• Cardiology - heart failure, arrhythmias, ACS, valvular disease
• Respiratory - COPD, asthma, pneumonia, TB, lung cancer
• Nephrology - AKI, CKD, glomerulonephritis, electrolyte disorders
• Gastroenterology - liver disease, IBD, GI bleeding, pancreatitis
• Endocrinology - diabetes, thyroid, adrenal, pituitary disorders
• Neurology - stroke, epilepsy, meningitis, movement disorders
• Infectious Disease - antibiotics, tropical medicine, sepsis
• Hematology/Oncology - anemias, leukemias, coagulation disorders
• Rheumatology - SLE, RA, vasculitis, crystal arthropathies
• Pharmacology - drug mechanisms, side effects, interactions

• Explain concepts and pathophysiology clearly
• High-yield MCQ-style questions with explanations
• Mnemonics and memory aids
• Differentials and clinical reasoning
• Quick revision summaries
• Recent evidence and guidelines

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ECG Mastery: Basics to Advanced

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MODULE 1 - Why ECG? The Big Picture

• Rhythm and rate
• Conduction system integrity
• Chamber size (hypertrophy)
• Ischemia and infarction (location, age, extent)
• Metabolic/electrolyte status
• Drug effects
• Pericardial disease

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MODULE 2 - The Cardiac Conduction System

SA Node (right atrium)
    ↓  (atrial depolarization = P wave)
AV Node (PR delay = AV node slowing)
    ↓
Bundle of His
    ↓
Right Bundle Branch  +  Left Bundle Branch
                            ↙         ↘
                    Left Anterior   Left Posterior
                      Fascicle        Fascicle
    ↓
Purkinje Fibers → Ventricular myocardium (= QRS)

• SA node fires at 60-100/min (dominant pacemaker)
• AV node fires at 40-60/min if SA fails (junctional escape)
• Purkinje / ventricle fires at 20-40/min (ventricular escape)
• Ventricular repolarization = ST segment + T wave

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MODULE 3 - ECG Paper and Calibration

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MODULE 4 - ECG Waveforms and Intervals

The Waves

The Intervals

• Regular rhythm: HR = 300 ÷ (number of large squares between R-R)
• Or: HR = 1500 ÷ (number of small squares between R-R)
• Irregular: count QRS complexes in 10-second strip × 6

1 large square = 300 bpm | 2 = 150 | 3 = 100 | 4 = 75 | 5 = 60 | 6 = 50

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MODULE 5 - The 12 Leads (Understanding the "Camera Angles")

Limb Leads (Frontal Plane)

Precordial Leads (Horizontal Plane)

Grouping Leads by Territory

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MODULE 6 - The Normal ECG (What to Expect)

Normal Sinus Rhythm Checklist

• Rate: 60-100 bpm
• P wave before every QRS; QRS after every P
• PR interval: 120-200 ms
• P wave: upright in I, II; inverted in aVR
• QRS: <110 ms, normal axis (-30° to +90°)
• R-wave progression in V1-V6 (R grows from V1 to V5)

P Wave Morphology

• Right atrial enlargement (P pulmonale): P wave >2.5 mm tall in II (peaked)
• Left atrial enlargement (P mitrale): P wave >120 ms wide, notched in II; terminal negative deflection in V1 >1 mm² (>1 small square wide AND deep)

QRS Axis

• Both upright → Normal
• I up, aVF down → Left axis
• I down, aVF up → Right axis
• Both down → Extreme axis

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MODULE 7 - Chamber Enlargement / Hypertrophy

Left Ventricular Hypertrophy (LVH)

• S in V1 + R in V5 or V6 ≥ 35 mm
• R in aVL ≥ 11 mm (Cornell criteria)
• Associated with: LV strain pattern (ST depression + T wave inversion in lateral leads I, aVL, V5, V6)

Right Ventricular Hypertrophy (RVH)

• R ≥ S in V1 (dominant R in V1)
• RAD (axis >+90°)
• rSR' in V1 is NOT RVH - that is RBBB
• ST depression + T wave inversion in V1-V3 (RV strain)

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MODULE 8 - Bundle Branch Blocks

Right Bundle Branch Block (RBBB)

• QRS ≥ 120 ms
• RSR' ("M-shaped" or "rabbit ears") in V1
• Wide, slurred S wave in I, V5, V6
• T wave inverted in V1 (secondary change - normal with RBBB)

RBBB = bunny ears in V1 (rSR' = ears of a rabbit)

Left Bundle Branch Block (LBBB)

• QRS ≥ 120 ms
• Broad, notched R (no Q, no S) in I, aVL, V5, V6
• rS or QS (deep S) in V1, V2
• T wave opposite to main QRS deflection (secondary change)

• LBBB: W in V1, M in V6
• RBBB: M in V1, W in V6

Fascicular Blocks (Hemiblocks)

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MODULE 9 - AV Blocks

First Degree AV Block

• PR interval > 200 ms (>1 large square)
• Every P conducts to QRS (just slowly)
• Usually benign; can be normal in athletes

Second Degree AV Block

• Progressive PR lengthening until a P wave is blocked (QRS dropped)
• "Longer, longer, longer, DROP - then you have a Wenckebach"
• PR after the dropped beat is shortest
• Usually at AV node level; generally benign
• Can be normal in athletes (vagal tone)

• Fixed PR interval; sudden non-conducted P wave (QRS drops without warning)
• Below AV node (His-Purkinje level) - more serious
• Often associated with wide QRS
• High risk of progressing to complete heart block → needs pacemaker

Third Degree (Complete) AV Block

• Complete dissociation: P waves and QRS complexes march independently
• P rate > QRS rate
• QRS escape rhythm: narrow (junctional, 40-60/min) or wide (ventricular, 20-40/min)
• Wide-complex escape = more severe (infranodal block)
• Emergency: Atropine (for narrow-complex), transcutaneous pacing, then permanent pacemaker

Wenckebach = Increasing PR before drop (I = Increasing) Mobitz II = Suddenly drops (II = abrupt, Sudden)

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MODULE 10 - Ischemia and Infarction

Spectrum of Ischemic ECG Changes

• Tall, broad, peaked T waves over ischemic zone
• First sign of complete coronary occlusion

• ST elevation in ≥2 contiguous leads
• Threshold: ≥1 mm (most leads), ≥2 mm (V1-V3 men), ≥1.5 mm (V1-V3 women)
• Represents full-thickness (transmural) injury
• Mechanism: epicardial injury current shifts ST vector outward

• Horizontal or downsloping ST depression ≥0.5-1 mm
• Mechanism: ischemia confined to subendocardium; ST vector shifts inward

• Symmetric, deep T wave inversions
• Wellens' syndrome: deep T inversions in V2-V3 = critical proximal LAD stenosis (do NOT stress test - risk of VF)

• Width ≥ 40 ms (1 small square)
• Depth ≥ 25% of R wave height in same lead
• Represent electrically dead (necrotic) myocardium
• Q waves in II, III, aVF = inferior MI; V1-V4 = anterior MI; I, aVL = lateral MI

Localization of STEMI

Evolution of STEMI Over Time

Minutes:    Hyperacute T waves (peaked, tall)
Hours:      ST elevation (convex/"tombstone" shape)
6-24h:      ST elevation + Q waves appear + T inversion begins
Days:       ST returns to baseline + T waves inverted + Q waves persist
Weeks-mos:  ST and T normalize; Q waves often persist permanently

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MODULE 11 - Arrhythmias

Approach to Any Arrhythmia (systematic)

1. Rate: Fast / slow / normal?
2. Regular or irregular?
3. QRS wide or narrow?
4. P waves present? What is the relationship to QRS?

Narrow Complex Tachycardias (QRS < 120 ms)

Wide Complex Tachycardias (QRS ≥ 120 ms) - THE HIGH-STAKES AREA

1. VT (ventricular tachycardia) - most dangerous, assume this first
2. SVT with aberrant conduction (LBBB/RBBB)
3. SVT with pre-excitation (WPW with AF = most dangerous SVT)
4. Pacemaker-mediated tachycardia

If in doubt, treat wide complex tachycardia as VT until proven otherwise Never give adenosine or verapamil to pre-excited AF (WPW+AF) - can precipitate VF

• AV dissociation (P waves marching independently) = definitive VT
• Capture beats (narrow QRS among wide) = definitive VT
• Fusion beats = definitive VT
• QRS duration > 160 ms
• Concordance (all precordial leads all-positive or all-negative)
• NW (extreme) axis deviation

Bradyarrhythmias

Ventricular Arrhythmias

• Wide (>120 ms), bizarre QRS
• No preceding P wave
• Compensatory pause
• Bigeminy (every other beat), trigeminy (every third)

• ≥3 consecutive wide QRS complexes at ≥100 bpm
• Sustained (>30 s) vs non-sustained (<30 s)
• Monomorphic (uniform QRS) vs polymorphic (varying QRS)

• Polymorphic VT with twisting QRS axis around baseline
• Occurs with long QT (congenital or acquired)
• Triggers: hypokalemia, hypomagnesemia, drugs (class IA/III antiarrhythmics, antipsychotics, antibiotics like azithromycin)
• Treatment: IV magnesium sulfate; correct electrolytes; stop offending drug

• Chaotic, irregular deflections, no organized QRS
• No cardiac output = cardiac arrest
• Immediate defibrillation + CPR

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MODULE 12 - Pre-excitation (WPW Syndrome)

• Short PR interval (<120 ms) - bypass of AV node
• Delta wave - slurred upstroke of QRS
• Wide QRS (>110 ms) - fusion of normal and accessory pathway conduction
• ST-T changes secondary to abnormal depolarization

• Positive delta in V1-V3, negative in aVL = left-sided pathway (most common)
• Negative delta in II, III, aVF = posterior/inferior pathway

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MODULE 13 - Metabolic and Drug Effects

Hyperkalemia (sequential changes as K+ rises)

Hypokalemia

• Flattened T waves
• Prominent U waves (U > T wave height = significant)
• Apparent QT prolongation (actually QU prolongation)
• Risk of Torsades

