  1. spinal cord (brain) - Cervical, thoracic, lumbar, sacral, coccygeal
  2. medulla oblongata contains vital autonomic functions
  3. Pons - Info between cerebellum and cerebrum, involved in urination, respiration and BP
  4. Cerebellum - movement coordination, balance and posture
  5. Midbrain - sensory and motor function
     • Brainstem = medulla, pons, and midbrain
  6. Diencephalon - thalamus (processes info) and hypothalamus (regulates autonomic & endocrine function)
  7. cerebral hemispheres - basal ganglia and neocortex

SNS

• Cell bodies of preganglionic neurons (short) are in thoracic and lumbar region connected via ACh
• Cell bodies of postganglionic (long) are near spinal cord
  • uses NE, with exception of sweat glands, which use ACh

PNS

• Cell bodies of preganglionic neurons (long) are in brain and sacral region connected via ACh
• Cell bodies of postganglionic (short) are near target tissue connected via ACh

Adrenergic Receptors

• α1 induces contractile effects
• β1 induces stimulatory effects
• β2 induces relaxing effects

Urination

• Detrusor muscle (smooth muscle) controlled by ANS
  • Relaxed = filling (SNS)
  • Contracted = emptying (PNS)
• Internal sphincter (smooth muscle) controlled by ANS
  • Contracted = filling (SNS)
  • Relaxed = emptying (PNS)
• External sphincter (skeletal muscle): somatic control
  • Contracted = filling
  • Relaxed = emptying
• Reflexes have sensors, afferents, CNS component, efferents, and effectors
• Referred pain = convergence of visceral and somatic afferents at level of spinal cord in the nucleus of the solitary tract

Genetic Approaches

• Genetic Modifications include loss of function, gain of function, and conditional gene manipulation with (Cre/lox)
• Transgenic mouse uses DNA randomly inserted into the genome by injecting the male pronucleus shortly after fertilization
• Knock-in (or Knock-out) mouse – Changes introduced into an endogenous gene via homologous recombination with manipulated DNA from the gene.
• Homologous recombination occurs with a type of genetic recombination in which nucleotide sequences are exchanged between two similar or identical molecules of DNA

Transgenic vs Targeted/Homologous Recombination

• Transgenic modifications result in random insertion of recombinant DNA into the host genome
• Targeted (knock-in/knock-out) modifications are directed toward a specific site in the genome

CRISPR/Cas9 nuclease

• Originates from bacterial immune system

• CRISPR/Cas9 also offers Ability to target many sites in the genome simultaneously

Cre/LoxP System

• Enzyme from bacteriophage that catalyzes site specific recombination of DNA between two LoxP sites
  • LoxP sites are in non-coding regions, in cells that do not express Cre
• Can use to delete gene X specifically from cells in a specific organ
• Groups should be counterbalanced with littermates

Kidney Anatomy

• Blood Supply:
  • Arterial: Abdominal aorta → renal artery → segmental → interlobar → arcuate → interlobular arteries
  • Venous: Renal vein → inferior vena cava
• Urine Flow Path: Cortex → medulla (pyramids) → calyces → renal pelvis → ureter → bladder → urethra (micturition)

Vascular Architecture of the Kidney

• Glomerular Circulation:
  • Cortical radial (interlobular) arteries → afferent arterioles → glomerular capillaries → efferent arterioles give rise to peritubular capillaries in cortical nephrons or vasa recta in juxtamedullary nephrons
• Nephron Structure:
  • Glomerulus + Tubule
  • Glomerular capillary + Bowman's capsule = Renal corpuscle
  • Podocytes are specialized epithelial cells forming filtration slits

Nephron Types & Functions

• Cortical Nephrons (90%):
  • Located in the outer 2/3rds of the cortex
  • Short loops of Henle and efferent arterioles form peritubular capillaries
• Juxtamedullary Nephrons (10%):
  • Located in the inner 1/3rd of the cortex
  • Long loops of Henle extending to the papilla tip
  • Efferent arterioles form vasa recta
  • Larger glomeruli with higher GFR

Juxtaglomerular Apparatus (JGA)

• Consists of macula densa, extraglomerular mesangium and granular cells
  • Macula Densa: Specialized thick ascending limb cells
  • Extraglomerular Mesangium
  • Granular Cells (Renin Production): Located in afferent arteriole

