Starling Equation Governs Fluid Movement

Net Filtration Force = (Pc - Pi) - (πc - πi)
                     = Hydrostatic gradient - Oncotic gradient

Where: - Pc = Capillary hydrostatic pressure (pushes fluid OUT) - Pi = Interstitial hydrostatic pressure (pushes fluid IN) — usually ~0, less important - πc = Capillary oncotic pressure (pulls fluid IN) — mainly from albumin - πi = Interstitial oncotic pressure (pulls fluid OUT)

For edema to develop, ONE of these must occur: 1. ↑ Capillary hydrostatic pressure (Pc ↑) — venous obstruction, right-sided HF 2. ↓ Capillary oncotic pressure (πc ↓) — hypoalbuminemia (nephrotic syndrome, cirrhosis, malnutrition) 3. ↑ Interstitial oncotic pressure (πi ↑) — increased protein leak to interstitium (inflammation, capillary leak) 4. ↓ Lymphatic drainage — obstruction, malignancy, infection

Nephrotic Syndrome (~1.5% prevalence in general population)

Definition: Proteinuria >3.5 g/day + hypoalbuminemia + hyperlipidemia + edema

Primary causes (60%): - FSGS (focal segmental glomerulosclerosis) — 40% - Membranous nephropathy — 20% - Minimal change disease — 15% - IgA nephropathy — 10% - Other GN — 15%

Secondary causes (40%): - Diabetes mellitus (~50% of secondary) - SLE (~10%) - Infection (HIV, HCV, syphilis) — 5–10% - Malignancy (solid tumors, hematologic) — 10% - Amyloidosis, light chain disease — 5–10% - Drugs (NSAIDs, INH, heroin) — 5% - Allergic (pollen, insect venom) — rare

Pathophysiology: - Heavy proteinuria (>3.5 g/day) → protein loss exceeds synthesis - ↓ Plasma oncotic pressure (πc ↓ from low albumin) - Edema results from Starling force imbalance - Secondary effects: - Hepatic compensatory albumin synthesis ↑ (but overwhelmed) - Liver synthesizes more apoB → ↑ cholesterol, ↑ LDL (nephrotic hyperlipidemia) - Proteinuria includes iron-binding proteins → iron loss → anemia - Loss of anticoagulant proteins (antithrombin III, protein S) → thrombosis risk ↑↑

Clinical Features: - Edema (pitting, symmetric): Periorbital (morning worst), lower extremities - Weight gain: Often 5–15 lbs overnight from fluid retention - Foamy urine: Proteinuria visible as foam - Lipiduria: “Oval fat bodies” on UA (lipid-laden tubular cells; pathognomonic if present)

Labs: - Albumin <2.5 g/dL (marked hypoalbuminemia) - Proteinuria 3.5–15 g/day (can range) - Cholesterol >300 mg/dL (nephrotic hyperlipidemia) - Complement: Variable (normal in FSGS; ↓C3 in PSGN/ANCA)

Complications: - Infection: ↓ Immunoglobulin loss; asplenic-like state (S. pneumoniae risk ↑) - Thrombosis: VTE, PE, renal vein thrombosis (RVT) — hypercoagulable from loss of anticoagulants + ↑ fibrinogen - Hypertension: From fluid retention - AKI: From volume depletion if diuretics too aggressive, or renal artery stenosis (if membranous on anticoagulation)

Management: 1. Identify cause: Serologies, imaging (kidney biopsy if diagnosis uncertain) 2. Reduce proteinuria: - ACE-I/ARB first-line (reduce intraglomerular pressure) - SGLT2 inhibitor (emerging; dapagliflozin reduces nephrotic proteinuria) - Finerenone (if CKD + proteinuria) 3. Edema control: - Sodium restriction: <2 g/day (reduces volume retention) - Diuretics: Furosemide (high-dose often needed; large proteinuria impairs diuretic secretion in tubules) - Caution: Overly aggressive diuresis → AKI (RVT risk if membranous) 4. Monitor & prevent complications: - Anticoagulation if RVT risk (SQ LMWH or warfarin if membranous) - Statin for nephrotic lipids - Pneumococcal vaccine + prophylaxis (splenectomy-like protection)

Congestive Heart Failure (CHF) / Acute Decompensated Heart Failure (ADHF)

Mechanism: Right-sided HF → venous congestion → ↑ Pc (hydrostatic pressure ↑)

Pathophysiology: - Impaired ventricular emptying → ↑ LV diastolic pressure → ↑ LA pressure → ↑ pulmonary vein pressure → ↑ capillary Pc - Backward flow → systemic venous congestion → hepatomegaly → ↑ JVP - Neurohormonal activation: RAAS ↑, SNS ↑ → Na retention → ↑ preload (further worsens HF)