Hypercalcemia

• Shortened QT interval
• Short ST segment or absent ST

Hypocalcemia

• Prolonged QT (prolonged ST segment)
• T wave remains normal

Digoxin

• "Reverse tick" or "Salvador Dali mustache" ST depression (scooping)
• Shortened QT
• T wave flattening or inversion
• Digoxin toxicity: PAT with block, ventricular bigeminy, PVCs, AV blocks

Hypothermia

• Bradycardia
• Osborn (J) wave: positive deflection at J point (most visible in V5, V6)
• Prolonged PR, QRS, QT
• Shivering artifact

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MODULE 14 - Pericarditis vs. STEMI

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MODULE 15 - Pulmonary Embolism ECG

• Deep S wave in Lead I
• Q wave in Lead III
• T wave inversion in Lead III

• Sinus tachycardia (most common sign)
• New RBBB (acute right heart strain)
• RAD
• T wave inversions V1-V4 (RV strain pattern)
• Atrial arrhythmias (AF, flutter)
• P pulmonale

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MODULE 16 - The Brugada Pattern

• Coved (convex) ST elevation ≥2 mm in V1-V2
• Down-sloping ST segment followed by T wave inversion
• Spontaneous or drug-induced

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MODULE 17 - The 14-Step Systematic ECG Approach (Exam and Clinical)

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MODULE 18 - High-Yield Exam Mnemonics

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MODULE 19 - Quick Clinical Decision Rules

• ST elevation ≥1 mm in ≥2 contiguous leads → Activate cath lab (STEMI protocol) - door to balloon <90 min
• New LBBB + chest pain → Same as STEMI (Sgarbossa criteria)
• ST depression V1-V4 + inferior STEMI → Posterior MI; do V7-V9
• Inferior STEMI + hypotension + clear lungs → Rule out RV MI with V4R

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Suggested Study Order for Exams

1. Paper calibration + waveform basics (Module 3, 4)
2. Leads and normal ECG (Module 5, 6)
3. Ischemia/STEMI localization (Module 10) - highest exam yield
4. Bundle branch blocks (Module 8)
5. AV blocks (Module 9)
6. Arrhythmias systematic approach (Module 11)
7. Metabolic effects (Module 13)
8. Practice 14-step approach on real ECGs (Module 17)

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ECG Visual Atlas: Stepwise Learning with Real ECGs

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LEVEL 1 - The Foundation

ECG 1: Normal Sinus Rhythm - Your Baseline

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ECG 2: Ventricular Depolarization - How the QRS is Born

• Phase 1 (septum): Depolarizes left → right. V1 sees it coming → small upward r wave. V6 sees it going away → small downward q wave.
• Phase 2 (ventricles): LV dominates, vector swings left → right. V1 sees it going away → deep S wave. V6 sees it coming → tall R wave.

• V1 = rS (small r, big S)
• V6 = qR (tiny q, big R)
• V1 → V5 = R wave progressively gets bigger (R-wave progression)

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LEVEL 2 - Atrial and Ventricular Enlargement

ECG 3: P Wave Morphology - Atrial Abnormalities

• RAE (P pulmonale): COPD, pulmonary hypertension, tricuspid stenosis, PE
• LAE (P mitrale): Mitral stenosis, mitral regurgitation, LVH, dilated cardiomyopathy

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ECG 4: LVH and RVH Patterns

• S in V1 + R in V5 or V6 ≥ 35 mm
• R in aVL ≥ 11 mm (women); ≥ 28 mm (men) - Cornell criteria
• LV strain pattern: ST depression + asymmetric T inversion in I, aVL, V5, V6

• Dominant R wave in V1 (R ≥ S in V1)
• Right axis deviation (axis > +90°)
• RV strain pattern: T inversion in V1-V3

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LEVEL 3 - Ischemia and Infarction (Highest Exam Yield)

ECG 5: The Mechanism of ST Deviation

• Panel A (Subendocardial ischemia): Injury current vector points inward → leads overlying the LV see ST depression. This is NSTEMI/unstable angina territory.
• Panel B (Transmural/epicardial ischemia): Injury current vector points outward → leads overlying the zone see ST elevation. This is STEMI territory.

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ECG 6: Anterior STEMI (LAD occlusion)

• ST elevation in V1-V4 (anteroseptal leads) - convex/oblique ST morphology
• Note the tall R waves progressing V1-V4, then cut short by the ST change
• This patient had a 90% LAD stenosis - went to cath lab immediately

1. Rate: ~70 bpm, sinus
2. ST elevation: V1, V2, V3, V4 - ≥2 mm in V1-V3 = diagnostic STEMI
3. Reciprocal changes: Look for ST depression in II, III, aVF (inferior leads)
4. Q waves: May be developing - marker of established necrosis
5. ACTION: Activate cath lab. Door-to-balloon time target: <90 min

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ECG 7: Anterolateral STEMI (LAD + circumflex territory)

• ST elevation spreading across V2-V6, I, and aVL = extensive anterolateral territory
• This is a large territory MI - "widowmaker" territory (proximal LAD)
• Patient had in-stent thrombosis of previous LAD stent

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ECG 8: Wellens Syndrome (Critical LAD Stenosis Warning)

• Deep, symmetric T-wave inversions in V2-V4 (precordial leads)
• Note: no current ST elevation, R waves preserved (no Q waves yet)
• Patient had chest pain that may have resolved

⚠️ DO NOT do a stress test on this patient - can precipitate VF and death. Refer urgently for coronary angiography.

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ECG 9: Left Main / Proximal LAD Occlusion - aVR Elevation

• ST elevation in aVR > 1 mV (the lead pointing at the right shoulder / LV cavity)
• Widespread ST depression in most other leads (I, II, aVL, V4-V6 at minimum)
• This pattern = diffuse subendocardial ischemia from left main occlusion

ST elevation in aVR + widespread ST depression elsewhere = Left main stenosis (78% sensitive, 83% specific) or severe proximal LAD disease

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LEVEL 4 - Bundle Branch Blocks

ECG 10: RBBB vs LBBB - The WiLLiaM MaRRow Rule

• WiLLiam = LBBB has W in V1, M in V6
• MaRRow = RBBB has M in V1, W in V6

• QRS ≥ 120 ms
• rSR' ("rabbit ears") in V1
• Wide slurred S in I, aVL, V5, V6
• T wave inverted in V1-V2 (secondary - normal with RBBB, not ischemia)

• QRS ≥ 120 ms
• Broad monophasic R in I, aVL, V5, V6 (no Q wave, no S wave)
• Deep QS or rS in V1
• T wave inverted in I, aVL, V5, V6 (secondary - normal with LBBB)

• RBBB: Often benign; new RBBB in acute anterior MI = proximal LAD (septal branch involvement)
• LBBB: New LBBB + chest pain = treat as STEMI (modified Sgarbossa criteria)

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LEVEL 5 - AV Blocks (Visual Patterns)

ECG 11-13: The Three AV Blocks

P----P----P----P      (every P conducts)
QRS  QRS  QRS  QRS   (every P has a QRS)
↕PR: >200ms (stretched but constant)

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P    P    P    P    P    P    P
QRS  QRS  QRS  ---  QRS  QRS  ---
PR:  ↑    ↑↑   ↑↑↑  drop  ↑    ↑↑   drop

• Benign, usually AV node level
• Common in athletes (high vagal tone) and inferior MI

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P    P    P    P    P    P
QRS  QRS  ---  QRS  QRS  ---
PR:   =    =         =    =   (CONSTANT then sudden drop)

• Dangerous - below the AV node (His-Purkinje)
• Associated with wide QRS, anterior MI
• Requires pacemaker - high risk of complete block

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P    P    P    P    P    P    P    P   (fast, ~70-80/min)
   QRS      QRS      QRS      QRS     (slow, 30-50/min)

• Narrow QRS escape = junctional (40-60/min) = AV node still working below block
• Wide QRS escape = ventricular (20-40/min) = dangerous, more hemodynamically unstable
• Emergency: atropine (narrow complex), transcutaneous pacing, urgent permanent pacemaker

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LEVEL 6 - Metabolic ECGs (Must Know for Exams)

ECG 14: Hyperkalemia - The Deadly Progression

• Peaked T waves = call for ECG immediately in any CKD/renal patient
• Sine wave = life-threatening emergency - give calcium gluconate NOW
• Treatment sequence: C-BIG-K-D (Calcium, Bicarbonate, Insulin+Glucose, Kayexalate, Dialysis)

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ECG 15: Hypokalemia - The U Wave

• Lead II (left): Flat T wave, barely visible, slight prolongation of the QT interval
• V3 (right): Prominent U wave labeled - note it is taller than the T wave in this lead

• T wave flattening → T wave inversion
• U wave prominence (U > T = significant hypokalemia)
• Apparent QT prolongation (actually QU prolongation - U wave merging with T)
• Risk: Torsades de Pointes especially if on QT-prolonging drugs

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ECG 16: Pericarditis with Cardiac Tamponade - Electrical Alternans

1. Sinus tachycardia (compensatory, filling impaired)
2. Low QRS voltage (<5 mm all limb leads and/or <10 mm chest leads) - fluid insulating the heart
3. Electrical alternans - QRS height alternates every other beat (arrows in V2, V4) - heart swinging inside fluid

• Diffuse saddle-shaped (concave) ST elevation in most leads (not just regional)
• PR segment depression (very specific for pericarditis)
• No reciprocal ST depression (except aVR)
• No Q waves

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LEVEL 7 - Clinical Syndromes (Advanced)

ECG 17: Inferior STEMI - RCA Occlusion

• ST elevation in II, III, aVF (inferior leads)
• Reciprocal ST depression in I and aVL (lateral leads)
• III > II elevation = more likely RCA (proximal)
• II > III elevation = more likely LCx

1. Right-sided leads (V3R, V4R): If ST elevation here = RV infarction (25-40% of inferior STEMIs)
   • RV MI = give fluids (not nitrates!), no diuretics, no morphine
2. Posterior leads (V7-V9) or V1-V2: Tall R + ST depression in V1-V2 = posterior extension
3. Complete AV block: RCA supplies AV node - inferior MI can cause bradycardia / heart block

