1. Normal ECG - Waves (P, QRS, T), how it's recorded, all leads (bipolar + augmented + chest), P-R interval significance, and Einthoven's Law (Lead II = Lead I + Lead III) - with labeled ECG diagrams
2. Cardiac Cycle - All 7 phases, pressure/volume changes, ejection fraction formula (normal ~60%), all 4 heart sounds with causes, and Frank-Starling law
3. Cardiac Output & Venous Return - Definition, Fick principle formula, cardiac index, all factors affecting CO and venous return, factors affecting stroke volume - with blood flow distribution diagram
4. Long-term BP Regulation - Full renin-angiotensin cascade, role of JGA (baroreceptor + macula densa), pressure-natriuresis mechanism, aldosterone/ADH - with equilibrium pressure graph
5. Coronary Circulation - All peculiarities (diastolic flow dominance, high O₂ extraction, etc.), metabolic regulation (adenosine), angina types + ECG changes, MI ECG sequence, and full table of cardiorespiratory changes during exercise
6. Circulatory Shock - 4-type classification table, 3 stages with physiological explanation, hypovolemic shock management principles

Glomerular Filtration

Definition

Excretion = Filtration - Reabsorption + Secretion

The Glomerular Filtration Membrane

1. Fenestrated Capillary Endothelium

• Perforated by thousands of tiny holes called fenestrae (~8 nm / 80 Å)
• Allows rapid passage of water and small solutes
• Endothelial proteins carry fixed negative charges (glycocalyx) - repel plasma proteins

2. Glomerular Basement Membrane (GBM)

• A meshwork of collagen and proteoglycan fibrillae
• Large spaces allow water and small solutes to pass freely
• Strongly negatively charged - major barrier to plasma proteins
• Damaged in diseases like diabetes (thickened GBM) and Goodpasture syndrome

3. Epithelial Cell Layer (Podocytes)

• Not a continuous layer; podocytes have long foot processes called pedicels
• Pedicels are separated by filtration slits bridged by thin slit diaphragms
• Slit diaphragm contains proteins nephrin and podocin - critical for preventing proteinuria
• Mutations in nephrin gene → absent filtration slit diaphragms → massive proteinuria

Filterability Table

Key point: Filterability depends on both molecular size AND electrical charge. Negatively charged molecules are filtered less readily than neutral or positively charged molecules of the same size (because the GBM is negatively charged).

Glomerular Filtration Rate (GFR)

• Normal GFR = 125 mL/min (180 L/day)
• Women: ~10% lower than men
• GFR declines progressively with age (see graph below)

Filtration Fraction

Filtration Fraction = GFR / Renal Plasma Flow = 125 / 625 = ~0.2 (20%)

• ~20% of the plasma flowing through the kidneys is filtered each minute
• The kidneys receive 22% of total cardiac output (~1100 mL/min blood flow, ~625 mL/min plasma flow)

Starling Forces Determining GFR

Filtration Coefficient (Kf)

Kf = GFR / Net filtration pressure = 125 / 10 = 12.5 mL/min/mmHg

• Kf is the product of hydraulic conductivity × filtration surface area
• Glomerular Kf is ~400x higher than in most other capillaries in the body
• Expressed per 100g kidney weight ≈ 4.2 mL/min/mmHg
• Reduced in chronic hypertension and glomerulonephritis (thickened GBM)

Factors Affecting GFR

1. Glomerular Hydrostatic Pressure (PG) - Primary Regulator

2. Bowman Capsule Hydrostatic Pressure (PB)

• Normal = 18 mmHg
• Increased by urinary tract obstruction (e.g., kidney stones, ureteral stones) → ↓ GFR → hydronephrosis if prolonged

3. Glomerular Colloid Osmotic Pressure (πG)

• Normal = 32 mmHg
• As blood passes through glomerular capillaries, ~1/5 of fluid is filtered → proteins concentrate → πG rises along the length of the capillary
• ↑ Plasma proteins → ↑ πG → ↓ GFR
• ↓ Plasma proteins (hypoalbuminemia, e.g., nephrotic syndrome, liver disease) → ↓ πG → ↑ GFR (filtration fraction increases)
• ↑ Renal blood flow → slower concentration of proteins → slower rise in πG → ↑ GFR

4. Filtration Coefficient (Kf)

• Decreased in diseases that reduce glomerular surface area or increase GBM thickness (e.g., chronic hypertension, glomerulonephritis, diabetic nephropathy)

Summary Table: Factors That Decrease GFR

Measurement of GFR - Inulin Clearance

• Freely filtered (filterability = 1.0)
• Not reabsorbed, secreted, or metabolized by the tubules
• Therefore: Amount filtered = Amount excreted

GFR = (Urine inulin conc. × Urine flow rate) / Plasma inulin conc.