Clinical Features: - Peripheral edema: Bilateral, gravity-dependent (worse in ankles/legs standing; sacral if bedbound) - Orthopnea, PND: Pulmonary edema from ↑ pulmonary capillary pressure - Elevated JVP: Hepatic venous congestion - Hepatomegaly: RV pressure transmits to liver - Weight gain: Acute (overnight gains 2–5 lbs = fluid) - Third heart sound (S3 gallop): Ventricular dysfunction - Bibasilar crackles: Pulmonary edema

Labs: - BNP or NT-proBNP ↑: (Natriuretic peptides from ventricular stretch) - Echocardiogram: Reduced ejection fraction (EF <40% = HF with reduced EF, HFrEF) or normal EF (HF with preserved EF, HFpEF) - Albumin normal (no massive protein loss like nephrotic) - Troponin elevation: If acute MI precipitated HF

Management: 1. Acute: - IV diuretics (furosemide) for fluid overload, pulmonary edema - Vasodilators (nitroglycerin, nitroprusside) to reduce afterload - Inotropes (dobutamine, milrinone) if shock - Oxygen/intubation if respiratory failure

2. Chronic:
   • ACE-I/ARB (GDMT cornerstone; reduce afterload, neurohormonal axis)
   • Beta-blocers (carvedilol, metoprolol) — slow HR, reduce contractility demand
   • Aldosterone antagonist (spironolactone) — RAAS inhibition
   • SGLT2 inhibitors (dapagliflozin, empagliflozin) — proven HF benefit
   • Diuretics (furosemide, torsemide) for volume management

Liver Cirrhosis (Hepatic Edema)

Mechanism: Complex; multiple Starling force abnormalities

Pathophysiology: 1. Portal hypertension (fibrosis/cirrhosis obstructs flow) → ↑ splanchnic capillary pressure (↑ Pc) 2. Decreased albumin synthesis (hepatocytes damaged) → ↓ πc 3. Splanchnic vasodilation (nitric oxide, other vasodilators ↑) → underfilling of systemic circulation → RAAS activation → Na retention

Clinical Features: - Peripheral edema: Often symmetric; worse in evening/lower extremities - Ascites: Abdominal fluid; tense, bulging abdomen; fluid wave positive - Spider angiomas, palmar erythema: Hyperestrogenism (liver can’t metabolize estrogen) - Jaundice: Bilirubin ↑ - Hepatomegaly: Cirrhotic liver may be shrunken (late cirrhosis) - Splenomegaly: Portal hypertension - Encephalopathy: Ammonia ↑ (liver dysfunction)

Labs: - Albumin LOW (<2.5 g/dL) - Bilirubin ↑ (>2 mg/dL) - INR ↑ (coagulopathy from ↓ clotting factors) - Platelets ↓ (splenomegaly from portal HTN) - AST/ALT mildly ↑ (or may be normal if burnt-out cirrhosis)

Management: 1. Address underlying liver disease: Abstain from alcohol, DAA for HCV, immunosuppression for autoimmune, etc. 2. Sodium restriction: <1.5–2 g/day (critical; Na retention is major problem) 3. Diuretics: Spironolactone (target low-dose; avoid ototoxicity) + furosemide (if needed for ascites) 4. Paracentesis: Therapeutic if tense ascites; improves breathing, comfort 5. TIPS: Transjugular intrahepatic portosystemic shunt (if refractory ascites; invasive; reserved for specific indications) 6. Liver transplant: Definitive; consider if decompensated despite medical management

Venous Insufficiency / Deep Vein Thrombosis (DVT)

Mechanism: ↑ Pc from venous obstruction/incompetence

Venous insufficiency (Chronic): - Valvular insufficiency → retrograde flow → venous HTN in lower extremity - Edema: Unilateral (usually one leg worse); warm, non-pitting initially; may pit if severe - Associated: Varicose veins, skin changes (hyperpigmentation, ulceration)

DVT (Acute): - Thrombosis blocks venous return → ↑ capillary pressure - Edema: Sudden, unilateral (swollen >2 cm circumference vs other leg); calf pain, warmth - Risk: Immobilization, cancer, hypercoagulable state, surgery - Diagnosis: Duplex ultrasound (gold standard) - Treatment: Anticoagulation (LMWH, DOACs, warfarin)

Lymphedema

Mechanism: ↓ Lymphatic drainage → fluid accumulates in interstitium

Causes: - Primary: Congenital hypoplasia/hyperplasia of lymph vessels (rare) - Secondary: Lymph node removal (cancer surgery), radiation, infection (cellulitis worsens)

Clinical Features: - Non-pitting edema (firm, woody; doesn’t leave impression) - Bilateral in primary; unilateral in secondary - Onset: Gradual; may not appear for years post-surgery

Management: - Compression stockings (not much helps; supportive) - Lymphatic massage, elevation - Limb protection (avoid infection, trauma)