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ECG 18: WPW (Wolff-Parkinson-White) Pattern

• Short PR (<120 ms) - bypassing the AV node
• Delta wave - slurred initial upstroke of QRS (most visible in lateral leads)
• Wide QRS (>120 ms) - fusion beat (normal + accessory pathway conduction)
• Pseudo-Q waves and ST-T changes - secondary to abnormal depolarization

• Orthodromic AVRT: Narrow complex tachycardia (down AV node, up AP) - treat with adenosine
• Antidromic AVRT: Wide complex tachycardia (down AP, up AV node)
• AF with WPW: Irregular wide complex tachycardia - VERY FAST rate (>250 bpm possible) → risk of VF

⚠️ Never give adenosine, digoxin, verapamil, diltiazem in AF+WPW - these block AV node but not accessory pathway, driving all conduction down the fast AP → VF Use: DC cardioversion (if unstable) or IV procainamide/ibutilide

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ECG 19: Pulmonary Embolism - S1Q3T3

1. Sinus tachycardia - most common, most sensitive
2. T-wave inversions V1-V4 - right heart strain pattern (right precordial leads)
3. New RBBB or RBBB morphology - acute RV pressure overload
4. S1Q3T3 - classic but actually uncommon (<20% of PE cases)
5. Right axis deviation
6. P pulmonale - peaked P waves from acute RA overload
7. Atrial fibrillation or flutter

• S in lead I (deep S = left lateral lead sees delayed RV activation)
• Q in lead III (inferior lead)
• T inversion in lead III (RV strain)

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ECG 20: Brugada Pattern

• Coved ST elevation ≥ 2 mm in V1 (and sometimes V2)
• Down-sloping ST segment
• T wave inversion in V1

• Risk of sudden cardiac death from VF (especially at night, during fever)
• Sodium channel mutation (SCN5A - autosomal dominant)
• Unmasked by: fever, cocaine, alcohol, flecainide, procainamide (sodium channel blockers)
• Treatment: ICD (implantable cardioverter defibrillator) for symptomatic patients
• Quinidine for recurrent VF episodes or fever-triggered events

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LEVEL 8 - Arrhythmia Recognition (Rhythm Strips)

How to Systematically Approach Any Rhythm Strip

1. RATE → Fast? Slow? Normal?
2. REGULAR? → Measure R-R intervals
3. QRS WIDTH → Narrow (<120ms) or Wide (≥120ms)?
4. P WAVES → Present? Before QRS? Normal morphology?

Arrhythmia Quick Recognition Table

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The Wide Complex Tachycardia Decision Tree

Wide Complex Tachycardia (QRS ≥120ms, Rate >100)
                    ↓
     Is patient UNSTABLE? (hypotensive, altered consciousness, pulmonary edema)
         YES ──────────────────→ SYNCHRONIZED DC CARDIOVERSION
          ↓NO
     Look for AV Dissociation?
         YES ──────────────────→ DEFINITELY VT → Amiodarone or Cardioversion
          ↓NO
     Capture beats or Fusion beats?
         YES ──────────────────→ DEFINITELY VT → Amiodarone
          ↓NO
     Brugada morphology criteria? QRS >160ms? Concordance?
         YES ──────────────────→ LIKELY VT → Amiodarone
          ↓NO
     Could this be AF + WPW? (irregular wide complex + very fast)
         YES ──────────────────→ Procainamide or Cardioversion (NOT adenosine/verapamil)
          ↓NO
     LIKELY SVT with aberrancy → Adenosine trial (have crash cart ready)

Rule: When uncertain, treat wide-complex tachycardia as VT. Adenosine is safe for narrow complex. For wide complex, amiodarone is the safest drug.

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LEVEL 9 - Special ECG Patterns (Exam Favourites)

Quick Pattern Recognition Summary

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Clinical Practice Summary Card

Every ECG you pick up, run through this checklist in 30 seconds:
━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━
1. RATE        → Count (300 rule) / Irregular → count × 6
2. RHYTHM      → P before QRS? Regular? Sinus?
3. PR          → 120-200ms? Short (WPW)? Long (AVB)?
4. QRS         → <110ms? Wide (BBB/VT/pace)?
5. AXIS        → I and aVF upright = normal
6. ST SEGMENTS → Elevation (which leads)? Depression?
7. T WAVES     → Inverted (where)? Peaked (hyperK)?
8. QT          → Prolonged (drugs/electrolytes/long QT)?
9. P WAVES     → Peaked (RAE)? Broad (LAE)?
10. U WAVES    → Prominent (hypoK)?
11. COMPARE    → With previous ECG!
━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━

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PRES - Posterior Reversible Encephalopathy Syndrome

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Definition

• Acute neurological symptoms (headache, seizures, visual disturbances, altered consciousness)
• Reversible vasogenic edema predominantly in the posterior cerebral regions
• An identifiable precipitating cause (hypertension, drugs, eclampsia, renal disease)

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Pathophysiology - Two Competing Theories

Theory 1 - Autoregulatory Failure (Hyperperfusion)

Sudden severe ↑ BP
      ↓
Cerebral autoregulation overwhelmed
      ↓
Forced vasodilation (loss of protective vasoconstriction)
      ↓
↑ Cerebral blood flow → capillary leakage into interstitium
      ↓
VASOGENIC EDEMA

• Explains posterior predominance: posterior circulation (vertebrobasilar) has less sympathetic innervation than anterior (carotid), making it more vulnerable to autoregulatory breakthrough
• Explains why rate of rise matters more than absolute BP level (eclampsia can cause PRES at relatively lower pressures)

Theory 2 - Endothelial Dysfunction (Toxic/Autoimmune)

Calcineurin inhibitors, chemotherapy, autoimmune states
      ↓
Direct endothelial injury → Blood-brain barrier breakdown
      ↓
Vasogenic edema (without high BP)

• Explains PRES occurring at normal or mildly elevated BP (e.g., cyclosporine toxicity)
• Explains PRES in sepsis, TTP, autoimmune diseases

Harrison's: "Both of these processes likely play some role in each of these disorders." - Harrison's Principles of Internal Medicine 22E, Ch. 318

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Causes / Precipitating Factors

1. Hypertensive Emergencies (Most Common)

• Malignant / accelerated hypertension (diastolic usually >125 mmHg)
• Hypertensive emergency from any cause: renal artery stenosis, acute glomerulonephritis, pheochromocytoma, Cushing's syndrome

2. Obstetric

• Eclampsia - most important single cause in young women
• HELLP syndrome (Hemolysis, Elevated Liver enzymes, Low Platelets)
• Pre-eclampsia with severe features

3. Immunosuppressive / Cytotoxic Drugs

Important: "Many of the substances implicated can cause this syndrome even at low doses or after years of treatment. Therefore, normal serum levels do not exclude them as inciting agents." - Harrison's 22E

4. Renal Disease

• End-stage kidney disease (ESKD) on dialysis
• Acute glomerulonephritis
• Thrombotic microangiopathy (TMA), HUS, TTP

5. Autoimmune / Inflammatory

• Systemic lupus erythematosus
• Vasculitis (PAN, granulomatosis with polyangiitis)
• Scleroderma (hypertensive crisis)

6. Other

• Post-carotid endarterectomy hyperperfusion syndrome
• Sepsis / multi-organ dysfunction
• Cocaine, amphetamines, sympathomimetics

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Clinical Features - The Four Cardinal Symptoms

• Focal neurological deficits (hemiparesis, aphasia) - reflect atypical or extensive PRES
• Papilledema and retinal haemorrhages (especially in hypertensive PRES)
• Cerebellar signs if posterior fossa involved
• Balint syndrome (simultanagnosia, optic ataxia, gaze apraxia) - rare, severe occipital involvement

Adams & Victor's Neurology: "The neurologic syndrome is usually dominated by symptoms referable to the occipital and adjacent parietal region."

Critical point: "The rapidity of rise, rather than the absolute value of pressure, is the most important risk factor." - Harrison's 22E

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Imaging - The Key to Diagnosis

MRI Brain (Gold Standard)

Distribution of Edema

• Frontal lobes
• Temporal lobes
• Cerebellum and brainstem
• Deep structures (basal ganglia, thalami) - rare
• Unilateral (rare)

Grainger & Allison's Radiology: "MRI demonstrates bilateral cortico-subcortical T2 confluent hyperintensities, predominantly in the watershed zones of parietal and occipital lobes... DWI demonstrates iso- or hypointense areas within the lesions, reflecting increased diffusivity and, therefore, vasogenic oedema."

CT Brain

• Less sensitive than MRI
• May show patchy hypodensity in posterior regions
• Used when MRI unavailable; can support diagnosis but not exclude it

MRA/CTA

• May show segmental vasospasm or vessel caliber changes (overlap with RCVS)
• Not required for diagnosis but obtained in atypical cases

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DWI Signal - The Critical Distinction

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Diagnosis

1. Compatible clinical syndrome (seizures, headache, visual disturbance, encephalopathy)
2. Characteristic MRI findings (posterior vasogenic edema)
3. Identifiable precipitant
4. Exclusion of alternative diagnoses

---

Treatment

1. Treat the Underlying Cause (Most Important)

• Hypertensive emergency: Controlled BP reduction
• Eclampsia: IV magnesium sulfate + antihypertensives + delivery of fetus
• Drug-induced: Stop the offending agent (cyclosporine, tacrolimus → switch to alternative immunosuppressant; rituximab, bevacizumab → discontinue)
• ESKD/fluid overload: Dialysis with careful volume removal

2. Blood Pressure Management

Adams & Victor's: "A typical target is a pressure of 150/100 mmHg or a 20 percent reduction in mean pressure."

