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RENAL PHYSIOLOGY - EXAM NOTES

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1. FUNCTIONAL ANATOMY OF THE NEPHRON

Key Numbers (High-Yield)

Glomerular Filtration Barrier (3 Layers)

1. Fenestrated capillary endothelium - pores 70-90 nm; first barrier to cells
2. Glomerular basement membrane (GBM) - no visible pores; charge-selective (anionic - repels albumin)
3. Podocytes with filtration slits - ~25 nm wide; size-selective

• Free passage of neutral substances <4 nm
• Almost total exclusion of substances >8 nm
• Mesangial cells: contractile; regulate GFR; secrete extracellular matrix; take up immune complexes; involved in glomerular disease progression

Nephron Segments & Their Key Features

Cortical vs. Juxtamedullary Nephrons

• Cortical nephrons (85%): short loops of Henle; glomeruli in outer cortex
• Juxtamedullary nephrons (15%): long loops reaching inner medulla; essential for urine concentration; have vasa recta

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2. RENAL BLOOD FLOW

Key Numbers

• Renal blood flow (RBF) = 1200 mL/min (~20-25% of cardiac output)
• Renal plasma flow (RPF) = 660 mL/min
• GFR = 125 mL/min (180 L/day)
• Filtration fraction (FF) = GFR/RPF = 125/660 ≈ 0.20 (20%)

Blood Supply (in order)

• Afferent arteriole > Efferent arteriole (diameter)
• Two capillary beds in series = unique feature of renal circulation

Regional Blood Flow

• Medulla is vulnerable to hypoxia (low flow + active Na⁺ reabsorption in thick ascending limb)
• PO₂ cortex: ~50 mmHg; PO₂ medulla: ~15 mmHg

Autoregulation of RBF

• Maintained over 90-220 mmHg perfusion pressure
• Mechanisms:
  1. Myogenic response - afferent arteriole contracts directly in response to stretch
  2. Tubuloglomerular feedback (TGF) - macula densa senses NaCl delivery; releases adenosine → afferent arteriole constriction
• ACE inhibitors in poor renal perfusion → block Ang II (which constricts efferent arteriole to maintain GFR) → GFR drops → acute kidney injury risk

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3. GLOMERULAR FILTRATION RATE (GFR)

Starling Forces Governing GFR

Factors Increasing GFR

• ↑ Afferent arteriole dilation (e.g., PGE₂, NO)
• ↓ Efferent arteriole constriction (Ang II constricts efferent → maintains GFR when BP falls)
• ↓ Plasma oncotic pressure (e.g., hypoproteinemia)
• ↑ Renal plasma flow

Factors Decreasing GFR

• Afferent arteriole constriction (catecholamines, adenosine, endothelin)
• ↑ Urinary back pressure (obstruction)
• ↑ Plasma oncotic pressure
• ↓ Glomerular capillary coefficient (Kf) - glomerulonephritis

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4. MEASUREMENT OF GFR - CLEARANCE CONCEPT

Clearance Formula

• C_x = clearance of substance X (mL/min)
• U_x = urine concentration of X
• V = urine flow rate (mL/min)
• P_x = plasma concentration of X

Ideal GFR Marker Requirements

1. Freely filtered (not protein-bound)
2. Not reabsorbed
3. Not secreted
4. Not synthesized or degraded by kidney
5. Not toxic

GFR Markers Comparison (High-Yield)

RPF from PAH Clearance

• At low plasma concentrations, PAH secretion is maximal → C_PAH ≈ effective RPF
• True RPF = C_PAH / extraction ratio (~0.92)
• RBF = RPF / (1 - Hematocrit)

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5. TUBULAR TRANSPORT - REABSORPTION & SECRETION

General Formula

Tubular Transport Maximum (Tm)

• Carrier-mediated transport becomes saturated at high concentrations
• Above Tm: excess substance appears in urine
• Splay: deviation from ideal titration curve; due to heterogeneity in Tm across nephrons + variability in affinity

Glucose Transport (Classic Exam Topic)