Structure of the Tubules

• Transporting Epithelium contain asymmetric cell membranes and Na⁺-K⁺-ATPase located only on basolateral surface
• Tight Junctions
  • Proximal Tubule has "Leaky" junctions for reabsorption
  • Ascending Loop of Henle has "Tight" junctions
  • Distal Nephron has "Tight-tight" junctions for controlled transport
• Segment Functions
  • PCT: High mitochondria, thick brush border (active transport)
  • TAL & DCT: High mitochondria, transport activity
  • CD: Contains principal and intercalated cells

Renal Innervation

• Afferent (Sensory) Innervation
  • Chemoreceptors: Monitor urine composition
  • Mechanoreceptors: Detect perfusion pressure
• Efferent (Sympathetic) Innervation
  • Affects afferent/efferent arterioles, PCT, and TAL
  • Uses NT: Norepinephrine (NE)

Clearance & Glomerular Filtration Rate (GFR)

• GFR Normal Range: 80 - 200 mL/min (varies with body weight)
• GFR Measurement:
  • Requires a freely filtered substance that is not reabsorbed, secreted, metabolized, or be toxic
  • GFR Calculation: GFR = (Ux × V) / Px
  • Inulin Clearance (Cin): Gold standard
  • Creatinine Clearance (Ccr): Endogenous, slightly overestimates GFR due to secretion

Fractional Clearance (FC)

• Fractional Clearance (FC) measures filtration restriction
  • FC = 1.0 means there is no restriction (e.g., inulin)
  • Large molecules have less filtration
• Cx/Cin = 1.0: Handled like inulin due to no secretion or reabsorption
• Cx < Cin (FC < 1.0): Reabsorbed
• Cx > Cin (FC > 1.0): Secreted
• Key Substances:
  • Glucose: FC = 0.0 (100% reabsorbed)
  • Phosphate: FC ~ 0.2 (80% reabsorbed, 20% excreted)
  • Water: FC ~ 0.01 (99% reabsorbed)
• Urine-to-Plasma (U/P) Inulin Ratio:
  • U/Pin = 1.0: No water reabsorption
  • U/Pin = 2.0: 50% water reabsorbed
  • U/Pin = 100: 99% water reabsorbed

Key Equations

1. Clearance Formula: Cx = (Ux × V) / Px
2. GFR Calculation: GFR = (Ux × V) / Px
3. Inulin Clearance: Cin = GFR
4. Creatinine Clearance (Ccr) ~ GFR

Typical Values for a 70 kg Adult

• Total RBF: ~1.2 L/min (25% of CO)
• Total renal plasma flow (RPF): ~600 mL/min (hct ~50%)
• Glomerular Filtration Rate (GFR): ~120 mL/min (~173 L/day)
• Plasma volume: ~3 L

Determinants of RBF

• Flow = Pressure Gradient / Resistance
• Resistance: Controlled by vessel radius
  • Low resistance in aorta, renal, segmental, interlobar, and arcuate arteries
  • Resistance vessels in series cause progressive BP drop
  • First resistance vessel: Interlobular artery → BP drops ~55 mmHg at the glomerulus
  • Minimal BP drop in glomerulus (~2-3 mmHg), substantial drop in efferent arteriole
  • Peritubular capillary BP ~20 mmHg
• Control: Resistance vessels before & after glomerulus regulate plasma flow & BP

Glomerular Filtration Process

• Glomerular filtrate refers to an ultrafiltrate of plasma
  • Contains water, small molecules (electrolytes, urea, peptides)
  • Excludes large proteins & blood cells
• Dextran Filtration depends on size and charge
  • Glomerular capillary wall has size-selective pores and a negative charge
  • Neutral dextran filters based on size, anionic dextran has more restrictions, and Cationic dextran is more facilitated
• Filtration of Proteins determined by size and charge Restriction occurs at:
  • Glomerular capillary endothelium (negative charge, glycocalyx)
  • Glomerular basement membrane (GBM) (negative charge, collagen scaffold)
  • Podocyte slit pores (size restriction due to specialized proteins)
• Protein Reabsorption:
  • Proximal tubule (PCT) reabsorbs most filtered protein (~98%), breaking them into amino acids for recirculation

Determinants of GFR

1. of Functional Glomeruli

2. Filtration Rate of Single Glomeruli (SNGFR)
   • All glomeruli are active (cannot be turned off)

Filtration Forces (Starling Pressures)