3. Seizure Management

• First-line: Benzodiazepines (lorazepam IV) for acute seizure control
• Maintenance: Levetiracetam (preferred - fewer interactions, no hepatic metabolism)
• Non-convulsive seizures: Screen with EEG; treat similarly
• Duration of anticonvulsants: Usually short-term - can discontinue once PRES resolved and no recurrent seizures (typically weeks, not indefinitely)

4. Monitoring

• Repeat MRI in 4-8 weeks to document radiological resolution
• BP monitoring long-term
• If drug-induced: discuss alternative immunosuppression with transplant/oncology team

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Prognosis

• Majority resolve completely within days to weeks with prompt treatment (clinical and radiological)
• Irreversible neurological deficits in ~10-15% - usually from:
  • Delayed diagnosis
  • Progression to cytotoxic edema / infarction
  • Intracranial haemorrhage (microhemorrhages or lobar bleeding)
• Mortality ~5-15% in severe cases, especially if associated with malignant hypertension, sepsis, or major organ failure
• Recurrence: Can occur if underlying cause not addressed

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PRES vs Key Differentials

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High-Yield Exam Summary

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Recent Evidence

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Renal Tubular Acidosis (RTA) - Complete Guide

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Overview and Framework

↓ HCO₃⁻  +  ↑ Cl⁻  +  Normal Anion Gap  =  RTA (or GI HCO₃⁻ loss)

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Normal Renal Acid-Base Physiology (Foundation)

Proximal Tubule (reabsorbs ~85-90% of filtered HCO₃⁻)

Tubular lumen                  Proximal tubule cell          Blood

HCO₃⁻ + H⁺  ──CA──→  H₂CO₃ → H₂O + CO₂     Na⁺ + HCO₃⁻ ──→ blood
                                 ↓ diffuses in
                              CO₂ + H₂O ──CA──→ H₂CO₃ → H⁺ + HCO₃⁻
                                                    ↓ Na⁺/H⁺ exchanger  ↓ NBC1 cotransporter
                                                  H⁺ secreted into lumen  HCO₃⁻ exits to blood

• Key transporters: Apical Na⁺/H⁺ exchanger (NHE3), apical H⁺-ATPase; basolateral Na⁺/HCO₃⁻ cotransporter (NBC1 / SLC4A4)
• Net result: HCO₃⁻ reabsorption, NO net acid excretion (urine pH unchanged)

Distal Tubule / Collecting Duct (secretes net acid, reabsorbs remaining 5-10% HCO₃⁻)

• Apical H⁺-ATPase (ATP6V0A4, ATP6V1B1 subunits) → secretes H⁺ into lumen
• Apical H⁺/K⁺-ATPase → secretes H⁺, reabsorbs K⁺
• Basolateral AE1 (SLC4A1) → exports HCO₃⁻ to blood in exchange for Cl⁻
• Intracellular carbonic anhydrase II (CA II) → generates H⁺ + HCO₃⁻
• Can reduce urine pH to as low as 4.5 (1000:1 H⁺ gradient)
• H⁺ is buffered in urine by titratable acids (phosphate) and ammonia → NH₄⁺

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Classification of RTA

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TYPE 1 - Distal RTA (Classical RTA)

Mechanism

1. Secretory defect: Reduced H⁺-ATPase activity (most common) - can't pump enough H⁺
2. Gradient defect: H⁺ leaks back from lumen to cell (amphotericin B - creates pores)
3. Rate-dependent: Adequate pump but insufficient capacity at high acid loads

Causes

• Autoimmune: Sjögren syndrome (most common cause in adults - can cause profound hypokalemia with weakness and respiratory arrest), SLE, rheumatoid arthritis, hypergammaglobulinaemia
• Drugs/toxins: Amphotericin B (gradient defect - creates membrane pores), lithium, ifosfamide, toluene (glue sniffing)
• Structural: Chronic obstructive uropathy, renal medullary sponge kidney, pyelonephritis
• Metabolic: Hypercalciuria, hyperparathyroidism, Wilson's disease, Fabry disease
• Other: Multiple myeloma, sickle cell disease

Clinical Features

1. Hyperchloremic, normal AG metabolic acidosis
2. Hypokalemia (often severe) - due to:
   • Loss of electrogenic H⁺ secretion → enhanced K⁺ secretion to maintain electroneutrality
   • Loss of H⁺/K⁺-ATPase reabsorptive activity
   • Compensatory hyperaldosteronism (itself causes K⁺ wasting)
3. Urine pH persistently >5.5 despite acidosis (cannot acidify below 5.5)

• Mechanism:
  • Metabolic acidosis → bone demineralization → hypercalciuria (calcium release from bone buffer)
  • Acidosis → impaired tubular citrate reabsorption → hypocitraturia (citrate is the most potent stone inhibitor)
  • Alkaline urine (pH >5.5) promotes calcium phosphate precipitation (brushite, apatite stones)
• Hypocitraturia is the most critical stone-forming factor in Type 1 RTA
• Stone type: Calcium phosphate (not calcium oxalate)

• Bone disease (rickets in children, osteomalacia in adults) from chronic acidosis
• Growth retardation in children
• Polyuria, polydipsia (from hypercalciuria-induced NDI)
• Muscle weakness (hypokalemia)
• Respiratory paralysis (severe hypokalemia - notably in Sjögren's) ⚠️
• Autosomal recessive form + sensorineural hearing loss (ATP6V1B1 mutation)

Diagnostic Tests

UAG = [Na⁺ + K⁺]urine - [Cl⁻]urine

• Give 0.1 g/kg NH₄Cl orally
• Normal: urine pH drops to <5.5 within 6 hours
• Type 1 RTA: fails to drop urine pH below 5.5

• Maximizes distal Na⁺ delivery and aldosterone → should lower urine pH <5.3 in normals
• Type 1 RTA: fails

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TYPE 2 - Proximal RTA

Mechanism

Normal: PCT reabsorbs HCO₃⁻ when serum level ≥ 24 mEq/L
Type 2 RTA: threshold lowered to ~15-18 mEq/L

Phase 1 (serum HCO₃⁻ above threshold): 
  → massive HCO₃⁻ spills into urine → urine pH >5.5 (alkaline)
  
Phase 2 (serum HCO₃⁻ falls below new threshold):
  → no more spilling → distal nephron can acidify → urine pH <5.5 (acid)

Causes

• Autosomal recessive: SLC4A4 mutation → NBC1 (basolateral Na⁺/HCO₃⁻ cotransporter) defect + ocular abnormalities (band keratopathy, glaucoma, cataract)

Brenner & Rector: "Fanconi syndrome is usually drug-associated; currently, important causes include aristolochic acid, ifosfamide, and acyclic nucleoside phosphonates (e.g., tenofovir, cidofovir, adefovir)."

Clinical Features

• Hyperchloremic normal AG metabolic acidosis
• Hypokalemia - worsens with alkali treatment (NaHCO₃ → ↑ distal Na⁺ and HCO₃⁻ delivery → ↑ K⁺ wasting)
• No nephrocalcinosis / rare nephrolithiasis (citrate excretion relatively normal, unlike Type 1)
• Rickets/osteomalacia (mainly from phosphate wasting in Fanconi syndrome)
• Growth retardation in children
• Features of Fanconi syndrome if present: glycosuria, aminoaciduria, phosphaturia, hypouricaemia
• With carbonic anhydrase inhibitors (acetazolamide): glaucoma treatment context

Diagnostic Tests

• Measure when serum HCO₃⁻ > 20 mEq/L (after alkali supplementation)
• Type 2 RTA: FEHCO₃ > 10-15% (massive bicarbonate wasting)
• Type 1 RTA: FEHCO₃ < 5% (distal nephron can recapture it)

Formula: FEHCO₃ = (Urine HCO₃⁻ × Plasma Cr) / (Plasma HCO₃⁻ × Urine Cr) × 100

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TYPE 3 - Mixed RTA (Rare)

• Cause: Autosomal recessive mutations in carbonic anhydrase II (CA II) gene
• Features proximal + distal defects combined
• Classic triad: RTA + osteopetrosis + cerebral calcification
• Also: mental retardation, fractures (from osteopetrosis)
• Very rare - mainly academic/exam question

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TYPE 4 - Hyperkalemic RTA (Most Common Type in Adults)

Mechanism

1. ↓ Na⁺ reabsorption in collecting duct → ↓ lumen electronegativity → ↓ K⁺ secretion → hyperkalemia
2. Hyperkalemia itself suppresses renal ammonia (NH₃) synthesis and excretion → ↓ NH₄⁺ excretion → H⁺ accumulates → metabolic acidosis

↓ Aldosterone → ↓ collecting duct Na⁺ reabsorption
      ↓
↓ Lumen electronegativity → ↓ K⁺ secretion → HYPERKALEMIA
      ↓
Hyperkalemia → ↓ renal NH₃ synthesis → ↓ NH₄⁺ buffering of H⁺
      ↓
H⁺ retention → HYPERCHLOREMIC METABOLIC ACIDOSIS

Causes

• Diabetic nephropathy - most common overall cause of Type 4 RTA
• Chronic interstitial nephritis
• NSAID use (suppress renin via prostaglandin inhibition)
• Calcineurin inhibitors (cyclosporine, tacrolimus)
• HIV nephropathy

• Addison's disease
• Bilateral adrenalectomy

• PHA type I: mutations in ENaC (autosomal recessive - severe) or mineralocorticoid receptor (autosomal dominant)
• PHA type II (Gordon's syndrome): gain-of-function WNK kinase mutations → hyperkalemia + hypertension + Type 4 RTA

Clinical Features

• Hyperkalemia (disproportionate to degree of acidosis) - the defining feature
• Mild metabolic acidosis (serum HCO₃⁻ 17-22 mEq/L, rarely severe)
• Urine pH <5.5 (distal acidification intact, but NH₄⁺ excretion is low)
• Mild-moderate CKD usually present
• No nephrocalcinosis, no nephrolithiasis
• Risk of cardiac arrhythmias from hyperkalemia

Harrison's: "In generalized distal RTA (type 4 RTA), hyperkalemia is disproportionate to the accompanying reduction in GFR."