• Transporter: SGLT-2 (apical, co-transports Na⁺ + glucose); GLUT-2 (basolateral, facilitated diffusion)
• SGLT-2 inhibitors (gliflozins) block glucose reabsorption → glucosuria → treat T2DM
• Phlorhizin: plant glucoside, inhibits SGLT → experimental glucosuria

Proximal Tubule (PCT) - Reabsorption Summary

• Reabsorbs ~65-67% of filtered Na⁺, water, K⁺, Cl⁻
• 100% of filtered glucose and amino acids (under normal conditions)
• ~90% of filtered HCO₃⁻
• Isotonic reabsorption - osmolarity stays the same (water follows Na⁺)
• Key transporter: Na⁺/H⁺ exchanger (NHE3) on apical membrane; Na⁺/K⁺-ATPase on basolateral

Thick Ascending Limb (TAL) - Critical for Concentration

• Impermeable to water (key feature)
• Active reabsorption via NKCC2 transporter (Na⁺-K⁺-2Cl⁻ cotransporter)
• Site of action of loop diuretics (furosemide - blocks NKCC2)
• Creates dilute tubular fluid and concentrated medullary interstitium
• "Diluting segment" of the nephron

Distal Tubule (DCT) & Collecting Duct - Fine Regulation

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6. RENIN-ANGIOTENSIN-ALDOSTERONE SYSTEM (RAAS)

Stimuli for Renin Release (from Juxtaglomerular Cells)

1. ↓ Renal perfusion pressure (baroreceptor mechanism in afferent arteriole)
2. ↓ NaCl delivery to macula densa (via TGF)
3. ↑ Sympathetic activity (β₁-adrenergic receptors on JG cells)

RAAS Cascade

Renin (from JG cells)
    ↓
Angiotensinogen (liver) → Angiotensin I (10 aa)
    ↓ ACE (lung, endothelium)
Angiotensin II (8 aa)
    ↓
1. Aldosterone release (adrenal cortex)
2. Efferent arteriole constriction → maintains GFR
3. ADH release
4. Thirst stimulation
5. Direct Na⁺ reabsorption in PCT
6. Sympathetic potentiation

Aldosterone Actions

• Acts on principal cells of DCT and collecting duct
• Genomic effect (hours): ↑ transcription of ENaC (epithelial Na⁺ channel) and Na⁺/K⁺-ATPase
• Net: Na⁺ retention + K⁺ excretion + H⁺ excretion
• Blocked by spironolactone (competitive antagonist) and eplerenone

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7. URINE CONCENTRATION MECHANISM

Countercurrent Multiplier (Loop of Henle)

• Descending limb: permeable to water, NOT solute → water moves out → tubular fluid becomes concentrated
• Ascending limb (thick): actively pumps NaCl OUT; impermeable to water → tubular fluid becomes dilute; interstitium becomes hyperosmotic
• This creates a single effect amplified by the countercurrent flow

Countercurrent Exchange (Vasa Recta)

• Vasa recta are hairpin capillaries alongside the loop of Henle
• Preserve the medullary osmotic gradient by passive exchange rather than washing it out
• Blood descending: loses water, gains solute
• Blood ascending: gains water, loses solute

Role of Urea

• Inner medullary collecting duct is permeable to urea (ADH-dependent)
• Urea enters medullary interstitium → contributes ~500 mOsm/kg of the 1200 mOsm/kg gradient
• Urea recycling: inner medulla → loop of Henle → continues

ADH (Vasopressin) and Urine Concentration

• Released from posterior pituitary in response to:
  • ↑ Plasma osmolarity (primary stimulus; detected by hypothalamic osmoreceptors)
  • ↓ Blood volume / pressure
• Acts via V2 receptors → cAMP → PKA → insertion of AQP-2 into apical membrane of collecting duct
• AQP-3 and AQP-4: constitutively expressed on basolateral membrane