Autoregulation of GFR and Renal Blood Flow

1. Myogenic mechanism - increased wall tension in the afferent arteriole causes smooth muscle contraction, reducing diameter and resistance compensation
2. Tubuloglomerular feedback (TGF) - via the macula densa; increased NaCl delivery → adenosine and TXA₂ released → afferent arteriolar constriction → ↓ GFR (negative feedback)

All Clinical Cases from Guyton - Renal Physiology

CLINICAL CASE 1: Acute Kidney Injury (AKI)

Definition & Classification

CASE 1A: Prerenal AKI

• Normal renal blood flow ~1100 mL/min (~22% of cardiac output)
• As RBF falls → ↓ GFR → ↓ Na⁺ filtered → ↓ tubular reabsorption → ↓ O₂ consumption
• This protective reduction allows the kidney to tolerate reduced blood flow down to ~20-25% of normal without major cellular damage
• Below this level → tubular epithelial cells become hypoxic → cell death → intrarenal AKI
• Oliguria (urine output < fluid intake) develops when RBF is significantly reduced
• Anuria (complete cessation of urine output) may occur with very severe reduction

CASE 1B: Intrarenal AKI - Acute Glomerulonephritis

• Most common cause: abnormal immune reaction 1-3 weeks after infection elsewhere in the body (classically Group A beta-hemolytic Streptococcus - post-streptococcal GN)
• Mechanism: antigen-antibody complexes deposit in glomerular capillaries → inflammatory reaction → ↓ GFR
• Features: hematuria, proteinuria, reduced urine output, edema, hypertension
• If the inflammation subsides, most patients recover; if severe/persistent → CKD

CASE 1C: Postrenal AKI

• Obstruction anywhere from the calyces to the bladder outlet
• Most common cause: kidney stones (calcium, urate, or cystine precipitation)
• Obstruction → ↑ Bowman capsule hydrostatic pressure → ↓ net filtration pressure → ↓ GFR → hydronephrosis
• Relief of obstruction usually restores GFR

CLINICAL CASE 2: Chronic Kidney Disease (CKD) and Uremia

Causes of CKD

The kidney can maintain relatively normal blood electrolyte concentrations and body fluid volumes until nephron number falls to less than 20-25% of normal. Below this, clinical uremia develops.

The Vicious Cycle of CKD → ESRD

• Surviving nephrons hypertrophy and vasodilate to compensate
• This causes hyperfiltration in remaining nephrons → ↑ glomerular pressure
• Over time, high pressure damages surviving glomeruli → glomerular sclerosis
• This triggers further nephron loss → the cycle continues
• Ultimately leads to end-stage renal disease (ESRD)

Uremia - Effects of Renal Failure on Body Fluids

CLINICAL CASE 3: Nephrotic Syndrome

1. Glomerular capillary permeability ↑ → plasma proteins (especially albumin) leak into filtrate
2. Plasma protein concentration falls to <1/3 of normal → plasma colloid osmotic pressure falls markedly
3. Capillaries throughout the body filter excess fluid into tissues → massive edema
4. Reduced plasma volume activates RAAS and sympathetic nervous system
5. Kidneys retain Na⁺ and water → blood volume partially restored
6. But proteins remain diluted → plasma oncotic pressure remains low → fluid continues leaking into tissues
7. Vicious cycle: more Na⁺/water retention → more dilution of plasma proteins → more edema

• Massive pitting edema (anasarca)
• Proteinuria >3.5 g/day
• Hypoalbuminemia
• Hyperlipidemia and lipiduria (compensatory liver protein synthesis makes lipoproteins)
• Frothy urine