Diagnostic Test

• Low renin + low aldosterone = hyporeninemic hypoaldosteronism (DM, NSAIDs)
• Low renin + high aldosterone = PHA (aldosterone resistance)
• High renin + low aldosterone = primary adrenal insufficiency Trans-tubular potassium gradient (TTKG): <6 in hypoaldosteronism or resistance

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Master Comparison Table

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Key Diagnostic Algorithm

Normal Anion Gap Metabolic Acidosis
         ↓
  Stool/GI losses?
  YES: Diarrhea → Urine AG negative (high NH₄⁺ excretion)
  NO → RTA likely → Urine AG POSITIVE (low NH₄⁺)
         ↓
  Check serum K⁺
  ┌─────────────────────────────┐
  │  K⁺ LOW (hypokalemia)       │           │  K⁺ HIGH (hyperkalemia) │
  │                             │           │                          │
  Check urine pH                            → TYPE 4 RTA
  │                             │              (aldosterone deficiency/
  Urine pH >5.5                 Urine pH <5.5  resistance)
  at all times                  with acidosis
  (even in acidosis)            but rises with
       ↓                        alkali dosing
  TYPE 1 RTA                         ↓
  (Distal)               Measure FEHCO₃ during HCO₃⁻ therapy
                         FEHCO₃ >10-15% → TYPE 2 RTA (Proximal)

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Urine pH Quick Rule

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Treatment

Type 1 (Distal) RTA

Type 2 (Proximal) RTA

Harrison's: "Therapy with NaHCO₃ will enhance delivery of HCO₃⁻ to the distal nephron and enhance renal potassium secretion, thereby causing hypokalemia. For this reason, potassium supplementation is often added to alkali therapy."

Type 4 RTA

Note: Fludrocortisone may cause fluid retention and hypertension; use cautiously in elderly and DM patients.

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High-Yield Mnemonics

Sjögren's, Amphotericin B, Drugs (lithium, toluene), Hypercalciuria, Autoimmune (SLE), Lithiasis (nephrocalcinosis), Toxins

Wilson's, Cystinosis, Tenofovir/ifosfamide, Myeloma, Ifosfamide, Aristolochic acid

Hyperkalemia, Hyporeninism, Hypoaldosteronism, Hyperchloremia - and it's the most High-frequency type in clinical practice

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Exam Scenarios

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Urine Examination in Renal Diseases - Complete Guide

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Why Urine Examination Matters

• Distinguish pre-renal, intra-renal, and post-renal AKI
• Point to the specific type of glomerular disease
• Diagnose ATN, interstitial nephritis, pyelonephritis
• Quantify proteinuria severity
• Monitor disease progression
• Guide whether a renal biopsy is needed

Goldman-Cecil: "In a normal person, the urine contains no red blood cells, urinary albumin excretion is <30 mg/day, and total urinary protein excretion is <140 mg/day."

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Structure of Urine Examination

URINE EXAMINATION
├── 1. MACROSCOPIC (Appearance, Colour, Odour)
├── 2. PHYSICAL (Volume, Specific Gravity, Osmolality, pH)
├── 3. DIPSTICK (Chemical)
│     ├── Protein, Blood, Glucose, Ketones
│     ├── Bilirubin, Urobilinogen
│     ├── Nitrite, Leukocyte esterase
│     └── pH, Specific gravity
├── 4. MICROSCOPY (Sediment)
│     ├── Cells (RBCs, WBCs, Epithelial cells)
│     ├── Casts (Hyaline, Granular, RBC, WBC, Tubular, Waxy, Fatty)
│     ├── Crystals
│     └── Organisms
└── 5. QUANTITATIVE TESTS
      ├── 24-hour urine protein / creatinine ratio
      ├── Albumin:Creatinine ratio (ACR)
      ├── Urine electrolytes (Na, K, Cl)
      ├── Urine osmolality
      └── FENa, Urea nitrogen

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PART 1 - Macroscopic Appearance

Colour

Odour

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PART 2 - Physical Properties

Volume

Specific Gravity (SG)

• Pre-renal AKI → SG >1.020 (concentrated, kidneys trying to retain water)
• ATN → SG ~1.010 (isosthenuria, tubular injury = can't concentrate)
• Diabetes insipidus → SG 1.001-1.005

Urine pH

Urine Osmolality

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PART 3 - Dipstick Analysis

Protein

• Detects albumin only - misses Bence-Jones protein (immunoglobulin light chains) in myeloma → need sulphosalicylic acid (SSA) test or urine protein electrophoresis
• False positive: concentrated urine, alkaline urine (pH >8), contamination with antiseptics
• False negative: dilute urine, non-albumin proteinuria

Blood (Haemoglobin)

• Detects intact RBCs, free haemoglobin, and myoglobin
• Positive dipstick + no RBCs on microscopy = haemoglobinuria (haemolysis) or myoglobinuria (rhabdomyolysis)
• Distinguish haemoglobin vs myoglobin by plasma colour:
  • Haemolysis → pink plasma (free Hb)
  • Rhabdomyolysis → clear plasma (myoglobin is rapidly cleared from plasma)

Other Dipstick Parameters

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PART 4 - Urine Microscopy (The Most Important Part)

How to Perform

1. Collect fresh midstream urine (examine within 1-2 hours - cells degenerate rapidly)
2. Centrifuge 12 mL at 1500-2000 rpm for 5 minutes (450g)
3. Decant supernatant, resuspend pellet in ~0.5 mL remaining urine
4. Place drop on slide with coverslip
5. View with subdued light; scan at ×100 first, then ×400 for detail
6. Count cells per HPF (high-power field ×400); casts per LPF (low-power field ×100)
7. Phase contrast microscopy preferred for dysmorphic RBCs

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CELLULAR ELEMENTS

1. Red Blood Cells (Erythrocytes)

NKF Primer: "In one study, up to 85% of patients with nondysmorphic microscopic hematuria had a urologic disorder, whereas 87.5% of those with dysmorphic hematuria had glomerular disease."

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2. White Blood Cells (Leukocytes)

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3. Renal Tubular Epithelial (RTE) Cells

• 12-20 μm, larger than PMNs, oval or egg-shaped
• A few are normal
• Many RTE cells = tubular injury → ATN, interstitial nephritis
• Lipid-laden RTE cells = oval fat bodies (nephrotic syndrome)

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CASTS - The Most Diagnostically Powerful Finding

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Cast Types - Detailed

• Protein alone (Tamm-Horsfall matrix only)
• Nearly transparent, low refractive index - need subdued light to see
• Non-specific - seen in: concentrated urine of normal individuals, dehydration, post-exercise, fever, diuretic use, early CKD
• Presence alone has little diagnostic value

• Fine or coarsely granular material (degenerated proteins or cells)
• Non-specific but almost always pathological
• Found in: ATN, glomerulonephritis, interstitial nephritis, volume depletion after exercise
• "Muddy brown" granular casts = the classic finding of ATN (from degenerated tubular cell debris)

• Fresh: brown/red, intact erythrocytes visible in matrix
• Degraded: pink-orange granular (hard to distinguish from coarsely granular)
• Pathognomonic of glomerulonephritis / intraparenchymal bleeding
• Also rare in: anticoagulant nephropathy, tubulointerstitial disease
• Context: always accompanied by dysmorphic haematuria, proteinuria, and granular casts ("the company they keep")

• PMNs embedded in hyaline matrix
• Pathognomonic of:
  • Pyelonephritis (distinguishes from lower UTI which never causes WBC casts)
  • Acute interstitial nephritis (drug-induced, etc.)
  • Also in: proliferative glomerulonephritis, lupus nephritis

• Sloughed tubular cells in hyaline matrix
• Classic early finding in ATN (tubular cell necrosis and sloughing)
• Also: severe interstitial nephritis

• Hyaline material with HIGH refractive index - appears waxy, brittle, with fissures at edges
• Form in dilated, atrophic tubules = marker of chronic parenchymal disease / advanced CKD
• Also in: post-infectious GN, amyloidosis, any severe chronic kidney disease
• "Broad" = dilated tubules = end-stage renal disease

• Oval fat bodies and free lipid droplets in cast matrix
• Characteristic of nephrotic syndrome with lipiduria
• "Maltese cross" = cholesterol esters rotating polarized light (seen under polarized light)
• Oval fat bodies = tubular cells that have reabsorbed luminal fat

• Haemoglobin casts: haemolysis
• Myoglobin casts: rhabdomyolysis (brown pigment, no RBCs)
• Bile casts: severe jaundice

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Cast Summary Table

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PART 5 - Crystals in Urine

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PART 6 - Proteinuria - Quantification and Types

Types of Proteinuria by Mechanism

Quantification Methods

• Most practical (random urine sample)
• Ratio of urine protein (mg/dL) to urine creatinine (mg/dL)
• Approximates 24-hour protein in g/day

• Preferred for screening and monitoring diabetic/hypertensive nephropathy

• Gold standard for proteinuria quantification
• Inconvenient; relies on adequate collection (check creatinine excretion ~15-20 mg/kg/day to assess completeness)

Significance of Proteinuria Levels

• Protein present when upright, absent when lying flat
• Common in adolescents (10-15% of young males)
• Benign - confirm by comparing first morning (recumbent) sample vs daytime sample

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PART 7 - Urine Electrolytes and Indices

Urine Sodium (UNa)

Fractional Excretion of Sodium (FENa)

FENa = (UNa × PCr) / (PNa × UCr) × 100

• False low (<1%) FENa in ATN: Contrast nephropathy, myoglobinuria (rhabdomyolysis), haemoglobinuria, early obstruction, some GN
• False high (>1%) FENa in pre-renal: Diuretic use (use FEUrea instead), CKD with salt wasting, adrenal insufficiency

Fractional Excretion of Urea (FEUrea)

FEUrea = (UUrea × PCr) / (PUrea × UCr) × 100

• More useful when diuretics have been given
• FEUrea <35% = pre-renal
• FEUrea >50% = intrinsic renal / ATN

Urine:Plasma Ratios in AKI

Urine Anion Gap (UAG) - for Normal AG Acidosis

UAG = [Na⁺ + K⁺]urine - [Cl⁻]urine

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PART 8 - Urine Findings by Disease (The "Urinary Fingerprints")

Comprehensive Disease-Urine Pattern Table

The "Telescoped Sediment" (Lupus Nephritis)

• RBC casts
• WBC casts
• Granular casts
• Waxy casts
• Fatty casts

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PART 9 - Key Exam Algorithms