Diabetes Insipidus - Quick Comparison

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8. POTASSIUM HANDLING

• Freely filtered at glomerulus
• PCT: reabsorbs ~65% passively
• TAL: reabsorbs ~25% via NKCC2
• DCT/Collecting duct: net secretion (principal cells) or reabsorption (intercalated cells) depending on K⁺ status

Factors Regulating K⁺ Secretion (DCT/CD)

• ↑ Secretion: aldosterone, high K⁺ intake, alkalosis, high tubular flow
• ↓ Secretion: acidosis, low tubular flow, low K⁺ intake, amiloride (blocks ENaC)

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9. ACID-BASE - RENAL CONTRIBUTION

HCO₃⁻ Reabsorption

• PCT reabsorbs ~90% of filtered HCO₃⁻
• Mechanism: H⁺ secreted via NHE3 → combines with filtered HCO₃⁻ → H₂CO₃ → CO₂ + H₂O (carbonic anhydrase IV on brush border) → CO₂ enters cell → carbonic anhydrase II → H₂CO₃ → H⁺ (secreted) + HCO₃⁻ (exits basolaterally)

Titratable Acid & Ammonium

• Titratable acid (mainly H₂PO₄⁻): H⁺ + HPO₄²⁻ → H₂PO₄⁻
• Ammonium (NH₄⁺): glutamine → NH₃ (in PCT) → combines with secreted H⁺ → NH₄⁺ (trapped in tubule)
• In chronic acidosis: ammoniagenesis is greatly upregulated (major adaptive response)

Net Acid Excretion

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10. DIURETICS - SITE & MECHANISM SUMMARY

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11. JUXTAGLOMERULAR APPARATUS (JGA)

Components

1. Juxtaglomerular (JG) cells - modified smooth muscle of afferent arteriole; produce renin
2. Macula densa - specialized DCT cells; sense NaCl; trigger TGF
3. Extraglomerular mesangial cells (Lacis cells) - between macula densa and glomerulus

Tubuloglomerular Feedback (TGF)

• ↑ NaCl delivery to macula densa → release of adenosine → constricts afferent arteriole → ↓ GFR
• Purpose: protects against excessive filtration and maintains glomerulotubular balance

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12. COMMONLY TESTED HIGH-YIELD POINTS

1. Filtration fraction = 20% (GFR/RPF = 125/660)
2. Inulin clearance = GFR; PAH clearance = RPF
3. Creatinine slightly overestimates GFR (tubular secretion)
4. If C_x > GFR → substance is secreted; if C_x < GFR → substance is reabsorbed
5. TAL is impermeable to water - the diluting segment
6. Aldosterone increases ENaC (Na⁺ in, K⁺ out); blocked by spironolactone
7. ADH inserts AQP-2 in collecting duct; central DI responds to desmopressin; nephrogenic does not
8. Furosemide blocks NKCC2 → loop of Henle; most potent diuretic
9. Thiazides decrease Ca²⁺ excretion (used in hypercalciuria/kidney stones)
10. Loop diuretics increase Ca²⁺ excretion (used in hypercalcemia)
11. Glucose renal threshold ~180 mg/dL (venous); Tm_G ~375 mg/min (men)
12. Splay: the curve deviates from ideal Tm due to nephron heterogeneity
13. ACE inhibitors in bilateral renal artery stenosis → ↓ Ang II → efferent arteriole dilates → GFR falls → acute kidney injury
14. RAAS stimuli: ↓ BP, ↓ NaCl at macula densa, ↑ sympathetic tone
15. Urea contributes ~500 mOsm/kg to the medullary gradient

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13. QUICK REFERENCE - SUBSTANCES & HANDLING

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CARDIOVASCULAR PHYSIOLOGY - EXAM NOTES

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1. KEY NUMBERS - MEMORIZE THESE

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2. FUNDAMENTAL EQUATIONS

CO = SV × HR

SV = EDV - ESV

EF = SV / EDV  (normal 55-65%)

MAP = Diastolic BP + 1/3(Pulse pressure)
    = CO × TPR

Pulse Pressure = Systolic - Diastolic BP
              ∝ SV / Arterial compliance