• GFR determined by net driving pressure (hydrostatic vs. oncotic pressure), water permeability (K+), and filtration surface area
• Pressure Gradients Across the Glomerulus:
  • Glomerular capillary pressure (PGC): ~55 mmHg
  • Bowman's space pressure (PBS): ~10 mmHg
  • Oncotic pressure in glomerular capillaries (πGC): Starts at ~25 mmHg, rises to ~35-45 mmHg
  • Oncotic pressure in Bowman's space (πBS): 0 (since no proteins are filtered)
• Driving Force for Filtration: Net Filtration Pressure (PUF) = (PGC - PBS) - (πGC - πBS)
  • PUF = (55 - 10) - (25 - 0) = 20 mmHg → Filtration

GFR & Renal Plasma Flow (RPF) Relationship

• Filtration Fraction (FF) = GFR / RPF (~20%)
• Changes in RPF affect GFR:
  • Low RPF: Rapid rise in πGC stops filtration early → low GFR
  • High RPF: Slower rise in πGC allows filtration to continue → higher GFR
  • Increased FF (e.g., due to vasoconstriction of efferent arteriole) increases GFR
  • Increased plasma protein concentration reduces GFR

Regulation of GFR

• Transcapillary Hydrostatic Pressure Gradient (∆P = PGC - PBS)
  • Increased PGC leads to increased GFR
  • Increased PBS (e.g., obstruction like prostate enlargement) leads to decreased GFR
• Glomerular Capillary Ultrafiltration Coefficient (Kf)
  • K₁ = Filtration surface area x Water permeability
  • ↑K→↑ GFR
  • Controlled by mesangial cell contraction (can decrease filtration surface area)
• Oncotic Pressure of Incoming Blood (πΑ)
  • ↑ πΑ (e.g., increased plasma protein concentration) → ↓ GFR
  • ↓ πΑ (e.g., nephrotic syndrome, low plasma proteins) → ↑ GFR

Regulation of GFR

• Controlled by:
  • Renal plasma flow (RPF), Glomerular capillary hydrostatic pressure (PGC), Glomerular ultrafiltration coefficient (Kf) – determined by surface area (SA) & water permeability and ultrafiltration and Oncotic pressure (πΑ) from plasma proteins
• Afferent (RA) and Efferent (RE) Arterioles on GFR
  • Relaxation of RA and RE increases RPF
  • Constriction Effects:
    • RA constricts → ↓ RPF, ↓ PGC, ↓ GFR
    • RE constricts → ↓ RPF, ↑ PGC (offsets effect on GFR)
    • Both RA & RE constrict → ↓ RPF, PGC unchanged, ↓ GFR
• Regulatory Systems of RA & RE
  • Volume depletion (low blood volume) activates vasoconstrictors and suppresses vasodilators and leads to ↓ GFR
  • Volume expansion (high blood volume) activates vasodilators and suppresses vasoconstrictors and leads to ↑ GFR
• Neural & Hormonal Control
  • Sympathetic Nervous System (SNS) vasoconstricts RA & RE and leads to ↓ RPF & GFR
  • Angiotensin II (AngII):
    • Moderate levels: leads to a Small ↓ GFR (offset effects of ↓ RPF & ↑ PGC)
    • High levels: leads to Severe vasoconstriction and Marked ↓ GFR
  • Nitric Oxide (NO) vasodilates RA & RE and increases Kf, leading to ↑ GFR
  • Prostaglandins (PGs) vasodilate
  • Atrial Natriuretic Peptide (ANP) is released due to a volume overload and:
    • Vasodilates RA leading to ↑ RPF, ↑ PGC & ↑ GFR
    • Inhibits Na+ reabsorption leading to ↑ Na+ excretion

Renal Hemodynamics & Physiologic Adaptations

• Volume Depletion:
  • SNS & AngII activated → RA & RE constrict →↓ RPF, GFR maintained or slightly reduced
• Volume Expansion:
  • NO & ANP activated → RA & RE relax → ↑ RPF, ↑ GFR
• Situations Affecting Renal Hemodynamics:
  • High protein diet & pregnancy leads to vasodilation →↑ RPF & GFR
  • Exercise leads to Vasoconstriction → ↓ RPF & GFR
• Renal Autoregulation of GFR maintains constant renal blood flow (RPF) despite BP changes Only RA participates in autoregulation
  • Mechanisms:
    • Myogenic response (fast, msec): RA constricts in response to increased BP to maintain constant RPF & GFR
    • Tubuloglomerular feedback (delayed, sec-min): Macula densa detects increased flow → RA constricts → Restores GFR

Renal Epithelial Sodium Transport & Body Fluid Compartments

• Luminal membrane: Na⁺ enters passively (via cotransporters, exchangers, or channels).
• Peritubular membrane: Na⁺ is actively pumped out via Na-K-ATPase.
• Transport mechanisms:
  • Passive: Diffusion, osmosis, solvent drag, facilitated diffusion (e.g., urea).
  • Primary active: Na-K-ATPase, H-ATPase, H-K-ATPase.
  • Secondary active: Na⁺-linked reabsorption (e.g., glucose, amino acids).
  • Coupled transport: Cotransport (e.g., Na⁺-glucose) & antiport (e.g., Na⁺-H⁺).