Algorithm 1: Approach to Proteinuria

Proteinuria detected on dipstick
          ↓
Confirm with spot PCR or 24h collection
          ↓
Is it orthostatic? (First morning void = recumbent)
   If yes → absent in first morning urine → orthostatic proteinuria (benign)
          ↓ No
Quantify: <150 mg/day = normal
   150mg-3.5g = subnephrotic → work up GN, DM, HTN
   >3.5 g/day = NEPHROTIC RANGE
          ↓
Check sediment:
   RBC casts + haematuria → Nephritic component → GN (biopsy likely)
   Fatty casts + oval fat bodies → Pure nephrotic (MCD, MN, FSGS)
   Both → Mixed nephrotic-nephritic (lupus, MPGN)

Algorithm 2: Approach to Haematuria

Haematuria (>3-5 RBCs/HPF or positive dipstick)
          ↓
Microscopy: RBCs present?
   No RBCs → Haemoglobinuria or Myoglobinuria
            Check plasma: pink = Hb; clear = myoglobin
          ↓ RBCs present
Dysmorphic RBCs? (>20% dysmorphic or acanthocytes >5%)
   YES → Glomerular origin → Check protein, casts, BP, creatinine
       → GN work up (ANCA, anti-GBM, complement, ASOT, ANA, anti-dsDNA)
   NO → Urological origin → Urology referral
      → (Stones, tumour, infection, trauma)
          ↓
RBC casts?
   YES → Glomerulonephritis / RPGN → Urgent nephrology
   NO → Isolated haematuria → Consider IgA nephropathy, thin GBM disease

Algorithm 3: AKI Differentiation by Urinalysis

AKI detected (↑ creatinine)
          ↓
Urinalysis + microscopy + FENa
          ↓
   ┌────────────────┬─────────────────┬─────────────────┐
   │ Pre-renal      │ ATN             │ Interstitial    │
   │ SG >1.020      │ SG ~1.010       │ Nephritis       │
   │ UNa <20        │ UNa >40         │                 │
   │ FENa <1%       │ FENa >2%        │ FENa variable   │
   │ Normal sediment│ Muddy brown     │ WBC casts       │
   │ (Hyaline casts)│ granular casts  │ Eosinophiluria  │
   │                │ Tubular cell    │ Mild proteinuria │
   │                │ casts           │                 │
   └────────────────┴─────────────────┴─────────────────┘
          ↓
RBC casts → Glomerulonephritis → RPGN?
   →  Urgent nephrology + biopsy

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Quick Summary Mnemonics

• Hyaline - non-specific
• Granular (muddy brown) - ATN
• RBC cast - GN (glomerulonephritis)
• WBC cast - pyelonephritis / AIN
• Tubular cell cast - ATN (early)
• Fatty cast - Nephrotic syndrome

Pre-renal = Concentrated (SG >1.020, UNa <20, FENa <1%) = Tubules working hard ATN = Diluted/Fixed (SG ~1.010, UNa >40, FENa >2%) = Tubules broken

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Ischaemic Nephropathy - Complete Guide

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Definition and Terminology

• Progressive loss of renal function caused by significant reduction in renal perfusion
• Due to renal artery stenosis (RAS) or occlusive disease of the main renal artery or its branches
• Resulting in chronic ischaemia of the renal parenchyma

Brenner & Rector: "Renal artery stenosis is much more common than renovascular hypertension. Not all stenoses are associated with hypertension."

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Epidemiology

• Atherosclerotic RAS (ARAS) is identified in 6.8% of individuals >65 years in population-based US surveys (>60% occlusion by Doppler)
• Among patients undergoing coronary angiography: ARAS found in 14-20%
• Among patients with peripheral vascular disease: RAS in 30-50%
• Among patients with abdominal aortic aneurysm: RAS in 33%
• Among patients presenting with unexplained ESKD: possible ARAS contribution in up to 40%
• Prevalence of high-grade RAS in hypertensive patients with azotemia rises from 3.2% in the 6th decade to >25% in the 8th decade
• ARAS accounts for ~85% of all RAS; fibromuscular dysplasia (FMD) accounts for ~10-15%

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Causes of Renal Artery Stenosis

1. Atherosclerotic RAS (ARAS) - 85%

• Plaque located at the proximal renal artery (ostium and proximal 1-2 cm) - often an extension of aortic plaque
• Usually bilateral in 30-40% of cases (or unilateral in a solitary kidney)
• Strongly associated with: hypertension, hyperlipidaemia, smoking, DM, CAD, PVD, aortic aneurysm
• Progressive - natural history studies show progression in ~50% over 5 years; ~10-15% develop complete occlusion
• Linked to very high cardiovascular mortality (the kidney disease is a marker of systemic vascular burden)

2. Fibromuscular Dysplasia (FMD) - 10-15%

• Affects mid-portion and distal renal artery (not the ostium)
• Noninflammatory disorder of vessel wall layers
• Medial fibroplasia = most common subtype (85% of FMD) → classic "string of beads" appearance (alternating stenoses and microaneurysms)
• Also affects cerebral arteries in 25% (screen for intracranial aneurysms)
• Rarely causes major loss of renal function
• Responds very well to balloon angioplasty alone (no stent needed)
• Smoking is a risk factor for progression

3. Other Causes (Rare)

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Pathophysiology

The Goldblatt Model

Two-kidney, one-clip model (2K1C) - equivalent to UNILATERAL RAS:
RAS (one kidney) → ↓ renal perfusion pressure
      ↓
Activation of Juxtaglomerular Apparatus → ↑ RENIN secretion
      ↓
Renin → Angiotensin I → ACE → ANGIOTENSIN II
      ↓                    ↓
  Vasoconstriction    ALDOSTERONE (adrenals)
      ↓                    ↓
  ↑ SVR              Na⁺ + H₂O retention
      ↓                    ↓
              HYPERTENSION (renin-dependent)
              Contralateral kidney excretes excess volume (natriuresis)

One-kidney, one-clip model (1K1C) - equivalent to BILATERAL RAS or solitary kidney:
Both kidneys ischaemic → ↑ RAAS + volume retention (no contralateral escape)
      ↓
VOLUME-DEPENDENT HYPERTENSION
      ↓
Flash pulmonary oedema episodes (volume overload without adequate natriuresis)
      ↓
Azotaemia (bilateral reduced GFR)

Goldman-Cecil: "Bilateral critical renal artery stenosis is a volume-dependent form of hypertension that, unlike unilateral renal artery stenosis, can cause azotemia."

Mechanisms of Renal Parenchymal Injury in Ischaemic Nephropathy

↓ Renal perfusion pressure (stenosis >70-80%)
         ↓
  Autoregulation overwhelmed:
  ┌──────────────────────────────────────┐
  │ ↓ Glomerular perfusion pressure      │
  │ ↓ GFR (filtration fraction changes) │
  │ Tubular ischaemia                    │
  └──────────────────────────────────────┘
         ↓
Chronic tubular hypoxia → Tubular atrophy
         ↓
Interstitial fibrosis (TGF-β, Ang II-mediated)
         ↓
Glomerulosclerosis (ischaemic glomeruli: wrinkled GBM,
                     collapsed capillaries, periglomerular fibrosis)
         ↓
Cortical loss → Small, shrunken, scarred kidney

1. Angiotensin II direct toxicity: Ang II causes efferent arteriolar constriction, mesangial proliferation, TGF-β upregulation → fibrosis
2. Oxidative stress: Reduced NO production, excess reactive oxygen species
3. Inflammatory infiltrate: Macrophages, T cells infiltrate ischaemic parenchyma → cytokine-mediated injury
4. Atheroemboli: Cholesterol crystals from unstable plaques embolise into interlobar vessels → additional ischaemia ("atheroembolic renal disease" - distinct but often coexistent)
5. Reperfusion injury: When stenosis worsens or revascularisation attempted - excess free radicals, proximal tubular necrosis, "no-reflow phenomenon"

Why the Posterior Circulation Matters

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Clinical Presentations

1. Renovascular Hypertension

• Accelerating, resistant (refractory to ≥3 drugs), or severe hypertension
• Onset of hypertension at unusual age (very young or very old)
• Previously well-controlled hypertension that suddenly worsens
• Hypertension onset following ACE inhibitor initiation (bilateral RAS unmasked)

2. Flash Pulmonary Oedema (Pickering Syndrome)

• Recurrent acute pulmonary oedema without clearly precipitating cardiac cause
• Classic in bilateral RAS or RAS to solitary kidney
• Volume-dependent hypertension → acute fluid overload → pulmonary oedema
• ECG: no acute MI; LV function may be relatively preserved
• Highly characteristic: should always prompt evaluation for bilateral RAS
• Can resolve dramatically with revascularisation

3. Ischaemic Nephropathy

• Progressive unexplained CKD in a patient with diffuse atherosclerosis
• Worsening renal function after starting ACE inhibitor or ARB (≥20-30% rise in creatinine) → strongly suggests bilateral RAS
• Asymmetric kidney sizes on imaging (one kidney >1.5 cm smaller than the other)
• Kidneys without proteinuria or haematuria (sediment typically bland)

4. Acute Renal Artery Occlusion

• Sudden flank pain ± haematuria ± nausea/vomiting
• Sudden onset anuria (if bilateral or solitary kidney)
• Causes: thrombosis on ARAS plaque, embolism (AF, endocarditis), dissection, trauma

5. Incidental Finding

• ARAS found on vascular imaging done for another reason (e.g., aortic aneurysm CT)

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Clinical Clues / "Red Flags" for RAS

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Imaging - The Diagnostic Approach

Angiographic Imaging

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Diagnostic Modalities Compared

Goldman-Cecil: "Current practice favors limiting invasive arteriography to carrying out endovascular intervention (e.g., stenting and/or angioplasty)."