Fick Principle:  CO = O₂ consumption / (AO₂ content - VO₂ content)

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3. CARDIAC MUSCLE & ACTION POTENTIALS

Ventricular Action Potential (5 Phases)

• Resting membrane potential: -90 mV (ventricular cells)
• Plateau phase (Phase 2) is unique to cardiac muscle - prevents tetanic contraction
• Refractory period = entire duration of action potential (functional significance: heart cannot be tetanized)
• Ca²⁺ entry (phase 2) triggers Ca²⁺-induced Ca²⁺ release (CICR) from sarcoplasmic reticulum via ryanodine receptors

SA Node (Pacemaker) Action Potential - No Phase 1 or 2

• SA node RMP: ~-60 mV (less negative than ventricle)
• Automaticity = spontaneous phase 4 depolarization
• Autonomic control: Sympathetic (β₁) → ↑ If → steeper phase 4 → ↑ HR; Parasympathetic (ACh/M₂) → ↑ K⁺ conductance → hyperpolarization → ↓ HR

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4. CARDIAC CONDUCTION SYSTEM

Pathway (in order)

SA Node → Internodal pathways → AV Node → Bundle of His → 
Right & Left Bundle Branches → Purkinje Fibers → Ventricular myocardium

Conduction Velocities

Intrinsic Rates (Hierarchy of Pacemakers)

• Dominant pacemaker = SA node (fastest; suppresses others by overdrive suppression)
• If SA node fails → AV node takes over (escape rhythm at 40-60 bpm)

ECG Intervals and Their Meaning

• Atrial repolarization is hidden within the QRS complex
• Prolonged QT → torsades de pointes risk

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5. CARDIAC CYCLE (7 Phases - Costanzo)

Heart Sounds Quick Reference

Venous Pulse Waves

• Absent a wave: atrial fibrillation
• Giant a wave: tricuspid stenosis, AV dissociation
• Giant v wave: tricuspid regurgitation

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6. PRESSURE-VOLUME LOOP (High-Yield Exam Topic)

              Aortic valve closes
                     ↑
LV pressure    B----C
(mmHg)        /      \
         A  /          \ D
           /            \
          ←→
          A = Mitral opens (fills)
          B = Mitral closes (IVC begins)
          C = Aortic opens (ejection)
          D = Aortic closes (IVR begins)

• Width of loop = stroke volume
• Area enclosed = stroke work (work done by ventricle per beat)
• Preload = EDV (position on x-axis at start of contraction)
• Afterload = aortic pressure (height of loop)
• Contractility = slope of end-systolic pressure-volume relationship (ESPVR)

Effects on P-V Loop

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7. FRANK-STARLING LAW

"The volume the ventricle ejects in systole depends on the volume present at end-diastole."

Mechanism

• ↑ Venous return → ↑ EDV → sarcomere stretched (optimal length) → ↑ overlap of actin-myosin → ↑ force of contraction → ↑ SV
• Molecular basis: ↑ stretch → ↑ Ca²⁺ sensitivity of troponin C + ↑ Ca²⁺ release

Clinical Significance

• Ensures cardiac output = venous return in steady state
• Allows both ventricles to pump equal volumes (prevents pulmonary congestion)
• In heart failure: Starling curve is flattened/shifted downward

Starling Curve Shifts

• Upward shift (same EDV → ↑ CO): ↑ contractility (catecholamines, digoxin)
• Downward shift (same EDV → ↓ CO): ↓ contractility (heart failure, hypoxia, acidosis, beta-blockers)

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8. PRELOAD, AFTERLOAD & CONTRACTILITY

Factors Affecting Stroke Volume

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9. CONTROL OF HEART RATE

Autonomic Regulation

• Sympathetic → ↑ cAMP → ↑ If (funny current) → faster phase 4 depolarization → ↑ HR
• Parasympathetic → ↑ K⁺ permeability → hyperpolarization → slower phase 4 → ↓ HR

Treppe Effect (Bowditch/Staircase Phenomenon)