Sodium Reabsorption by Nephron Segments

• Proximal Tubule (PCT) – 65-70% Reabsorbed (Bulk Reabsorption)
  • Early PCT: Na⁺-H⁺ exchanger (NHE3) major transporter, Na⁺ transport coupled to glucose, amino acids, phosphate, lactate via specialized co-transporters.
    • Passive paracellular Cl⁻ movement (small amount).
  • Late PCT: Na⁺-H⁺ exchange coupled with anion-Cl⁻ exchangers → Cl⁻ reabsorbed transcellularly
    • Cl⁻ gradient allows passive Na⁺ reabsorption
    • HCO₃⁻ reabsorption in early PCT; Cl⁻ reabsorption in late PCT
  • Stimulated by a-adrenergic nerves, ANGII, increased plasma oncotic pressure.
    • Inhibited by Atrial natriuretic peptide (ANP), nitric oxide (NO), increased arterial BP
• Thick Ascending Limb of Henle (TALH) – 20-25% Reabsorbed
  • Major transporters: Na+-H+ exchanger (NHE3), Na⁺/K⁺/2Cl⁻ cotransporter (NKCC2) – primary transporter
    • Cl⁻ transported across peritubular membrane via K+-Cl-cotransporter
    • ROMK channel recycles K⁺ → generates a lumen-positive charge
  • Has key characteristics of no water reabsorption and Na⁺ reabsorption is load-dependent
  • Stimulated by: a-adrenergic nerves, ANGII; Inhibited by: Prostaglandins
• Distal Nephron (Distal Convoluted Tubule & Collecting Duct) – 8-10% Reabsorbed
  • Distal Tubule: Na⁺-Cl⁻ cotransporter (NCC) – thiazide-sensitive; Always impermeable to water and Aldosterone stimulates NCC → increases NaCl reabsorption.
  • Collecting Duct has Na+ reabsorbed via ENaC (epithelial sodium channel)., Principal cells: Reabsorb Na⁺, secrete K⁺
    • Aldosterone stimulates ENaC → increases Na+ reabsorption → generates lumen-negative potential. H₂O permeability is ADH-dependent.
  • Aldosterone (major), ANGII; Inhibited by: ANP, NO, prostaglandins.

Balance States

• Positive Na⁺ balance: Intake > output → Na⁺ accumulation → ECF expansion.
• Negative Na⁺ balance: Output > intake → Na⁺ depletion → ECF contraction.
• Normal Na⁺ balance: Intake = output.

GFR & Sodium Excretion

• Sodium Filtration calculation: GFR X PNa determines filtered Na⁺ load
• Reabsorption: 99.5% of filtered Na⁺ is reabsorbed, meaning only ~0.5% is excreted
• Glomerulotubular balance maintains constant fraction of Na+ reabsorption despite changes in GFR
• Na+ excretion formula:
  • • UNaV = Filtered Na+ - Reabsorbed Na⁺,
  • Filtered Na⁺ = GFR x PNa
  • Fractional reabsorption = (Reabsorbed Na⁺ / Filtered Na⁺) x 100
  • Fractional excretion = 100 - Fractional Reabsorption.

Key Systems That Alter Na+ Transport

1. Antinatriuretic Systems
   • Renin-Angiotensin-Aldosterone System (RAAS):
     • ANGII stimulates Na⁺ reabsorption in PCT, TALH, and distal nephron
     • Aldosterone Increases Na⁺ reabsorption in DCT/CD via ENaC & NCC.
   • Sympathetic Nervous System (SNS) increases Na⁺ reabsorption via a-adrenergic activation
2. Natriuretic Systems (Na+ Losing – Activated by Na+ Excess)
   • Atrial Natriuretic Peptide (ANP): Inhibits Na+ reabsorption in PCT, TALH, and CD.
   • Prostaglandins (PGE2): Inhibit Na+ reabsorption in TALH.
   • Nitric Oxide (NO): Vasodilates reduces Na+ reabsorption.