Functional Tests (Physiological Significance)

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Pathology (Kidney Biopsy / Nephrectomy Findings)

• Small, shrunken kidney on the stenotic side
• Finely granular surface (ischaemic cortical scarring)
• May show large cortical scars (from atheroemboli)

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The Renin-Angiotensin System in RAS

UNILATERAL RAS:
↓ Perfusion pressure → ↑ Renin → ↑ Ang II → HTN
Contralateral kidney: pressure natriuresis compensates → volume normal
RAAS-dependent hypertension → ACE-I/ARB very effective for BP
BUT: ACE-I may worsen stenotic kidney GFR (removes efferent constriction)

BILATERAL RAS (or solitary kidney with RAS):
Both kidneys ischaemic → ↑ Renin + volume retention (no contralateral escape)
ACE-I or ARB → removes efferent arteriolar tone in BOTH kidneys
→ Precipitous ↓ GFR → ACUTE KIDNEY INJURY ⚠️

• A rise in creatinine >20-30% after starting ACE-I/ARB is pathognomonic of bilateral RAS or RAS to solitary kidney
• This is not an absolute contraindication to ACE-I/ARB - a monitored trial is acceptable
• But close monitoring of creatinine and K⁺ is mandatory
• If creatinine rises >30% from baseline = stop ACE-I/ARB and investigate for bilateral RAS

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Management

Goals of Therapy (Brenner's Framework)

1. Blood pressure control - prevent cardiovascular morbidity and mortality
2. Preservation of renal function - prevent progression to ESKD
3. Volume regulation - prevent flash pulmonary oedema
4. Prevent vascular progression - anti-atherosclerotic therapy

Medical Therapy (Cornerstone of Management for ARAS)

The CORAL and ASTRAL Trials - Landmark Evidence

• 806 patients with ARAS randomised to revascularisation + medical vs medical alone
• Result: No difference in BP control, renal function, hospitalisation, or mortality
• Criticism: 40% of enrolled lesions were not haemodynamically significant (<60% stenosis); excluded patients clinicians thought would definitely benefit

• 947 patients with ARAS >60% randomised to renal artery stenting + medical vs medical alone
• All patients received aggressive medical therapy (irbesartan ± amlodipine, statin, antiplatelet)
• Result: No difference in the composite renal/cardiovascular endpoint
• Criticism: Average stenosis 67%; well-preserved baseline GFR; excluded patients with recent flash pulmonary oedema or rapidly deteriorating renal function; may have underpowered for truly high-risk patients

Goldman-Cecil: "For atherosclerotic renal artery stenosis, renal artery revascularization may reduce the intensity of required medical therapy but does not lead to better control."

Revascularisation - When to Consider

• Atherosclerotic ostial lesions require stenting (angioplasty alone has >50% restenosis rate due to elastic recoil of aortic plaque)
• Non-ostial ARAS and FMD → angioplasty alone preferred
• Procedural complication rate ~5.2% (cholesterol embolisation, dissection, branch occlusion)

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FMD vs ARAS - Comparison

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Prognosis and Natural History of ARAS

• Progression: ~50% show progression on serial imaging over 5 years
• Occlusion rate: ~10-15% progress to complete occlusion
• Renal atrophy: Kidney length decreases ~0.7 cm/year on the stenotic side without treatment
• Cardiovascular mortality is the dominant outcome - not ESKD
  • 5-year CV mortality: ~20-30% in ARAS patients
  • ARAS patients have 3-4x higher rate of myocardial infarction than matched hypertensives without RAS
• ESKD: Significant bilateral ARAS contributes to ~5-12% of incident ESKD in patients >50 years (often underdiagnosed)

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Atheroembolic Renal Disease (Related but Distinct)

• Cholesterol crystals embolise from aortic/renal artery plaques into small renal vessels
• Triggers: Catheter manipulation, aortic surgery, anticoagulation (dislodges friable plaque)
• Clinical: Acute or subacute renal failure, often after angiography or cardiac catheterisation
• Systemic features: Livedo reticularis, blue toe syndrome, eosinophilia, ↑ ESR, ↓ complement
• Urine: May show eosinophiluria, haematuria, mild proteinuria
• Biopsy: Cholesterol clefts (biconvex needle-shaped spaces after cholesterol dissolved) in small vessels, surrounded by giant cell reaction
• No specific treatment; statin therapy; supportive; often irreversible

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High-Yield Exam Summary

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Clinical Approach Algorithm

Suspected Renovascular Disease
            ↓
Clinical clues: resistant HTN / flash pulmonary oedema /
progressive CKD in atherosclerotic patient /
creatinine rise with ACE-I / asymmetric kidneys
            ↓
RENAL DUPLEX ULTRASOUND (first-line)
Peak systolic velocity >200 cm/s; RAR >3.5
Kidney size asymmetry
            ↓
Confirm: CTA (preferred) or MRA (if GFR adequate)
            ↓
RAS confirmed?
    ↓ YES
Haemodynamically significant? (>70-75% stenosis, or gradient >20 mmHg)
    ↓ YES
Unilateral vs Bilateral?
            ↓
┌──────────────────────────────────┬─────────────────────────────────┐
│ UNILATERAL ARAS, stable          │ BILATERAL ARAS or high-risk:    │
│ → Medical therapy:               │ Flash pulmonary oedema /        │
│   ACE-I/ARB + CCB + statin +    │ Rapidly ↓ GFR / Refractory HTN │
│   antiplatelet + risk factor     │ → Consider STENTING             │
│   modification                   │   + aggressive medical therapy  │
│ Monitor creatinine closely        │                                 │
└──────────────────────────────────┴─────────────────────────────────┘
            ↓
FMD?
→ BALLOON ANGIOPLASTY ALONE (no stent)
→ Screen cerebral vessels

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Hypertension in Chronic Kidney Disease (CKD)

The Bidirectional Relationship - The Core Concept

Hypertension  ──────►  Glomerulosclerosis / arteriosclerosis
                              │
                              ▼
                          CKD progression
                              │
                              ▼
    Na/water retention ◄── ↓GFR, ↓Na excretion
    RAAS activation ◄───── Ischaemic nephrons
    SNS overactivity ◄──── Afferent neural signals
    Endothelial dysfunction
                              │
                              ▼
                     Worsening Hypertension

• Comprehensive Clinical Nephrology 7E Ch.35

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Part 1 - Pathophysiology of Hypertension in CKD

1. Sodium and Water Retention (PRIMARY driver)

• As nephrons are lost, the remaining nephrons cannot adequately excrete a daily sodium load
• The kidney "resets" its pressure-natriuresis curve - a higher arterial pressure is needed to achieve the same sodium excretion
• This leads to volume expansion and raised cardiac output
• In ESKD/dialysis patients, this becomes the overwhelmingly dominant mechanism
• Key concept: Guyton's principle - the kidney is the ultimate long-term regulator of BP; when it fails, hypertension is inevitable

2. RAAS Activation

• Reduced renal perfusion (from nephrosclerosis, afferent arteriolar disease) activates the juxtaglomerular apparatus
• Renin release → Ang II generation → systemic vasoconstriction + aldosterone secretion
• Intrarenal RAAS is activated even when systemic renin levels appear normal
• Ang II also promotes glomerular hypertension (efferent arteriolar constriction) → intraglomerular pressure elevation → further proteinuria and nephron damage

3. Sympathetic Nervous System (SNS) Overactivity

• Damaged renal parenchyma generates afferent neural signals via renal sensory nerves → central SNS activation
• This causes peripheral vasoconstriction, tachycardia, and further RAAS activation
• Explains why even anuric bilateral nephrectomy patients can have hypertension reduced after the failed kidneys are removed
• Explains why renal denervation was explored as a therapy

4. Endothelial Dysfunction / Reduced Nitric Oxide

• Uraemic toxins impair endothelial NO synthase
• Reduced NO → loss of vasodilation → increased vascular resistance
• Also promotes platelet aggregation and atherosclerosis

5. Disordered Circadian BP Profile - Non-Dipping

• Normal individuals show a 10-20% nocturnal BP dip (dippers)
• CKD patients frequently become non-dippers or reverse-dippers (BP rises at night)
• Mechanism: nocturnal sodium redistribution from the periphery + fluid shift from dependent oedema in recumbency
• Non-dipping pattern is independently associated with faster CKD progression and higher CV events
• Ambulatory BP monitoring (ABPM) is therefore particularly important in CKD

6. Secondary Causes Superimposed on CKD

• Renovascular disease (ARAS, FMD) - covered in previous session
• Primary hyperaldosteronism (can cause CKD)
• Sleep apnoea (extremely common in CKD - up to 50-80% of dialysis patients)
• Erythropoiesis-stimulating agents (EPO/darbepoetin) - dose-dependent HTN, especially with rapid Hb rise

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Part 2 - Consequences: Why Does BP Control Matter?

Cardiovascular Risk

• Hypertension confers markedly increased risk of: stroke, coronary heart disease, peripheral vascular disease, vascular dementia, and heart failure in CKD patients
• CKD patients have a cardiovascular mortality risk 10-30x higher than the general population - much of this is BP-driven

Renal Outcomes

• Poorly controlled BP (SBP >160) → creatinine elevation in 10-20% of patients over time
• 2-5% progress to ESKD with poorly controlled SBP over 10-15 years
• Despite this being a relatively small fraction, hypertension is the second most common cause of ESKD after diabetes (USA and Europe) because it is so prevalent

APOL1 Polymorphism (Exam Trap)

• African Americans with hypertension have 2-6x higher ESKD incidence than white patients
• Driven partly by APOL1 gene polymorphisms - expressed in podocytes → lysosomal swelling, mitochondrial dysfunction, impaired autophagy → accelerated glomerulosclerosis
• Hypertensive African Americans show more severe arteriolosclerosis, more glomerulosclerosis

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Part 3 - BP Targets in CKD (The Controversial Core)

The Key Trials You Must Know

The J-Curve Problem

• A post-hoc IDNT analysis showed that in overt diabetic nephropathy:
  • Lowest kidney event risk at SBP 120-130 mmHg
  • Increased death risk below SBP 120 mmHg
  • Increased events at very high and very low BP = J-curve
• The benefit of BP lowering has a plateau - going too low increases risk

Current Recommendations (2023-2024 Guidelines)

General CKD target: SBP <130 mmHg (ACC/AHA 2017, ESH 2023, KDIGO 2024)

• The Cochrane 2024 meta-analysis [PMID 39403990] (6 RCTs, 7348 participants) found: lower targets vs standard showed little to no difference in mortality, cardiovascular events, or ESKD progression - moderate certainty evidence. However, lower targets did reduce stroke risk. This ongoing controversy means the target must be individualised.