• ↑ HR → ↑ intracellular Ca²⁺ accumulation → ↑ contractility
• Explains why faster heart rates generate more force (to a point)

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10. VASCULAR PHYSIOLOGY

Blood Pressure Relationships

MAP = CO × TPR

Pulse Pressure = Systolic - Diastolic
               ∝ Stroke Volume / Arterial Compliance

↑ Pulse pressure: aortic regurgitation, hyperthyroidism, fever, 
                  arteriosclerosis (↓ compliance)
↓ Pulse pressure: aortic stenosis, cardiac tamponade, heart failure

Poiseuille's Law (Resistance)

R = 8ηL / (πr⁴)

F = ΔP / R

• Radius is the dominant factor (r⁴ relationship)
• Small change in radius → large change in resistance and flow
• Arterioles = site of greatest resistance = primary regulators of blood flow

Series vs. Parallel Circuits

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11. MICROCIRCULATION & CAPILLARY EXCHANGE

Starling Forces (Capillary)

• Net filtration at arterial end; net reabsorption at venous end
• Excess filtered fluid → lymphatics (prevents edema)

Causes of Edema

1. ↑ Capillary hydrostatic pressure (heart failure, venous obstruction)
2. ↓ Plasma oncotic pressure (hypoalbuminemia, liver disease, nephrotic syndrome)
3. ↑ Capillary permeability (inflammation, burns, sepsis)
4. Lymphatic obstruction (lymphedema)

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12. CORONARY CIRCULATION

Key Features

• Left coronary (LAD + circumflex): supplies LV anterior wall, septum, lateral wall
• Right coronary: supplies RV, SA node (60%), AV node (90%), inferior LV

Unique Regulation

• LV coronary flow occurs primarily in diastole (systole compresses vessels)
• RV coronary flow occurs in both systole and diastole (lower wall pressure)
• O₂ extraction is already near-maximal (~70%) at rest → must increase flow to meet demand
• Coronary reserve: ability to ↑ flow 4-5× baseline during exercise

Regulation of Coronary Blood Flow

• Metabolic (dominant): adenosine, CO₂, H⁺, K⁺, O₂ deficit → vasodilation
• Myogenic autoregulation
• Sympathetic: α₁ (constriction) + β₂ (dilation) - net dilation during exercise

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13. BARORECEPTOR REFLEX (Short-term BP Control)

Receptors

• Carotid sinus (CN IX, Hering's nerve) and aortic arch (CN X, vagus)
• Respond to stretch (pressure); firing rate ∝ arterial pressure

Reflex Arc

↓ BP
→ ↓ Baroreceptor firing
→ ↓ Input to NTS (nucleus tractus solitarius)
→ ↑ Sympathetic outflow + ↓ Parasympathetic outflow
→ ↑ HR, ↑ Contractility, ↑ Vasoconstriction (TPR)
→ BP restored

Clinical Correlates

• Orthostatic hypotension: on standing, gravity pools blood in legs → ↓ venous return → baroreceptor reflex kicks in → ↑ HR, ↑ TPR
• Carotid sinus massage: stimulates baroreceptor → vagal activation → ↓ HR (used to terminate SVT)
• Cushing reflex (cerebral ischemia): ↑ ICP → ↑ BP (compression of vessels → CO₂ buildup → medullary vasoconstriction centers) → bradycardia (via baroreceptors)

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14. CHEMOREFLEX CONTROL

Peripheral Chemoreceptors (Carotid & Aortic Bodies)

• Respond to: ↓ PO₂ (<60 mmHg), ↑ PCO₂, ↓ pH
• Response: ↑ Sympathetic → vasoconstriction in muscle/renal/splanchnic beds; initial ↓ HR (then overridden by hyperpnea)

Central Chemoreceptors (Medulla)

• Respond to: ↑ PCO₂ / ↓ pH (NOT primarily O₂)
• Brain ischemia → ↑ local CO₂ → medullary chemoreceptors → maximal sympathetic activation → hypertension + bradycardia (Cushing reflex)