Diuretics

• First-Line Treatment for Hypertension (HTN)
  • Loop Diuretics (Most Potent) inhibit NKCC2 in TALH
    • Example: Furosemide (Lasix) but causes K⁺wasting & hypokalemia
  • Thiazide Diuretics (Most Prescribed) inhibit NCC in DCT
    • Example: Hydrochlorothiazide.
  • K⁺ Sparing Diuretics inhibit ENaC or Aldosterone
    • Amiloride (ENaC blocker), Spironolactone (Aldosterone antagonist); With risk of hyperkalemia

Renal Calcium Handling

• Calcium Storage: Stores 99% in bone/ICF, 1% in ECF
• Proximal Tubule handles reabsorption of 65-70% via bulk, passive, and Na⁺-driven reabsorption of calcium
• TALH: reabsorbs 20-25% via passive, paracellular and NKCC2-dependent reabsorption.
• Distal Nephron will reabsorb 9% through active calcium channels and regulated reabsorption.
• Calcium regulation:
  • PTH & Vitamin D: Increase Ca²⁺ reabsorption in TALH & distal tubule.
  • High Plasma Ca²⁺: Inhibits TALH reabsorption via Ca²⁺-sensing receptors and ↓ NKCC2.
  • Furosemide: Blocks NKCC2 -> ↓ Ca²+ reabsorption (used for hypercalcemia).
  • Thiazide Diuretics: ↓ Ca²+ excretion (used for kidney stones).

Renal Phosphate Handling

• Phosphate Storage 85% in bone, 14% in cells, <1% in ECF
• Proximal Tubule reabsorbs 80% via Na⁺-PO₄³⁻ cotransport (active, saturable);
• PTH lowers TMAX → ↓ PO₄³⁻ reabsorption → ↑ PO₄³⁻ excretion (phosphaturia)
• Acidosis ↑ Urinary PO₄³⁻ excretion (important buffer)
• Chronic Kidney Disease (CKD):
  • ↑ PTH (secondary hyperparathyroidism)
  • ↓ Calcitriol (active Vitamin D) → ↓ Ca2+ absorption.
• Potassium Regulation
  • Hyperkalemia → spastic paralysis and Hypokalemia → flaccid paralysis.
• Regulatory Hormones:
  • Insulin, Beta-adrenergic agonists, Aldosterone Move K⁺ into cells (↓ ECF K⁺).
  • Alpha-adrenergic stimulation (exercise) Moves K⁺ out of cells (↑ ECF K⁺).
  • Acid-base changes: Alkalosis → K+ into cells; Acidosis → K+ out of cells.
• Proximal Tubule & TALH: Always reabsorbed.
• Distal Nephron (Cortical CD – Principal Cells): Main site of secretion via ROMK channels.
• Regulation:
  • Aldosterone
    • ↑Na⁺-K⁺-ATPase → ↑ IC K⁺
    • Opens ROMK → ↑ K+ secretion
    • Stimulates ENaC → ↑ lumen negativity → ↑ K+ secretion
  • Flow Rate ↑ Tubular flow (diuretics, ADH suppression) → ↑ K+ secretion
  • Non-resorbable anions ↑ Lumen negativity → ↑ K+ secretion

Three Lines of Defense: Acid-Base Balance

1. Immediate (Buffering - msec-min) with HCO₃⁻ and primary extracellular buffer
2. Respiratory Compensation (sec-min) with CO₂ removal, shifting the HCO₃⁻ buffer system, depleting HCO₃ stores
   • Chemoreceptors respond to pH and PCO₂ to adjust respiration rate
3. Renal Compensation (hrs-days).
   • PCT and TALH: Reabsorption of filtered HCO₃⁻ and NHE3
   • Distal nephron: Generation of new HCO₃⁻ via H+ secretion and NH₄⁺ excretion andH-ATPase and H-K-ATPase

Lung Structure

• A = alveolar, a = arterial, V = ventilation, v = venous
• Conducting airways: Z0-Z16, 150 mLs held, no gas exchange, clean warm and humidify air with thick cartilage and smooth muscle
  • Segmental bronchi (Z4-Z7)
  • Terminal bronchioles last (Z16) and airflow is turbulent/transitional
• Respiratory bronchioles (Z17) - gas exchange begins, density of alveoli increases and sheds connective tissue towards Z23
  • Type I and II epithelia that make surfactant, airflow is laminar, and alveolar macrophages keep surfaces sterile