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Part 4 - Drug Treatment: What to Use and Why

Step 1 - RAAS Blockade (CORNERSTONE)

• CKD + proteinuria (albumin >30 mg/mmol or PCR >300 mg/g)
• CKD + diabetes (even microalbuminuria = ACR 3-30 mg/mmol)
• CKD + hypertension (with or without proteinuria)

1. Systemic BP reduction
2. Reduced intraglomerular pressure - blocks Ang II-mediated efferent arteriolar constriction → reduces glomerular filtration pressure → reduces proteinuria
3. Anti-fibrotic effects - Ang II drives TGF-β production and interstitial fibrosis
4. Reduced proteinuria - independent of BP - proteinuria itself is nephrotoxic

• Lewis 1993 (Captopril in Type 1 DM): 43% reduction in doubling of creatinine; significant reduction in death/dialysis/transplant - INDEPENDENT of BP lowering
• IDNT (Irbesartan, Type 2 DM): ARB reduced composite endpoint 20% vs placebo, 23% vs amlodipine (same BP achieved) - proves class-specific renal benefit beyond BP
• RENAAL (Losartan, Type 2 DM): Doubling of creatinine ↓25%, ESKD risk ↓28% vs placebo - same BP achieved
• REIN (Ramipril, non-DM proteinuric): 50% lower ESKD risk over 3 years with ramipril vs conventional Rx at same BP
• AASK: Ramipril superior to amlodipine AND metoprolol in slowing CKD in African Americans:

• Both are equivalent for renoprotection - choose based on tolerability
• ACEi → cough (bradykinin-mediated, ~10-15%): switch to ARB
• ARB → no cough, angioedema much rarer
• DO NOT combine ACEi + ARB (dual RAAS blockade) - ONTARGET trial showed no additional benefit but increased AKI, hyperkalaemia, hypotension

• Check creatinine and K⁺ at 1-2 weeks after initiation
• Creatinine rise ≤30% = acceptable (haemodynamic, reversible) - do NOT stop
• Creatinine rise >30% = investigate for bilateral RAS, volume depletion - withhold
• Hyperkalaemia (K⁺ >5.5-6.0 mmol/L) = reduce dose or use potassium binders

• Patiromer and Sodium Zirconium Cyclosilicate (SZC/Lokelma) - allow RAAS to be continued in patients who would otherwise require dose reduction due to hyperkalaemia

Step 2 - SGLT2 Inhibitors (THE GAME-CHANGER)

• Osmotic diuresis → volume depletion → BP reduction 4-6 mmHg systolic
• Glucosuria → caloric loss → weight reduction 1-4 kg
• Natriuresis

• Tubuloglomerular feedback (TGF) restoration - the key mechanism:
  • Blocks SGLT2 in proximal tubule → ↑Na delivery to macula densa → restores TGF → afferent arteriolar constriction → ↓intraglomerular pressure
  • This mirrors the mechanism of ACEi/ARB (efferent constriction) but acts on the afferent side
• Anti-inflammatory and anti-fibrotic effects
• Reduced hypoxia in renal medulla (reduces O₂ demand in proximal tubule)

Key exam point: DAPA-CKD included non-diabetic CKD patients - and still showed massive benefit. SGLT2i are no longer just for DM.

• Euglycaemic DKA: 13/1000 patient-years (withhold perioperatively/during fasting/illness)
• Genital mycotic infections (Candida)
• UTI risk (modest)
• NOT a major hyperkalaemia risk (unlike RAAS)

Step 3 - Finerenone (Nonsteroidal MRA - New Agent)

• Selective, nonsteroidal MRA - different from spironolactone/eplerenone (steroidal)
• More selective for mineralocorticoid receptor → less off-target sex hormone effects
• Higher tissue distribution in heart and kidney vs steroidal MRAs

• FIDELIO-DKD (T2DM + CKD stage III, UACR 852 mg/g median): 18% ↓ composite kidney failure/sustained 40% eGFR decline/renal death + reduced CV events
• FIGARO-DKD (T2DM + CKD, wider range): 13% ↓ composite major adverse CV events

Step 4 - Diuretics

Step 5 - Calcium Channel Blockers (CCBs)

• Dihydropyridine CCBs (amlodipine, nifedipine): Effective BP reduction; vasodilatory; no direct renoprotection (inferior to RAAS in proteinuric disease as shown in AASK/IDNT); can worsen proteinuria by dilating afferent arteriole → ↑ intraglomerular pressure
• Non-dihydropyridine CCBs (diltiazem, verapamil): Also reduce proteinuria; preferred when CCB needed and proteinuria is present; additive with ACEi to reduce proteinuria
• CCBs are excellent add-on agents - combine well with RAAS blockers

Step 6 - Other Agents

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Part 5 - Treatment Algorithm

CKD + Hypertension
         │
         ▼
Start ACEi or ARB (maximally tolerated dose)
+ Low-sodium diet (<2g Na/day), weight loss, exercise
         │
         ├── DM present? → Add SGLT2 inhibitor early
         │
         ├── eGFR still declining/proteinuria persistent? 
         │     → Optimise SGLT2 inhibitor + consider finerenone
         │
         ├── BP still >130/80? → Add thiazide (if eGFR≥30)
         │                        or loop diuretic (eGFR<30)
         │
         ├── Still uncontrolled? → Add CCB (dihydropyridine)
         │
         ├── Still uncontrolled? → Add beta-blocker or alpha-blocker
         │
         └── Resistant HTN (≥4 drugs)?
               → Check adherence, ABPM (white coat?), 
                 exclude secondary causes (OSA, primary aldosteronism, RAS)
                 Consider renal denervation (emerging)

• Sodium restriction: <2g/day (sodium, not NaCl) - critical in CKD
• DASH diet (high potassium foods - use with caution in advanced CKD due to hyperkalaemia risk)
• Weight reduction: each 1 kg loss → ~1 mmHg SBP fall
• Exercise: 30 minutes moderate intensity most days
• Alcohol restriction: ≤2 units/day
• Smoking cessation (accelerates CKD progression and CV risk)

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Part 6 - Hypertension in Dialysis Patients (ESKD)

• As residual renal function approaches zero, volume overload becomes the near-sole driver
• Fluid removal with dialysis is the primary antihypertensive intervention in ESKD
• "Dry weight" optimisation - reducing post-dialysis target weight to eliminate excess fluid

• Intradialytic hypertension (BP rises during dialysis) - occurs in ~10-15% of haemodialysis patients - associated with endothelin release, RAAS activation, sympathetic activation
• Post-dialytic hypotension risk limits aggressive fluid removal
• BP measurement timing matters: pre-dialysis, post-dialysis, and ABPM give different readings
• Nocturnal/home dialysis achieves better BP control by more physiological fluid removal

• Loop diuretics have no role in anuric ESKD patients
• Hydralazine + beta-blocker + CCB combination common
• ACEi/ARB can be used in dialysis (though no longer filtering, CV benefit persists)
• Avoid renally-cleared drugs: atenolol, sotalol (accumulate)

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Part 7 - Resistant Hypertension in CKD

1. Volume overload (inadequate diuresis - under-dosed loop diuretics)
2. Medication non-adherence (up to 50% in some studies)
3. White coat hypertension (must exclude with ABPM/home BP)
4. Primary aldosteronism (check renin-to-aldosterone ratio; common, underdiagnosed)
5. Obstructive sleep apnoea (very common in CKD)
6. Renovascular disease (ARAS - previous session)
7. High dietary sodium intake

• ABPM to confirm true resistance
• Check renal sodium handling: 24h urine sodium
• Renin/aldosterone ratio (screen for primary aldosteronism)
• Renal artery duplex Doppler (screen for RAS)
• Sleep study (OSA)
• Add spironolactone 25-50mg (evidence from PATHWAY-2 trial: most effective 4th agent) - but watch K⁺ in CKD
• Renal denervation: SPYRAL HTN trials show benefit in resistant HTN; CKD-specific evidence emerging

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Part 8 - Hypertensive Nephrosclerosis (Hypertensive CKD)

• Afferent arteriolar hyalinosis - PAS-positive homogeneous pink material replaces the arteriolar wall
• Interlobular artery fibromuscular intimal thickening (arteriosclerosis - "onion skinning" in malignant HTN)
• Ischaemic glomerulosclerosis - wrinkling/collapse of GBM, periglomerular fibrosis, capillary tuft retraction
• Tubular atrophy, interstitial fibrosis

• Long-standing uncontrolled hypertension (often >10-15 years)
• Bland urine sediment (minimal proteinuria, few cells/casts) - important distinction from glomerulonephritis
• Proteinuria usually <1g/day (non-nephrotic)
• Gradual slow decline in eGFR
• Fundoscopy: AV nipping, silver/copper wiring, cotton wool spots, flame haemorrhages (hypertensive retinopathy)

• BP typically >180/120 mmHg with end-organ damage
• Acute renal failure: fibrinoid necrosis of arterioles ("onion skinning")
• Haematuria + proteinuria (mimics GN) + red cell casts possible
• Associated with TMA (thrombotic microangiopathy): MAHA + thrombocytopenia
• Treatment: IV labetalol or nicardipine (reduce MAP by 20-25% in first hour; NOT more - risk of watershed infarcts)
• Renal recovery is possible with BP control even from AKI

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Exam Summary Tables

Key Trials Mnemonics

• Captopril trial (Lewis 1993) - Type 1 DM
• AASK - African Americans
• Losartan = RENAAL - Type 2 DM
• MDRD - non-DM, proteinuria
• REIN - non-DM, ramipril, 50% ↓ESKD
• IDNT - Irbesartan, Type 2 DM

• DAPA-CKD (dapagliflozin, DM and non-DM)
• CREDENCE (canagliflozin, DM)
• EMPA-KIDNEY (empagliflozin)

Drug Selection at a Glance

Creatinine Rise Rules

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Recent Evidence Update

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