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15. SPECIAL CIRCULATIONS

Pulmonary Circulation

• Low pressure (PAP = 25/8 mmHg, mean ~15 mmHg), low resistance
• Hypoxic pulmonary vasoconstriction (HPV): unique - hypoxia causes vasoconstriction (opposite to systemic) → redirects blood from poorly ventilated areas (V/Q matching)
• Pulmonary hypertension: mPAP >20 mmHg

Cerebral Circulation

• Autoregulation: 60-150 mmHg (tight)
• CO₂ = dominant regulator (↑ PCO₂ → vasodilation; ↓ PCO₂ → vasoconstriction)
• Blood-brain barrier; no sympathetic innervation of intracerebral vessels

Fetal Circulation

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16. CARDIAC FUNCTION & VASCULAR FUNCTION CURVES

Cardiac Function Curve

• Plots cardiac output vs. right atrial pressure (RAP)
• ↑ RAP (= ↑ preload) → ↑ CO (Frank-Starling)
• Shifts upward: ↑ contractility, ↓ afterload
• Shifts downward: heart failure, ↑ afterload

Vascular Function Curve

• Plots venous return vs. RAP
• ↑ RAP → ↓ venous return (back pressure opposes return)
• x-intercept = mean systemic filling pressure (MSFP, ~7 mmHg) - pressure when CO = 0
• Shifts right (higher MSFP): ↑ blood volume
• Rotates counterclockwise: ↑ TPR (↓ venous return at all RAP values)

Steady-State Operating Point

• Intersection of cardiac function curve and vascular function curve
• ↑ Contractility: cardiac curve shifts up → ↑ CO, ↓ RAP
• ↑ Blood volume: vascular curve shifts right → ↑ CO, ↑ RAP
• ↑ TPR: cardiac curve shifts down (↑ afterload) + vascular curve rotates → ↓ CO, variable RAP

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17. COMMONLY TESTED HIGH-YIELD POINTS

1. CO = SV × HR = 5 L/min normal; EF = SV/EDV (normal >55%)
2. MAP = DBP + 1/3 PP = CO × TPR
3. SA node is the dominant pacemaker (60-100 bpm); AV node = 40-60; Purkinje = 20-40
4. AV node has slowest conduction (PR interval delay = atrial emptying time)
5. Purkinje fibers have fastest conduction (4 m/s)
6. Plateau (phase 2) of cardiac AP = L-type Ca²⁺ channels; prevents tetany
7. SA node upstroke (phase 0) = Ca²⁺ (NOT Na⁺ unlike ventricle)
8. S1 = mitral closure (start of systole); S2 = aortic closure (start of diastole)
9. S3 = rapid filling into dilated ventricle = sign of heart failure in adults
10. S4 = atrial kick into stiff ventricle = hypertensive heart disease, hypertrophic cardiomyopathy
11. LV coronary flow is predominantly in diastole (systolic compression)
12. Pulmonary circulation is unique - hypoxia causes vasoconstriction
13. Baroreceptors respond to stretch: high pressure → ↑ firing → ↓ sympathetic → ↓ HR
14. Pulse pressure ∝ SV/compliance; widened in AR, arteriosclerosis; narrowed in AS, tamponade
15. ↑ TPR → ↑ MAP + ↓ CO (both curves shift negatively)
16. Foramen ovale → ligamentum arteriosum is wrong: Foramen ovale → fossa ovalis; Ductus arteriosus → ligamentum arteriosum
17. Fick principle: CO = VO₂ / (CaO₂ - CvO₂); normal VO₂ = 250 mL/min
18. Ejection fraction <40% = systolic heart failure; preserved EF with diastolic dysfunction = HFpEF
19. Cardiac tamponade: equalization of diastolic pressures; pulsus paradoxus; muffled S1 S2; ↑ JVP
20. Starling law ensures cardiac output = venous return in steady state

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18. QUICK COMPARISON - SYSTOLIC vs. DIASTOLIC HEART FAILURE

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19. CARDIOVASCULAR RESPONSE TO EXERCISE

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