Path of Diffusion

• Alveolar fluid → alveolar epithelium → epithelial basement membrane → IS → capillary basement membrane → capillary endothelial membrane → blood → RBC within 0.75 sec, 3 alveoli, where CO₂ more soluble (5x as rapid)

Inspiration

• Work: diaphragm contracts down vs, secondary inspiratory muscles include external intercostals and sterno-cleidomastoids

Expiration

• Passive (uses recoil), with secondary expiratory muscles: including internal intercostals and abdominal muscle

Spirometry

• TLC (6L), FRC (ERV + RV), ERV (2 L), RV (1.2L), IRV (2.5L), FVC (5L), IC (IRV + Vт), Vт (0.5L), VC (5L)
• Can only measure VC values, cannot measure anything with RV (use helium dilution)
• Pulmonary diseases decrease VC

Pulmonary Mechanics

• Trans-pulmonary pressure (PTP) = PALV - PPL
  • PALV=0, PPL = -5, so PTP normally + 5 and PTP is pushing lungs out and the pleural space acts as a vacuum
  • Diaphragm generates trans pleural differences
• Pneumothorax - breach of thoracic cavity, PPL is equilibrates to 0 cm

Compliance

• How easy lungs stretch, C = AV/ΔΡ and where AV = Vт = 0.5 and ΔΡ = 2.5 so C = 0.2 (NORMAL)
• Low compliance = small change in ∆V/AP (pulmonary fibrosis)
• High compliance = high change in ∆V/AP (emphysema)
• Compliance inversely proportional to lung recoil

Air Flow Equation (Poiseullie's Law)

• (Poiseullie's Law)
  • Flow V = ΔPr⁴/8ηl, where r = radius, n = viscosity, l = length
• Resistance R = 8ηl/r⁴, radius has greatest effect on both bc exponential

Resistance

• As we move toward lower lung volumes (exhalation), resistance increases and major resistance includes segmental bronchi
  • ↑SNS (Epi/NE) and leads to ↑bronchodilation
  • ↑PNS (ACh) and leads to ↑bronchoconstriction
• Α receptors in vasculature causes constriction, while B receptors in pulmonary system causes relaxation and asthma leads to and increased airway resistance -Mild is related to cold or exercise induced (SNS agonist) -Moderate is related to allergen induced (SNS agonist + anti-histamine) and severe with extensive inflammation (corticosteroids)

Equal Pressure Point: pressure

• EPP is in pressure in airway = pressure in pleural space
• Normally EPP is in segmental bronchi

Work of Breathing

• FVC measurements with Restrictive Diseases - inflation restriction (pulmonary fibrosis, edema) where
• FEV1 (2.7) / FVC (3.0) = 90% and Due to decreased TLC
• More work done to inspire, flatter compliance line (AEC) due to small ∆V/ΔΡ
• Obstructive diseases affect expiration is obstructed and caused by emphysema and asthma - FEV1 (1.0) / FVC (3.0) = 33% - Due to increase RV and Factors: strength of chest and abdominal muscles, airway resistance, lung size, elastic properties
• less work done to spire, work required to expire, steep slop

Work equals AV/ΔΡ with Compliance equal to AEC, ABCDA = total work of breathing

• Hysteresis
• Is a difference in inflation and deflation lines on PV curve - due to greater P required to open a previously closed airway than keep an airway from closing

Elastic forces include

• Tissue lung with elastin, collagen) (3) and
• Those caused by surface tension at air and water interface in alveoli (2⁄3)

Surfactant

• Decreases surface tension by disrupting rigid structure of H2O (dipalmitoylphosphatidylcholine reduces ST) and no surfactant will influence ↑ compliance greatly
• LaPlaces Law equals with (pressure req to keep alveoli open) P = 2T/r and where T = surface tension in wall of sphere

Alveolar Ventilation with a minute ventilation

• Equals Vт (500mL) x RR (12) = 6000mL/min
• Alveolar ventilation equals (Vт - anatomical dead space (500mL - 150mL)) x RR (12) = 4200mL/min (70%)
• Influenced by VT, RR, exercise, age, altitude and disease.
• Depth is greater than frequency.

Dalton's Law

• Is a sum of individual pressures equals where include O2 (21%), N2 (79%), CO2 and H2O trace amts - Atm O2 =