CLINICAL CASE 4: Renal Interstitial Nephritis and Pyelonephritis

Pyelonephritis

• Bacterial infection of the renal interstitium, most commonly from E. coli (fecal origin)
• Route of infection: bloodstream, or more commonly ascending infection via ureters from bladder

1. Incomplete bladder emptying - residual urine allows bacteria to multiply
2. Urinary tract obstruction - impairs flushing of bacteria
3. Vesicoureteral reflux - urine propelled back up ureters during micturition, carrying bacteria to the renal pelvis

• Primarily affects the medulla initially → impaired countercurrent mechanism → inability to concentrate urine (earliest sign)
• Long-standing pyelonephritis: progressive tubular, glomerular, and interstitial damage throughout the kidney → CKD

CLINICAL CASE 5: Tubular Transport Disorders

Bartter Syndrome

• Autosomal-recessive mutation in Na-K-2Cl transporter in the thick ascending limb of the loop of Henle
• Results in: impaired Na⁺ reabsorption → salt wasting → volume depletion → RAAS activation → hypokalemia, metabolic alkalosis, hyper-reninemia, hyperaldosteronism
• Blood pressure is normal or low (despite high renin/aldosterone) because volume depletion counteracts vasoconstriction
• Treatment: replace NaCl and K⁺; NSAIDs (reduce prostaglandin-mediated vasodilation); spironolactone (aldosterone antagonist)

Gitelman Syndrome

• Autosomal-recessive mutation in thiazide-sensitive NaCl co-transporter in the distal tubule
• Similar to Bartter syndrome but milder: salt wasting, volume depletion, RAAS activation, hypokalemia, metabolic alkalosis
• Also associated with hypomagnesemia (impaired Mg²⁺ reabsorption in distal tubule)
• Treatment: NaCl + K⁺ + Mg²⁺ supplementation; spironolactone

Liddle Syndrome

• Autosomal-dominant gain-of-function mutation in amiloride-sensitive epithelial Na⁺ channel (ENaC) in distal and collecting tubules
• Results in: excessive Na⁺ reabsorption → hypertension, metabolic alkalosis, hypokalemia
• Resembles primary hyperaldosteronism BUT: renin is low, aldosterone is low (because Na⁺ retention suppresses the RAAS)
• Treatment: amiloride (directly blocks ENaC); NOT spironolactone (because aldosterone is not elevated)

CLINICAL CASE 6: Renal Artery Stenosis - Two-Kidney Goldblatt Hypertension

1. ↓ Pressure in ischemic kidney → ↑ Renin secretion → ↑ Angiotensin II
2. Angiotensin II → vasoconstriction → ↑ arterial pressure
3. ↑ Arterial pressure → normal kidney increases Na⁺/water excretion (pressure natriuresis)
4. The ischemic kidney cannot respond to increased pressure (has low perfusion pressure)
5. Net effect: sustained hypertension
6. Elevated angiotensin II also causes the normal kidney to retain salt/water → adds to hypertension

Warning: ACE inhibitors in bilateral renal artery stenosis can cause AKI by removing the angiotensin II-driven efferent constriction that maintains GFR.

CLINICAL CASE 7: Treatment of Renal Failure - Dialysis

Indications for Dialysis

• Severe AKI (temporary, until kidney function recovers)
• ESRD (permanent) - over 800,000 patients in the USA are on ESRD therapy

Principles of Dialysis (Artificial Kidney)

• Blood passes through minute channels bounded by a thin semipermeable membrane
• On the other side of the membrane is a dialysate solution with a composition similar to normal plasma
• Small molecules (urea, creatinine, electrolytes) diffuse from blood into dialysate down concentration gradients
• Normal plasma electrolytes are maintained in the dialysate so they are NOT removed
• Larger molecules (proteins) are too big to pass through the membrane

Limitations of Dialysis vs. Transplantation

• Dialysis cannot replace all kidney functions (erythropoietin production, Vitamin D activation, renin-angiotensin regulation)
• Health of dialysis patients remains significantly impaired
• Kidney transplantation restores function more completely and patients live longer with fewer complications
• ~25,000 kidney transplantations are performed per year in the USA
• Requires lifelong immunosuppressive therapy → risk of infections and some cancers